BookPDF Available

Cytochrome P450 in Cancer Susceptibility and Treatment. Mittal B, Tulsyan S, Kumar S, Mittal RD, Agarwal G. Adv Clin Chem. 2015;71:77-139. doi: 10.1016/bs.acc.2015.06.003. Epub 2015 Jul 21. PMID: 26411412

Authors:
Rama Devi Mittal at Sanjay Gandhi Post Graduate Institute of Medical Sciences
Rama Devi Mittal
Balraj Mittal at Babasaheb Bhimrao Ambedkar University
Balraj Mittal
Sonam Tulsyan at Sanjay Gandhi Post Graduate Institute of Medical Sciences
Sonam Tulsyan
Surendra Kumar at Johns Hopkins University
Surendra Kumar
Show all 6 authorsHide
Download full-text PDF
Read full-text
Download citation

Figures

Figures - uploaded by Gaurav Agarwal
Author content
All figure content in this area was uploaded by Gaurav Agarwal
Content may be subject to copyright.
Content uploaded by Gaurav Agarwal
Author content
All content in this area was uploaded by Gaurav Agarwal on Oct 16, 2017
Content may be subject to copyright.
This chapter was originally published in the book Advances in Clinical Chemistry, Vol. 71 published by
Elsevier, and the attached copy is provided by Elsevier for the author's benefit and for the benefit of the
author's institution, for non-commercial research and educational use including without limitation use in
instruction at your institution, sending it to specific colleagues who know you, and providing a copy to
your institution’s administrator.
All other uses, reproduction and distribution, including without limitation commercial reprints, selling or
licensing copies or access, or posting on open internet sites, your personal or institution’s website or
repository, are prohibited. For exceptions, permission may be sought for such use through Elsevier's
permissions site at:
http://www.elsevier.com/locate/permissionusematerial
From Balraj Mittal, Sonam Tulsyan, Surendra Kumar, Rama Devi Mittal and Gaurav Agarwal,
Cytochrome P450 in Cancer Susceptibility and Treatment. In: Gregory S. Makowski, editor, Advances in
Clinical Chemistry, Vol. 71, Burlington: Academic Press, 2015, pp. 77-139.
ISBN: 978-0-12-802256-6
© Copyright 2015 Elsevier Inc.
Academic Press
Provided for non-commercial research and educational use only.
Not for reproducti
on, distribution or commercial use.
CHAPTER FOUR
Cytochrome P450 in Cancer
Susceptibility and Treatment
Balraj Mittal*
,1
, Sonam Tulsyan*, Surendra Kumar*,
Rama Devi Mittal
†
, Gaurav Agarwal
{
*Department of Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh,
India
†
Department of Urology and Renal Transplant, Sanjay Gandhi Post Graduate Institute of Medical Sciences,
Lucknow, Uttar Pradesh, India
{
Department of Endocrine Surgery, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow,
Uttar Pradesh, India
1
Corresponding author: e-mail addresses: bml_pgi@yahoo.com; balraj@sgpgi.ac.in
Contents
1. Introduction 78
2. Classification, Nomenclature, and Structure of Cytochromes P450 79
3. Drug Metabolism 82
3.1 Oxidation 83
3.2 Reduction 83
3.3 Hydrolysis 83
4. Genetic Variations in CYP450 Isoforms 83
4.1 CYP1A1 (CYP450 Family 1, Subfamily A, Polypeptide 1) 84
4.2 CYP2A6 (CYP450 Family 2, Subfamily A, Polypeptide 6) 84
4.3 CYP2B6 (CYP450 Family 2, Subfamily B, Polypeptide 6) 89
4.4 CYP2C8 (CYP450 Family 2, Subfamily C, Polypeptide 8) 89
4.5 CYP2C9 (CYP450 Family 2, Subfamily C, Polypeptide 9) 89
4.6 CYP2C19 (CYP450 Family 2, Subfamily C, Polypeptide 19) 90
4.7 CYP2D6 (CYP450 Family 2, Subfamily D, Polypeptide 6) 90
4.8 CYP2E1 (CYP450 Family 2, Subfamily E, Polypeptide 1) 91
4.9 CYP3A4 (CYP450 Family 3, Subfamily A, Polypeptide 4) and CYP3A5 (CYP450
Family 3, Subfamily A, Polypeptide 5) 91
5. CYP450 in Cancer Susceptibility 92
5.1 Breast Cancer 92
5.2 Esophageal Cancer 93
5.3 Colorectal Cancer 94
5.4 Gall Bladder Cancer 95
5.5 Hepatocellular Cancer 96
5.6 Head and Neck Cancer 96
5.7 Lung Cancer 98
5.8 Prostate Cancer 98
5.9 Stomach/Gastric Cancer 100
Advances in Clinical Chemistry, Volume 71 #2015 Elsevier Inc.
ISSN 0065-2423 All rights reserved.
http://dx.doi.org/10.1016/bs.acc.2015.06.003
77
Author's personal copy
5.10 Urinary Bladder Cancer 101
6. CYP450 in Anticancer Therapy 101
6.1 CYP450 and Cancer Pharmacogenetics 101
6.2 CYP450 Inhibitors in Anticancer Therapy 118
7. Conclusion 121
Acknowledgments 121
References 121
Abstract
Cytochrome 450 (CYP450) designates a group of enzymes abundant in smooth endo-
plasmic reticulum of hepatocytes and epithelial cells of small intestines. The main func-
tion of CYP450 is oxidative catalysis of various endogenous and exogenous substances.
CYP450 are implicated in phase I metabolism of 80% of drugs currently in use, including
anticancer drugs. They are also involved in synthesis of various hormones and influence
hormone-related cancers. CYP450 genes are highly polymorphic and their variants play
an important role in cancer risk and treatment. Association studies and meta-analyses
have been performed to decipher the role of CYP450 polymorphisms in cancer suscep-
tibility. Cancer treatment involves multimodal therapies and evaluation of CYP450 poly-
morphisms is necessary for pharmacogenetic assessment of anticancer therapy
outcomes. In addition, CYP450 inhibitors are being evaluated for improved pharmaco-
kinetics and oral formulation of several anticancer drugs.
1. INTRODUCTION
Cytochrome P450 (CYP450), a large superfamily of heme-thiolate
proteins, are involved in the metabolism of both exogenous and endogenous
compounds [1]. CYP450 are characterized spectrophotometrically by an
intense absorption band at 450 nm in the presence of reduced carbon mon-
oxide (CO) [2]. These CYP450 enzymes contain an active heme iron center
bound to a protein molecule through highly conserved cysteine thiolate
ligand. They were first discovered in 1955 in rat liver microsomes. The
highest concentration of these enzymes is found in the liver and small intes-
tine [3]. Intracellularly, CYP450 are located on protein-synthesizing smooth
endoplasmic reticulum and energy-producing mitochondria. Many forms of
CYP450 enzymes exist in nature and are responsible for phase I metabolism
of xenobiotics. Due to their pivotal role in the metabolism of most antican-
cer drugs, CYP450 play a very important role in response and toxicity of
many drugs. Genetic variations in CYP450 genes are implicated in inter-
individual differences in susceptibility of various cancers as well as treatment
outcomes in terms of toxicity and efficacy of chemotherapeutic drugs.
78 Balraj Mittal et al.
Author's personal copy
This review will unravel the important role of CYP450 with cancer sus-
ceptibility, anticancer therapy outcomes, and various CYP450 inhibitors
involved in modified action of some anticancer drugs.
2. CLASSIFICATION, NOMENCLATURE, AND STRUCTURE
OF CYTOCHROMES P450
CYP450 are found in all organisms from protists to plants to humans
[4]. However, these enzymes were not found in Escherichia coli [5,6].In
humans, 57 genes and more than 59 pseudogenes have been identified in
CYP450 superfamily. All these genes and pseudogenes are divided among
18 families and 43 subfamilies on an amino acid sequence basis [7]. The
members of families share >40% homology (e.g., CYP2C, CYP2B), while
members of subfamilies share >55% homology (e.g., CYP2C8, CYP2C9,
CYP2C19). To date, more than 21,000 distinct CYP450 proteins have been
identified [8]. A list of CYP450 families, subfamilies, and the genes/
pseudogenes along with their function is shown in Table 1.
X-ray crystallography has clearly elucidated the secondary and tertiary
structure of CYP450 proteins. It consists of a signature motif, an
N-terminal hydrophobic anchor, and a proline-rich region. The signature
motif has a cysteine ligand tethered to an iron residue found in the
heme-binding domain. This cysteine and several flanking residues are highly
conserved and have the formal PROSITE signature consensus pattern
[FW]-[SGNH]-x-[GD]-{F}-[RKHPT]-{P}-C-[LIVMFAP]-[GAD] [9].
Because of the vast variety of reactions catalyzed by CYP450, their activities
and properties differ in many aspects.
Cytochrome P450 genes and alleles are represented according to the
guidelines given in nomenclature committees—Cytochrome P450 Home-
page (http://drnelson.uthsc.edu/CytochromeP450.html) and CYP Allele
Nomenclature Committee (http://www.cypalleles.ki.se/), respectively.
These enzymes are designated with the abbreviation CYP. It is followed
by a number representing the family, a capital letter representing the subfam-
ily, and another number for the identification of the gene. The convention is
to italicize the name when referring to the gene. For example, CYP2C9 is
the gene that encodes the enzyme CYP2C9—one of the enzymes involved
in drug metabolism (Fig. 1).
On the basis of taxonomy, CYP450-containing monooxygenases can be
divided into two classes, class I (prokaryotic/bacterial/mitochondrial) and
class II (eukaryotic microsomes). Class I CYP450 systems have three
79CYP450 in Cancer Treatment
Author's personal copy
Table 1 Classification of CYP450
Family Subfamily Genes/Pseudogenes Function
CYP1 CYP1A CYP1A1,CYP1A2 Drug and steroid (especially
estrogen) metabolism,
benzo(a)pyrene toxification
CYP1B CYP1B1
CYP1D CYP1D1P
CYP2 CYP2A CYP2A6,CYP2A7,
CYP2A13,CYP2AB1P,
CYP2AC1P
Drug and steroid metabolism
CYP2B CYP2B6,CYP2B7P
CYP2C CYP2C8,CYP2C9,
CYP2C18,CYP2C19,
CYP2C23P,CYP2C58P,
CYP2C59P,CYP2C60P,
CYP2D CYP2D6,CYP2D7,
CYP2D8P
CYP2E CYP2E1
CYP2F CYP2F1,CYP2F2P
CYP3 CYP3A CYP3A4,CYP3A5,
CYP3A7,CYP3A43,
CYP3A51P,CYP3A52P,
CYP3A54P,CYP3A137P
Drug and steroid (including
testosterone) metabolism
CYP4 CYP4A CYP4A11,CYP4A22,
CYP4A26P,CYP4A27P,
CYP4A44P,CYP4B1
Arachidonic acid or fatty acid
metabolism
CYP4F CYP4F2,CYP4F3,CYP4F8,
CYP4F9P,CYP4F10P,
CYP4F22,CYP4F23P,
CYP4F24P,CYP4F11,
CYP4F12,CYP4F25P
CYP5 CYP5A CYP5A1 Thromboxane A2 synthase
CYP7 CYP7A CYP7A1 Bile acid biosynthesis 7-alpha
hydroxylase of steroid nucleus
CYP7B CYP7B1
CYP8 CYP8A CYP8A1 Varied (bile acid biosynthesis;
prostacyclin synthase)
CYP8B CYP8B1
80 Balraj Mittal et al.
Author's personal copy
Table 1 Classification of CYP450—cont'd
Family Subfamily Genes/Pseudogenes Function
CYP11 CYP11A CYP11A1 Steroid biosynthesis
CYP11B CYP11B1,CYP11B2
CYP17 CYP17A CYP17A1 Steroid biosynthesis, 17-alpha
hydroxylase
CYP19 CYP19A CYP19A1 Steroid biosynthesis:
aromatase synthesizes
estrogen
CYP20 CYP20A CYP20A1 Unknown function
CYP21 CYP21A CYP21A2 Steroid biosynthesis
CYP24 CYP24A CYP24A1 Vitamin D degradation
CYP26 CYP26A CYP26A1 Retinoic acid hydroxylase
CYP26B CYP26B1
CYP26C CYP26C1
CYP27 CYP27A CYP27A1 Varied (bile acid biosynthesis,
activates vitamin D3)
CYP27B CYP27B1
CYP27C CYP27C1
CYP39 CYP39A CYP39A1 7-Alpha hydroxylation of
24-hydroxycholesterol
CYP46 CYP46A CYP46A1 Cholesterol 24-hydroxylase
CYP51 CYP51A CYP51A1 Cholesterol biosynthesis
Root s
y
mbol for c
y
tochrome P450 Subfamil
y
Family Gene identifie
r
CYP2C9
Figure 1 CYP450 nomenclature.
81CYP450 in Cancer Treatment
Author's personal copy
compounds, a FAD-containing flavoprotein (NADPH- or NADH-
dependent reductase), an iron–sulfur (FeS) protein, and CYP450, whereas
the class II microsomal CYP450 systems contains two compounds,
NADPH:P450 reductase (flavoprotein containing both FAD and FMN)
and CYP450 [10,11]. Most eukaryotic microsomal CYP450 have two com-
pounds and belong to class II/class E [1,12,13].
3. DRUG METABOLISM
Drug or xenobiotic metabolism is an enzymatic process by which
lipophilic chemical compounds are converted into hydrophilic
by-products, so that they can be easily excreted out of the body through kid-
ney. The rate of metabolism determines the duration and intensity of the
pharmacological action of the drugs. These reactions are also necessary to
detoxify the poisonous compounds.
Drug metabolism is categorized under three phases. In phase
I metabolism, various enzymes act to introduce a reactive or polar group into
xenobiotics. CYP450 enzymes are responsible for phase I metabolism. In
phase II reactions, these transformed compounds are further conjugated
to polar compounds. Finally in phase III, the conjugated xenobiotics are
being excreted out by efflux transporters. Phase I oxidative reactions cata-
lyzed by CYP450 include hydroxylation, epoxidation, dealkylation, deam-
ination, and dehalogenation (Fig. 2).
NADP+
NADPH
Reduction
Reduced
Reduced
P450
Oxidized
Reductase Fe
Oxidation and reduction
Phase I metabolism by cytochrome P450
H
y
drol
y
sis
Oxidized Drug
+
O2
Drug-OH
+
H2O
Figure 2 Three categories of phase I drug metabolism: oxidation, reduction, and
hydrolysis.
82 Balraj Mittal et al.
Author's personal copy
3.1 Oxidation
Oxidation is the most common reaction of the phase I metabolism. It
involves the addition of a single oxygen atom onto the drug molecule in
the presence of CYP450 monooxygenase and NADPH, as depicted by
the following reaction:
RH + O2+ NADPH + H +!ROH + H2O + NADP+
This reaction may convert a prodrug to a pharmacologically active
metabolite (bioactivation), active to less active or inactive metabolite
(inactivation), and inactive to more active or toxic metabolite (lethality or
toxicity). For example, cyclophosphamide (CP) is a prodrug activated by
CYP450 enzymes to form the active metabolite 4-hydroxycyclophosphamide.
3.2 Reduction
Reduction is another phase I reaction that takes place under anaerobic con-
ditions. It usually involves the addition of hydrogen to the drug molecule.
They are catalyzed by CYP450 reductases, also known as NADPH:
ferrihemoprotein oxidoreductase, NADPH:hemoprotein oxidoreductase,
and NADPH:P450 oxidoreductase. CYP450 reductase is membrane-bound
enzyme required for electron transfer to CYP450 in eukaryotic microsomes
from FAD- and FMN-containing enzyme NADPH:cytochrome P450
reductase. The general scheme of electron flow is:
NADPH !FAD !FMN !P450 !O2
Examples of drugs subject to reduction include prontosil, chloramphen-
icol, parathion, warfarin, and halothane.
3.3 Hydrolysis
Hydrolysis is the third type of phase I reaction. Unlike the others, hydrolysis
is catalyzed by esterases and amidases and not CYP450-mediated reactions.
Carboxyl esterases activate irinotecan (IRI), a prodrug, into its active topo-
isomerase inhibitor SN-38 [14].
4. GENETIC VARIATIONS IN CYP450 ISOFORMS
CYP450 represents a large family of highly polymorphic isozymes.
The different alleles are summarized at the Human CYP Allele Nomencla-
ture Committee home page (www.cypalleles.ki.se). In general, CYP450
83CYP450 in Cancer Treatment
Author's personal copy
with family numbers 1–3 have less substrate affinity, are less conserved dur-
ing evolution, and therefore are more polymorphic than family numbers
5–51 that are well conserved and have high substrate affinity [15]. The most
important polymorphic enzymes are CYP1A1, CYP2A6, CYP2B6,
CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, and
CYP3A5. Their common genetic variants, effect on enzyme activity, and
minor allele frequencies in different populations are shown in Table 2. Based
on Hapmap data (www.hapmap.org), there are striking dissimilarities with
respect to frequencies of these variants among various ethnicities.
4.1 CYP1A1 (CYP450 Family 1, Subfamily A, Polypeptide 1)
CYP1A1 (chr. 15q24) plays a significant role in the activation of tobacco
carcinogens such as polycyclic aromatic hydrocarbons, aromatic amines
(AA), and benzo[a]pyrenes [16–21]. Genetic variants with T3801C (*2A)
and the A2455G (*2C) substitution are the two most frequently studied
polymorphisms. These two variants can occur independently, but a com-
bined variant (*2B) has been detected as well. All three variants result in
an increased enzyme activity. The allele frequency of T3801C varies from
40–80% in Asians to 2–3% in Caucasians [22,23]. The A2455G polymor-
phism appears absent in Africans and African-Americans, while in other eth-
nic groups it has an allele frequency of 10–20% [24]. Another
polymorphism, C2453A (*4), which results in a threonine to asparagine
amino acid change on codon 461, was present in only 7% of Caucasians [24].
4.2 CYP2A6 (CYP450 Family 2, Subfamily A, Polypeptide 6)
CYP2A6 (chr. 19q13.2) metabolizes several important therapeutic drugs,
toxins and procarcinogens, as well as nicotine and its metabolite, cotinine
[22,25]. Many polymorphisms with functional significance have been iden-
tified. Four polymorphisms, CYP2A6*2,CYP2A6*4,CYP2A6*5, and
CYP2A6*20, result in null enzyme activity. In CYP2A6*2, a single amino
acid change renders the enzyme inactive, in CYP2A6*4, a gene deletion
accounts for the majority of poor metabolizers (PMs) in Asians (www.
cypalleles.ki.se). Eight CYP2A6 alleles (*6, *7, *10, *11, *12, *17, *18,
and *19) lead to enzymes with reduced activity, and three genetic polymor-
phisms in the promoter region of CYP2A6 have reduced transcriptional
activity (alleles *1D, *1H, *9). Because nicotine conversion to cotinine is
mediated by CYP2A6, the effect of these alleles has been substantially stud-
ied with respect to smoking behavior and nicotine dependence, suggesting
84 Balraj Mittal et al.
Author's personal copy
that CYP2A6 genetic variation could play a role in smoking and tobacco-
related cancer risk [22,26–29].
4.3 CYP2B6 (CYP450 Family 2, Subfamily B, Polypeptide 6)
The human CYP2B6 gene (chr. 19q13.2) is highly polymorphic. To date,
no mutation causing an important loss of function has been identified except
for the rare CYP2B6*28 allele carrying 1132C>T that results in protein
truncation at arginine 378 [30]. There appears to be some variant alleles
(CYP2B6*6, CYP2B6*16, and CYP2B6*18) associated with lower expres-
sion/activity [30–32]. Of these, CYP2B6*6is rather common in several dif-
ferent populations (20–30%), whereas both CYP2B6*16 and CYP2B6*18
are common in African ancestry where the allele frequency is relatively high
(7–9%) [30,31].
4.4 CYP2C8 (CYP450 Family 2, Subfamily C, Polypeptide 8)
The CYP2C8 gene is located on chromosome 10q24 in a multigene cluster
containing the other CYP2C subfamily members CYP2C9, CYP2C18, and
CYP2C19. CYP2C8 is expressed mainly in the liver where it participates in
the metabolism of important drugs. To date, several coding region single
nucleotide polymorphisms have been described in the CYP2C8 gene
(www.cypalleles.ki.se) with important interethnic variations. For example,
CYP2C8*2is present mainly in Africans, whereas CYP2C8*3and
CYP2C8*4are mainly distributed in Caucasians [33–35]. Other variants
leading to amino acid changes are extremely rare. CYP2C8*3results in
two amino acid substitutions (R139K and K399R) reported to be in total
linkage disequilibrium. Only two studies have reported individuals that
carry one of these polymorphisms [36,37].
4.5 CYP2C9 (CYP450 Family 2, Subfamily C, Polypeptide 9)
CYP2C9 is 18% of CYP450 protein in liver microsomes. Enzymes
encoded by this gene are involved in drug metabolism as well as synthesis
of cholesterol, steroids, and other lipids. CYP2C9*2(Arg144Cys) and
CYP2C9*3(Ile359Leu) are the two most widely studied genetic variants.
These result in decreased enzymatic activity. Both variants are mainly pre-
sent in Caucasians with allele frequencies of 10–15% (*2) and 4–10% (*3).
The CYP2C9*2variant appears absent in Asians and Africans. Interestingly,
both CYP2C9*2(4–7%) and CYP2C9*3(4%) are present in Asian-
Indians [38].
89CYP450 in Cancer Treatment
Author's personal copy
4.6 CYP2C19 (CYP450 Family 2, Subfamily C, Polypeptide 19)
Another gene located on same chromosome (chr. 10q24) is CYP2C19.It
encodes a liver enzyme involved in the metabolism of 5–10% of all drugs
currently used [“Cytochrome P450 2C19 Genotyping.” Genele X.
Retrieved October 2014]. Polymorphisms in CYP2C19 result in poor drug
metabolism [39].
Several variants in CYP2C19 gene resulted in loss of enzyme activity.
Most commonly, CYP2C19*2(G19154A; splicing defect) and
CYP2C19*3(G17948A; stop codon) alleles were studied with respect to
cancer [40]. These variants are most common in Asians (35%) and less in
Africans (17%) or Caucasians (15%) [40]. The frequency of CYP2C19*2
variant allele is 22% in Asian-Indians [41].
4.7 CYP2D6 (CYP450 Family 2, Subfamily D, Polypeptide 6)
CYP2D6 is an important polymorphic enzyme in drug metabolism. It is
responsible for metabolism of 25% of all drugs currently used [42,43].In
addition, its polymorphisms significantly affect the metabolism of about
50% of all drugs [44–47]. It has been most widely studied because it
exhibits differences in enzyme expression in various populations.
CYP2D6 gene variants are divided into alleles causing null (PM),
decreased (intermediate metabolizer, IM), normal (extensive metabolizer,
EM), and ultrarapid (ultrametabolizer, UM) activity. Null alleles are
CYP2D6*3 (A2549del), CYP2D6*4(splice defect), CYP2D6*5(gene
deletion), and CYP2D6*6(T1707del), whereas the common alleles with
severely reduced activity are represented by CYP2D6*10,CYP2D6*17,
and CYP2D6*41 (splicing defect). The allele frequency in Caucasians for
the specific *3,*4, and *6variants are 1–2%, 20%, and 3%, respectively [48].
Approximately 7–10% of Caucasians, 5–10% of Mexican-Americans, and
1–2% Asians lack this enzyme and are considered as PMs [49–53]. For Cau-
casians, the *4variant is carried by 75% of all PMs [48]. Gene duplication
events include functional, partly functional, and nonfunctional genes. An
investigation revealed the following gene duplications events: *1N,
*2N, *4N, *6N, *10 N, *17 N, *29 N, *35 N, *43 N,
and *45 N[54]. Many of the novel variant duplications were found in
African-Americans. Duplication or multiduplications of active CYP2D6
genes results in ultrarapid enzyme activity.
Large interethnic differences in CYP2C19 alleles exist. PMs are mainly
found in Europe and UMs in North Africa, whereas IMs are mainly located
90 Balraj Mittal et al.
Author's personal copy
in Asia [45]. However, no studies have reported the effects of ultrarapid
metabolizers on phenotypes.
4.8 CYP2E1 (CYP450 Family 2, Subfamily E, Polypeptide 1)
CYP2E1 gene, located on chromosome 10q26.3, encodes an enzyme
involved in the metabolism of drugs, hormones, and xenobiotic toxins [55].
This enzyme accounts for 7% of total CYP450 enzymes in liver.
Three polymorphisms in CYP2E1 gene have been mostly studied. Of
these, CYP2E*5is found in the 50-regulatory region. It consists of two var-
iants, G1293C (PstI) and C1053T (RsaI), whereas CYP2E*6(T7632A) is
detected with DraI. The frequency of the variant allele of CYP2E1 DraI
polymorphism is 9% in Caucasians and African-Americans and 35% in
Japanese [56].
4.9 CYP3A4 (CYP450 Family 3, Subfamily A, Polypeptide 4) and
CYP3A5 (CYP450 Family 3, Subfamily A, Polypeptide 5)
Of particular importance is the CYP3A4 (chr. 7q22.1) gene that encodes for
the predominant CYP450 in human liver. In general, members of the
CYP3A subfamily are the most abundant CYP450 enzymes in humans.
They account for 30% of liver and 70% of intestinal CYP450 [57,58].
CYP3A4 is responsible for the oxidative metabolism of approximately
60% of clinically used drugs [59]. There are four CYP3A human genes
(CYP3A4, CYP3A5, CYP3A7, and CYP3A43) and three pseudogenes
(CYP3AP1, CYP3AP2, and CYP3AP3)[60,61]. Of these four, CYP3A4
and CYP3A5 are polymorphically significant.
Several variants have been identified in CYP3A4 gene, but only one has
been frequently studied with respect to carcinogenesis. The 392G variant
of this CYP3A4*1B polymorphism results in a 1.5 to 2-fold higher pro-
moter activity in vitro [62]. This variant seems to be rare in Asians, but fre-
quent in African-Americans (35–67%). About 2–9% of Caucasians were
found to be a carrier of the variant allele [63].
CYP3A5 is located near CYP3A4 on chromosome 7 (chr. 7q22.1). Its
expression is influenced by a gene polymorphism (*3; A6986G) present
in intron 3. The 6986G variant results in a splicing defect resulting in the
absence of enzyme expression. The expression of the *3 allele varies widely
between ethnicities, with 70% in African-Americans and 20% in Cauca-
sians [63].CYP3A5*3was shown to be in close linkage with
CYP3A4*1B [64].
91CYP450 in Cancer Treatment
Author's personal copy
5. CYP450 IN CANCER SUSCEPTIBILITY
Polymorphisms in CYP450 have been extensively studied with
respect to genetic predisposition to cancer and clinical outcome in terms
of response and toxicity to anticancer drugs. Various studies have also shown
the significance of CYP450 polymorphisms in cancer susceptibility. In
hormone-related cancers like breast and prostate, CYP450 involved in
metabolism of steroid hormones also influences cancer susceptibility.
CYP1A1,CYP1B1,CYP2D6, and CYP2E1 also affect the metabolism of
various environmental carcinogens. Therefore, most association studies have
focused their analysis on CYP450 associated with cancer risk.
5.1 Breast Cancer
CYP450 involved in the estrogen pathway are considered as important can-
didate genes for the susceptibility to breast carcinoma.
CYP1A1 participates in estradiol hydroxylation, and therefore, polymor-
phisms in this gene might affect genetic predisposition to breast cancer. Four
CYP1A1 gene polymorphisms [3801T/C, 2455A/G (Ile462Val), 3205T/
C, and 2453C/A (Thr461Asp)] have been studied in relation to breast can-
cer. Some studies have found a positive correlation of CYP1A1*2A (3801T/
C) with breast cancer [65–67], while others could not validate these findings
[68–70]. Similarly for CYP1A1*2C (2455A/G), there are studies with both
significant [66,68,70] and nonsignificant association with breast cancer sus-
ceptibility [71]. For CYP1A1*3(3205T/C) polymorphism, no association
with breast cancer susceptibility was found in Caucasians and African-
Americans [72]. Another study found CYP1A1*4allele to be a significant
risk factor for breast carcinoma, particularly among postmenopausal
women [73]. However, still another study did not find any significant dif-
ference in frequency of CYP1A1*4polymorphism between breast cancer
cases and controls [74]. Furthermore, a meta-analysis consisting of 17 studies
found no significant association of CYP1A1*2A,CYP1A1*2C, and
CYP1A1*4polymorphisms with breast cancer risk [75].
CYP1B1*3was associated with a twofold increased risk of breast cancer
in Shanghai females. In this study, variant homozygotes were significantly
associated with modification of estrogen concentration [76]. A Turkish
study reported similar results [77]. There may be an association of estrogen
and CYP1B1 polymorphism on breast cancer risk. A recent meta-analysis
showed that CYP1B1 Arg48Gly, Ala119Ser, and Asn453Ser polymorphisms
92 Balraj Mittal et al.
Author's personal copy
were not associated with breast cancer risk [78]. Another meta-analysis
involving 40,303 subjects also observed no association of CYP1B1
Val432Leu polymorphism with breast cancer risk [79].
In a study on Mexican patients with breast cancer, significant CYP3A4
overexpression was found in breast cancer stroma and gland regions in com-
parison with healthy tissue [80]. Similarly, studies have also observed
CYP3A4 overexpression in tumor breast tissue when compared to normal
tissues [81,82].
CYP2C19 with a major function in estrogen catabolism has been exten-
sively studied in respect to breast cancer. In a Finnish study of 842 breast
cancer cases, a deletion of 60 kb in CYP2C19 showed significant association
with triple-negative breast cancer (p¼0.021) [83]. Another CYP2C19
allele, CYP2C19*17, an ultrarapid metabolizer phenotype, was associated
with decreased breast cancer risk, suggesting that CYP2C19 may lead to
increased catabolism of estrogens hence reduced risk [84].
It is now evident that estrogen-metabolizing genes are associated with an
increased breast cancer risk. However, future studies should also focus on
specific substrate levels to further understand modulation of estrogen metab-
olism by CYP450 in the etiology of breast carcinoma.
5.2 Esophageal Cancer
Esophageal cancer is generally linked with excessive alcohol intake and
tobacco use especially for squamous cell carcinoma. Conflicting results have
been published regarding the association of CYP1A1 polymorphisms with
risk of esophageal cancer in Asians and Caucasians [85–90]. In one study,
CYP1A1 MspI T/C polymorphism was not associated with esophageal can-
cer [91]. A meta-analysis evaluated 13 studies involving CYP1A1 A2455G
and CYP1A1 T3801C polymorphisms [92]. Results revealed a significant
association between the CYP1A1 A2455G polymorphism and esophageal
cancer risk. On stratification, this polymorphism was found to be significant
in Asians and esophageal squamous cell carcinoma patients. An updated
meta-analysis of 27 studies also found CYP1A1 A2455G polymorphism
to be significantly associated with esophageal cancer. Subgroup analysis fur-
ther revealed significant association of this polymorphism in Asians as well as
in Caucasians. However, no significance was observed for CYP1A1 MspI
polymorphism [93].
A threefold increased risk of esophageal cancer was observed in patients
with CYP2C19 PM phenotype [94]. A meta-analysis of 15 case-controlled
93CYP450 in Cancer Treatment
Author's personal copy
studies was performed to determine the association of CYP2C19*2and
CYP2C19*3polymorphisms with digestive tract cancer risk [95].It
reported that CYP2C19*2polymorphism was significantly associated with
esophageal cancer susceptibility, especially in Asians [95]. However, same
study did not find any correlation of CYP2C19*3polymorphism with
esophageal cancer risk [95].CYP2E1 (*1/*1) has been associated with a
three- to fivefold increased risk of esophageal cancer in Chinese [96],
whereas the *6 allele was associated with increased risk in South
Africans [97]. However, tandem repeats in the 50-flanking region of CYP2E1
gene were associated with an increased risk of cancer in Japanese [98].Ina
small study, CYP3A5*3was associated with an almost twofold lower risk
of esophageal cancer among South-African subjects of mixed ancestry [99].
5.3 Colorectal Cancer
Few CYP450 gene polymorphisms were found to be associated with
increased risk of colorectal cancer. In Caucasians, CYP1A1*2was associated
with an increased risk of colorectal cancer [100,101]. On the contrary, a
Spanish study reported lower risk of colorectal cancer for the CYP1A1*4
polymorphism [102]. However, same study also showed increased risk of
colorectal cancer in individuals with CYP1A2*1F and exon 1 CYP1B1
polymorphisms [102].
For CYP2C9 polymorphisms, carriers of *2 and *3 alleles were signifi-
cantly associated with decreased risk of colorectal cancer [103,104]. A recent
study reconfirmed that the CYP2C19*2polymorphism was associated with
30% reduced risk of colorectal cancer [101]. However, no association was
also seen in other studies [101,105]. A recent meta-analysis on 16 studies also
reported a significant association of CYP2C9*2polymorphism with colo-
rectal cancer risk, but no such association for CYP2C9*3polymorphism
was observed [106].
CYP2E1*2B polymorphism was associated with an increased colorectal
cancer risk among Hungarians [107]. However, this result could not be
reproduced among Dutch Caucasians [108]. Recently, a meta-analysis
reported significant association of variant genotype of CYP2E1 RsaI/PstI
with colorectal cancer risk. Similar results were observed between CYP2E1
96-bp insertion polymorphism and colorectal cancer risk [109].
In order to adequately assess potential CYP450 gene polymorphisms in
colorectal cancer risk, association studies in different populations with ade-
quate power are clearly required.
94 Balraj Mittal et al.
Author's personal copy
5.4 Gall Bladder Cancer
Gallbladder carcinoma is a highly aggressive cancer with female predomi-
nance. Moreover, presence of cholesterol gallstones is observed in
60–70% of patients with gallbladder cancer (GBC). Interindividual differ-
ences in the effectiveness of the activation/detoxification of environmental
carcinogens and endogenous estrogens may play a crucial role in cancer sus-
ceptibility. Polymorphisms in CYP450 genes might contribute to GBC
susceptibility.
Cholesterol 7 alpha hydroxylase (CYP7A1) is a rate-limiting enzyme for
cholesterol catabolism and bile acid synthesis. One study reported that CC
genotype as well as the C allele of CYP7A1 A204C polymorphism conferred
high risk for GBC. Subgroup analysis found that the CC genotype was asso-
ciated with GBC patients without stones [110]. Thus, it may be conferred
that genetic variations in CYP7A1 have some role in susceptibility to gall-
stone disease.
In a North Indian study involving 142 cases of GBC and 171 healthy
controls, the CYP1A1 6235T/C transition was assessed. The authors found
the CC genotype to be significantly associated with higher risk of GBC and
this risk was higher in men relative to women after sex stratification. The
same study showed that tobacco usage by GBC patients resulted in signifi-
cantly increased cancer risk for the TC genotype. Thus, higher risk of the
TC genotype in men may be related to tobacco usage [111]. Another North
Indian case-controlled study on 410 GBC cases and 230 healthy subjects
found that CYP1A1 MspI (CC), CYP1A1 Ile462Val, and CYP1A1 haplo-
type (C-val) were significantly associated with GBC susceptibility [112].
However, three other studies did not find any association of CYP1A1
3801T/C polymorphism with GBC risk [113–115]. In a meta-analysis of
three studies, no association between GBC risk and the CYP1A1 Ile462Val
polymorphism was observed [116].
CYP1B1 is also involved in estrogen metabolism. However, a study
evaluating the role of CYP1B1 Val432Leu polymorphism with GBC sus-
ceptibility did not find any significant association with cancer risk [116].
CYP17 is the main enzyme involved in both hormone biosynthesis and
in xenobiotic metabolism. A recent study reported no association of CYP17
(rs2486758 and rs743572) polymorphisms with GBC susceptibility. How-
ever, TC of rs2486758 and AG of rs743572 genotypic combination were
found to be associated with increased GBC susceptibility in tobacco
users [117].
95CYP450 in Cancer Treatment
Author's personal copy
5.5 Hepatocellular Cancer
In addition to excessive alcohol consumption, chronic infection with hep-
atitis B (HBV) and C viruses (HCV) are major causes of hepatocellular car-
cinoma (HCC). Therefore, studies on the risk of cytochrome P450
polymorphisms and HCC are usually performed in hepatitis-infected
patients.
CYP1A1*2A polymorphism was found to be associated with threefold
increased HCC risk in Taiwanese HBV carriers [118]. However, a similar
study in Italian HCV patients could not reproduce this finding [119].
This could have been caused by the low allele frequency in Caucasian
population.
Spanish Caucasians with EMs of CYP2D6 phenotype showed a sixfold
increased risk of HCC [120]. In line with this finding, the PMs of this gene
(*3,*4, and *6) had a 90% decreased risk of HCC [119]. It suggests that PMs
of CYP2D6 may confer a reduced risk of HCC, especially in HCV-infected
individuals.
CYP2E1*5was found to be associated with an increased risk of HCC in
Japanese population [121]. A study has also found wild genotype to be asso-
ciated with increased risk of HCC in Taiwanese [122]. The increased risk
found in Taiwanese also involved alcohol or tobacco usage [123].
5.6 Head and Neck Cancer
Head and neck cancer (HNC) is associated with smoking and alcohol intake.
Tobacco smoking results in exposure to numerous carcinogens. Although
CYP450 enzymes such as CYP1A1, CYP1B1, CYP2D6, and CYP2E1
metabolize carcinogens to their inactive derivatives, they occasionally con-
vert procarcinogens to more potent carcinogens.
The CYP1A1 (426Val/Val) polymorphism was related to increased oral
cancer risk in various populations [124–126]. However, statistical signifi-
cance of CYP1A1 4889A/G polymorphism with HNC patients was not
seen in Caucasians [127]. In a study of Polish patients, CYP1A1∗4 allele
and CYP1A1∗4/∗4 genotype were associated with HNC risk [128]. How-
ever, Reszka et al. [129] found no significant association of CYP1A1 462Val
alleles with increased HNC risk in Polish patients. Moreover, in a recent
meta-analysis study, no association between CYP1A1 Ile462Val polymor-
phism and HNC risk was found [130]. The same meta-analysis showed a
significant association between CYP1A1 MspI polymorphism and HNC risk
96 Balraj Mittal et al.
Author's personal copy
with a more pronounced effect in smokers [130]. Another meta-analysis
performed on 13 case–control studies (1515 cases and 2233 controls) showed
no significant association of CYP1B1*2Ile462Val polymorphism with oral
carcinoma risk [131]. However, in subgroup ethnicity analysis, increased
cancer risk was observed in Asians [131].
Furthermore, many studies showed that patients carrying the CYP1A1
(∗1A/∗2A) genotype presented with increased HNC risk [132–135]. How-
ever, no statistically significant difference in the CYP1A1∗2A and
CYP1A1∗2A/∗2A frequency was found by another study [128].
A variant genotype of CYP1B1*2was associated with several-fold
increase in HNC cancer risk among cases of tobacco usage [136]. It also
showed variant genotype of CYP1B1*3to be significantly associated with
HNC susceptibility especially among tobacco chewers [136]. Another study
reported the presence of variant genotypes of CYP1B1∗3 at a significantly
higher frequency in smokers [137]. However, Li et al. [138] failed to find any
significant association between tobacco smoking and CYP1B1∗3 in HNC.
These conflicting results could be explained by the differences in frequencies
of CYP1B1 polymorphism in different populations.
Extensive studies to evaluate association between the high metabolizing
CYP2D6 phenotype and HNC risk in smokers have been performed
[139–141]. In an Indian study, HNC patients with CYP2D6∗4 allele pres-
ented with increased risk, while those with CYP2D6∗10 allele showed no
change or even a small decrease in risk when compared to consumers of
tobacco or alcohol and nonconsumers [142]. Another study from Spain
and Germany reported that CYP2D6 ultrarapid metabolizer patients had
increased risk of developing HNC [143,144].
CYP2E1 polymorphism in HNC susceptibility has been studied with
conflicting results. Absence of association with CYP2E1 PstI with HNC
in Brazilians [145] and oral cancer in South Indians [146] was seen. Similarly,
Gajecka et al. [128] and Tai et al. [147] did not reveal any association between
the CYP2E1 RsaI polymorphism and the overall risk of larynx cancer in
Polish and Chinese, respectively. In addition, several other studies
[97,140,148–150] have not found significant differences in allelic variants
in patients with HNC, including oral cancer. However, another study
reported the association of CYP2E1 RsaI and CYP2E1 PstI polymorphisms
with HNC in Asians [151,152].
Differences in the genetic background in the etiology of HNC might be
the reason for ethnicity variability and the inconsistency of these results.
97CYP450 in Cancer Treatment
Author's personal copy
5.7 Lung Cancer
A large number of association studies on CYP450 gene polymorphisms in
correlation with lung cancer have been performed. Variations in results have
been observed in respect to differences in ethnicities as well as alleles.
CYP1A1*2polymorphism was associated with an increased risk of lung
cancer in different populations [16,153–159]. In a study among 217 Chinese
cases and 404 controls, an increased risk of variant CYP1A1*2B with
tobacco use was noted for incidence of squamous cell carcinoma [155]. Sim-
ilar results were also shown by a Japanese study [157]. Shi et al. [160] sum-
marized data from 46 studies and conducted a meta-analysis of CYP1A1
polymorphisms and lung cancer risk in Chinese. This study confirmed
the association between the CYP1A1*2C allele variant with increased lung
cancer risk. For the same polymorphisms, an eightfold increase in suscepti-
bility to lung cancer was demonstrated in a North Indian population [161].
CYP2A6 gene has an important role in tobacco metabolism. However,
association studies have found controversial results with respect to the dele-
tion in CYP2A6 gene (*4) in lung cancer. Some studies have shown
increased risk [162], while others found decreased risk [27,163,164].
A single study reported that homozygous CYP2C19 “PM” carriers had
more than threefold increased risk of lung cancer [94].
CYP2E1 *5,*6, and *7alleles have been widely studied in lung cancer.
Most studies did not find any association of CYP2E*5and CYP2E*6with
lung cancer [56,98,158,165–169]. However, some also reported increased
risk of lung carcinoma with CYP2E1*6polymorphism [170,171].
In a study on 801 Germans with small cell lung cancer and 432 controls, a
2.25-fold increased risk of small cell lung cancer was noted in homozygous
carriers of CYP3A4*1B [172].CYP3A5, which is situated near CYP3A4 on
chromosome 7, has also been associated with lung carcinoma. An Asian
study of 133 cases and 270 controls reported higher allelic frequency of
CYP3A5*1in Taiwanese lung cancer patients [173].
Although CYP450 genes coding for enzymes involved with tobacco
metabolism were considered, not all studies demonstrated a significant asso-
ciation. Result variability could be explained by ethnicity differences and
study power.
5.8 Prostate Cancer
Prostate cancer is considered to be the most important hormone-related
cancers in men [174–179].
98 Balraj Mittal et al.
Author's personal copy
CYP1A1*2C conferred a higher risk of prostate cancer in Japanese
[180,181]. For the CYP1B1*2polymorphism, the variant genotype was
associated with increased risk in Caucasians [178]. In another study, poor
metabolizing CYP2D6 phenotype was associated with increased prostate
cancer risk in 153 smoking Danes, but not smoking Swedish males [182].
In a meta-analysis on all cancers (52 studies), CYP1B1 A453G polymor-
phism was found to increase prostate cancer risk [183].
CYP3A4*1B was originally suggested to decrease the oxidative deactiva-
tion of testosterone, resulting in more dihydrotestosterone. This metabolite
induces prostate cancer. The CYP3A4*1B variant was most common in
African-Americans, who have the highest prostate cancer incidence world-
wide. Therefore, men with this variant were expected to have increased pros-
tate cancer risk [62,184,185]. Furthermore, meta-analysis showed the G allele
of CYP3A4*1B polymorphism was significantly associated with increased risk
of prostate cancer among Africans [186]. However, one study among 622
Caucasian prostate cancer patients found the opposite results [187].
It was argued that the CYP3A4, for which in vivo functionality is lacking,
is probably in linkage disequilibrium with a more functional variant.
A candidate gene proposed for this hypothesis was CYP3A5 [62]. Persons
with the CYP3A5*3variant did not express the gene and had decreased
activity, possibly leading to increased testosterone [59]. Subsequently, hap-
lotype analyses were performed with combinations of the CYP3A4 and
CYP3A5 variants. The combination of CYP3A4*1B/CYP3A5*3increased
prostate cancer risk [62].
Inconclusive studies have been reported for CYP17 gene variants which
encodes an enzyme of interest in testosterone metabolism. Most of the stud-
ies observed increased risk of prostate cancer for those who carried the A2
variant of the gene [59,188–191]. Others, however, observed increased risks
for those with A1 (wild-type) [179,192]. A limited meta-analysis (based on
three studies) revealed an increased risk of prostate cancer in A2 carriers of
African descent [193].
Prostate cancer risk has been associated with polymorphisms of CYP19
(aromatase). Either short (seven or eight) repeats of 4[TTTTA] [194,195]
repeats as well as a C to T SNP in exon 7 [177] have been proposed as risk
factors for prostate cancer. Carriage of these variants was associated with an
almost doubled risk and the C to T transition was also associated with a
higher tumor grade.
In conclusion, a variety of CYP450 polymorphisms have been associated
with an increased risk of prostate cancer risk of which CYP3A,CYP11A,
99CYP450 in Cancer Treatment
Author's personal copy
CYP17, and CYP19 seem to be most prominent. Future studies should focus
on multilocus approaches.
5.9 Stomach/Gastric Cancer
CYP450 gene polymorphisms are considered important in the inter-
individual variance in effect modifiers for the associations with gastric can-
cer. Many studies have been performed to determine the association of
CYP2E1 polymorphism with stomach and gastric cancer. However, the
results were inconsistent and ethnic differences reported. Few studies
showed a significant association of CYP2E1 RsaI polymorphism with stom-
ach cancer risk [196,197], while others found no association [186,198–200].
Recently, a study in an Indian population also found no role of CYP2E1
RsaI polymorphism in predisposition to stomach cancer [201].
CYP2E1 RsaI polymorphism has widely been studied in gastric cancer as
well. One study found that the CYP2E1 RsaI variant genotype was associ-
ated with reduced risk of upper gastrointestinal tract cancer [199]. Another
study found an association of gastric cancer with CYP2E1 RsaI[197].
Results were confirmed by meta-analysis which concluded that
CYP2E1-PstI/RsaI polymorphism may be a risk factor for gastric cancer
in Asians [197]. However, a recent meta-analysis study did not find any sig-
nificant association of CYP2E1 RsaI/PstI polymorphisms with gastric cancer
risk [202].
CYP1A1 gene polymorphisms are not as extensively studied as CYP2E1
polymorphisms in gastric cancer. A Chinese study identified 90 gastric can-
cers patients with *2A allele to be at 50% lower risk [203]. Meta-analysis of
11 studies for CYP1A1 MspI and 8 studies for CYP1A1 Ile462Val polymor-
phisms found no association with gastric cancer [204]. Interestingly, meta-
analysis of two studies of CYP1A2*1F polymorphism found a significant
association with gastric cancer [204].
Deletion of the CYP2A6 gene was associated with a fourfold increased
risk of tobacco-mediated gastric carcinoma [205]. Similarly, CYP2C19*2
and CYP2C19*3were associated with a threefold increased risk of gastric
cancer [94]. In an Indian study, CYP1A1,CYP1A2, and CYP2E1 gene
polymorphisms were evaluated in patients with Helicobacter pylori infection
for gastric cancer risk. The authors reported significant association of
96-bp insertion of CYP2E1 with increased risk of gastric cancer even in
the absence of infection. However, CYP1A2 CC or CT (rs762551) was
associated with reduced gastric cancer risk [206].
100 Balraj Mittal et al.
Author's personal copy
5.10 Urinary Bladder Cancer
Although a large number of studies have been carried out to explore the
association of CYP gene polymorphism with susceptibility to urinary blad-
der, most are small and population-based [207].
As such, meta-analysis has proven useful to assess these relationships. For
example, meta-analysis of six studies found that the CYP2E1 RsaI/PstI poly-
morphism was associated with bladder cancer risk, especially in Caucasians
[208]. Recently, meta-analysis (1059 bladder cancer cases and 1061 controls)
was performed to assess CYP1A1*2B A/G (I1e462Val) and CYP1A1*2A
T/C (MspI) polymorphisms in bladder cancer susceptibility [209]. Unfortu-
nately, no association was found. However, another meta-analysis (1658
cases and 1593 controls) showed that the CYP1B1 L432V polymorphism
was associated with urinary cancer risk [210].
Meta-analysis studies observed in CYP450 polymorphisms with various
cancers are shown in Table 3.
6. CYP450 IN ANTICANCER THERAPY
6.1 CYP450 and Cancer Pharmacogenetics
Treatment of cancer involves various drug therapies. Unfortunately, the
therapeutic index of these drugs is very narrow. As such, there is a need
to study the pharmacodynamic and pharmacokinetic properties of these
compounds. Furthermore, it is common to find large interindividual varia-
tion in drug-metabolizing capacity and treatment response in patients
receiving identical therapy. CYP450 compose the main phase
I-metabolizing enzymes involved in the metabolism of a large number of
these anticancer drugs. As discussed above, CYP450 are highly polymorphic
with a wide variation in interethnic allele frequencies. It is logical to assume
that these variations affect the enzyme activity and, as such, may be respon-
sible for the observed variation in treatment response and toxicity. CYP450
involved in various anticancer therapies are shown in Table 4.
6.1.1 Tamoxifen
Tamoxifen, an antiestrogen, is used worldwide in the prevention and treat-
ment of hormone-positive breast cancer. However, its use is restricted
because of a number of side effects, i.e., increased risk of deep vein throm-
bosis, pulmonary embolism, and endometrial cancer [231]. Tamoxifen is
metabolized by various CYP450 enzymes. It is converted by CYP2D6 to
101CYP450 in Cancer Treatment
Author's personal copy
Table 3 Meta-Analysis Studies of CYP450 Polymorphisms and Cancer Risk
Cancer CYP450 Variants Sample Size Association References
Breast
cancer
CYP1A1
3801T/C,
Ile462Val, and
Thr461Asp
17 studies No [75]
CYP1B1
Arg48Gly,
CYP1B1
Ala119Ser, and
CYP1B1
Asn453Ser
11,321 cases and
13,379 controls;
10,715 cases and
11,678 controls;
11,630 cases and
14,053 controls
No [78]
CYP1B1
Val432Leu
19,028 cases and
21,275 controls
No [79]
CYP1B1
Arg48Gly,
CYP1B1
Ala119Ser, and
CYP1B1
Val432Leu
1135 cases and
1235 controls
No [211]
Esophageal
cancer
CYP1A1
A2455G and
CYP1A1
T3801C
1881 EC cases and
3786 controls
Significant
association,
particularly in
Asians
[92]
CYP1A1
Ile462Val,
CYP1A1 MspI
4215 cases and
6339 controls
Significant
association
[93]
CYP2C19*23252 cases and
6269 controls
Significant
association
[95]
Colorectal
cancer
CYP2C9*2,
CYP2C9*3
9463 cases and
11,416 controls
Significant
association of
CYP2C9*2
[106]
CYP2E1 RsaI/
PstI, DraI T/A
and 96-bp
insertion
polymorphisms
12, 5, and 4 studies Association with
CYP2E1
RsaI/PstI and
96-bp insertion
polymorphisms
[109]
102 Balraj Mittal et al.
Author's personal copy
Table 3 Meta-Analysis Studies of CYP450 Polymorphisms and Cancer Risk—cont'd
Cancer CYP450 Variants Sample Size Association References
Gall
bladder
cancer
CYP1A1
rs1048943
391 cases and 1085
controls
No [116]
Head and
neck
cancer
CYP1A1
Ile462Val
CYP1A1 MspI
4639 patients and
4701 controls;
4168 patients and
4638 controls
Association with
CYP1A1 MspI
genetic variant
[130]
CYP1A1
Ile462Val
1515 cases and
2233 controls
Increased cancer
risk of CYP1A1
Ile462Val
polymorphism
among Asians
[131]
Lung
cancer
CYP1A1 MspI 46 studies Association of
CYP1A1 MspI
variant
[212]
Prostate
cancer
CYP3A4*1B 3810 cancer and
3173 controls
Association of
variant genotype,
especially in
African population
[186]
CYP1B1
G119T and
CYP1B1 A453G
52 studies Association of
CYP1B1 A453G
[183]
CYP17 T/C 2404 patients and
2755 controls
Association in
Africans
[193]
Stomach/
gastric
cancer
CYP2E1 PstI/
RsaI
2066 cases and
2754 controls
Association in
Asians
[196]
CYP2E1 PstI/
RsaI
3022 cases and
4635 controls
Association in
smokers
[202]
CYP1A1 MspI,
CYP1A1
Ile462Val and
CYP1A2*1F
11, 8, and 2 studies Associations
between CYP1A1
MspI and
CYP1A2*1F
polymorphism and
gastric cancer
[204]
Continued
103CYP450 in Cancer Treatment
Author's personal copy
4-hydroxytamoxifen (10%), an active metabolite which has 50–100-fold
higher affinity than the parent molecule for estrogen receptors [232]. How-
ever, 90% of tamoxifen is converted to inactive N-desmethyltamoxifen by
CYP3A4/5 enzymes [232]. Further, N-desmethyltamoxifen can be metab-
olized by CYP2D6 to endoxifen (4-hydroxy-N-desmethyltamoxifen)
which significantly contributes to the therapeutic effect (Fig. 3)[233].
Although early studies identified CYP2D6 as the most significant
CYP450 enzyme in activation of tamoxifen to 4-OH tamoxifen, a minor
role for CYP2B6, CYP2C9, CYP2C19, and CYP1A2 has also been
described [213,214]. Several studies have demonstrated that breast cancer
patients with CYP2D6 PM genotype had significantly lower plasma
endoxifen concentration with a worse relapse-free and disease-free survival
than those with heterozygous and wild-type genotypes [234–238]. A study
by Schroth et al. showed that tamoxifen-treated patients with the *4, *5,
*10, *41 CYP2D6 alleles had significantly more recurrences of breast can-
cer, shorter relapse-free periods, and worse event-free survival rates com-
pared with carriers of functional alleles [234]. This study also showed that
patients with the CYP2C19 high enzyme activity promoter variant *17
had a more favorable clinical outcome than carriers of *1, *2, and *3 alleles.
In an Italian trial, CYP2D6 PMs showed reduced tamoxifen efficacy [239].
Another study found that CYP2D6*6 may affect breast cancer-specific sur-
vival in tamoxifen-treated patients in a cohort of breast cancer patients from
the United Kingdom [240].
Therefore, CYP2D6 genotypes are important for tamoxifen antiestrogen
therapy.
Table 3 Meta-Analysis Studies of CYP450 Polymorphisms and Cancer Risk—cont'd
Cancer CYP450 Variants Sample Size Association References
Urinary
bladder
cancer
CYP1B1A
L432V
1658 cases and
1593
Significant
association
[210]
CYP1A1
(CYP1A1*2B)
A/G
(I1e462Val) and
CYP1A1*2A
T/C (MspI)
1059 cases and
1061 controls
No [209]
CYP2E1 RsaI/
PstI
1510 cases and
1560 controls
Association,
especially in
Caucasians
[208]
104 Balraj Mittal et al.
Author's personal copy
Table 4 CYP450 Involved in Various Anticancer Therapies
Drug P450 Involved Cancer References
Tamoxifen CYP3A,
CYP2D6,
CYP1B1,
CYP2C9,
CYP2C19
Breast cancer [213,214]
Cyclophosphamide CYP2B6,
CYP2C19,
CYP3A4
Leukemias, lymphomas,
retinoblastoma,
neuroblastoma
[215]
Docetaxel CYP3A
(CYP1B1)
Breast, NSCLC, prostate [216]
Paclitaxel CYP2C8
(CYP3A)
Ovary, breast, NSCLC,
Kaposi’s sarcoma
[34,217,218]
Ifosfamide CYP3A,
CYP2B6
Cervix, soft tissue sarcoma [219,220]
Irinotecan CYP3A Colon, rectum [221]
Imatinib CYP3A CML, GIST [222]
Flutamide CYP1A2 Prostate [223,224]
Tegafur CYP2A6,
CYP2C8,
CYP1A2
Colon, breast, stomach [225]
Gefitinib CYP3A
(CYP2D6)
NSCLC [226]
Etoposide CYP3A4
(CYP2E1,
CYP1A2)
Testicule, SCLC [227,228]
Teniposide CYP3A ALL, NHL [227,228]
Thalidomide CYP2C19 Multiple myeloma and
prostate cancer
[229]
Vincristine CYP3A Acute leukemia, NHL,
Hodgkin’s disease,
neuroblastoma,
rhabdomyosarcoma
[230]
105CYP450 in Cancer Treatment
Author's personal copy
6.1.2 Cyclophosphamide
CP, a nitrogen mustard alkylating agent, is commonly used in cancer che-
motherapy, mainly in breast [241,242]. It is given as a prodrug and 90% is
activated to the 4-hydroxylated CP (4-OH CP) compound by various
hepatic CYP450 enzymes [243] including CYP3A4, CYP3A5 [244],
CYP2B6 [245], CYP2C8 [246], CYP2C9, and CYP2C19 [247]. The
4-OH CP is in equilibrium with aldophosphamide, which in turn decom-
poses into the active DNA alkylating agent as well as cardio-toxic phos-
phoramide mustard and uro-toxic acrolein [248,249] (Fig. 4). The active
metabolite diffuses into cancer cells [250] and is responsible for cell death
due to its alkylating ability [249,251]. Genetic variations are associated with
functional effects on enzyme expression, concentration, and activity. Phar-
macogenetic variations in drug metabolism are one of the possible mecha-
nisms that influence therapeutic outcome. Most studies published thus far
have correlated genetic variations in CP drug-metabolizing enzymes
(DME) with respect to disease-free survival (PFS) and overall survival in
breast cancer [252–254]. A few have reported on treatment response and
toxicity [195,255].
Various in vitro studies have demonstrated the major role of CYP2B6 to
activate CP [215,245]. A recent study demonstrated that CYP2B6,
CYP3A4, and CYP2C9 were responsible for 45%, 25%, and 12% of CP
hydroxylation in human liver, respectively [215]. Minor contributions were
attributed to CYP1A2 (7%), CYP2A6 (6.2%), CYP2C8 (2.3%), CYP2E1
(2.1%), CYP2C19 (0.6%), and CYP2D6 (0.2%).
Oxidation and reduction H
y
drol
y
sis
Tamoxifen metabolism
Phase I metabolism by cytochrome P450
Therapeutically
active
Tamoxifen
Tamoxifen
Endoxifen
N-desmethyltamoxifen
4 OH-tamoxifen
CYP2D6
CYP3A4/5
Liver
CYP2D6
CYP3A4,CYP2B6,CYP2C9,
CYP2C19
CYP2C9 and other CYPs
CYP3A4/5
Reduction
Figure 3 Metabolism of tamoxifen.
106 Balraj Mittal et al.
Author's personal copy
Pharmacokinetic studies have shown that patients with CYP2B6*5,
CYP2B6*6, and CYP2B6*7 variant genotype have lower CYP2B6 protein
concentration when compared to heterozygous and homozygous wild types
[256,257]. These findings are in line with the high plasma concentration of
the CYP2B6 substrate efavirenz in CYP2B6*6/*6 individuals [32], but
were not confirmed by pharmacokinetic studies involving the CYP2B6 sub-
strate bupropion, in which CYP2B6*6/*6 does not differ from *1/*1[258].
The 516G>T SNP (encoding the Gln172His change; allele frequency
26%), which is present in the *6, *7, *9, and *13 alleles, correlated to three-
fold decreased activity in studies on the CYP2B6 substrate efavirenz
[259,260]. In contrast, population kinetic analyses on bupropion hydroxyl-
ation did not show an effect of CYP2B6*5[258]. The conversion of CP to
4OH-CP as a function of total CYP450 protein was not different between
CYP2B6*6/*6 and CYP2B6*1/*1[256]. Recent studies have also corre-
lated the role of allelic variants for CYP2C19 with decreased drug clearance,
suggesting a profound role in CP metabolism [261]. However, the role of
CYP2C9 in CP activation is thought to be minimal [262]. Tulsyan et al.
[263] studied eight polymorphisms in CYP450 genes to assess their corre-
lation with treatment outcome in breast cancer. This study demonstrated
that variant CYP2B6 alleles had a major influence on the treatment out-
come, with CYP2B6*5 and *9 in the prediction model for treatment
response, grade 2–4 anemia, and dose delay/reduction, respectively. Fur-
thermore, it showed that the determination of higher order gene–gene
interactions of CYP450 polymorphisms may be important in predicting
CP-based treatment outcomes can be useful in future personalized breast
Oxidation and reductionReduction
CYP3A4
CYP3A5
CYP2C8 CYP3A4 CYP2C19
CYP3A5
CYP2B6 2-Dechloroethyl
cyclophosphamide
Chloroacetaldehyde
4-Hydroxycyclophosphamide
Aldophosphamide
Phase I metabolism by cytochrome P450
CYP2B6 CYP2A6 CYP2C9
Cyclophosphamide
H
y
drol
y
sis
Cyclophosphamide
Liver
via transporter
Figure 4 Metabolism of cyclophosphamide.
107CYP450 in Cancer Treatment
Author's personal copy
cancer therapy. We carried out a study on North Indian breast cancer
patients receiving CP-based chemotherapy. We followed 111 patients for
treatment response and 234 patients for grade 2–4 toxicity. A generalized
multianalytical approach was used to determine the influence of variant gene
combinations encoding phase 0 (SLC22A16); phase I (CYP450,NQO1);
phase II (GST,MTHFR,UGT2B15); and phase III (ABCB1) DMEs along
with response and toxicity of chemotherapeutic drugs. Results showed that
CYP450 polymorphisms are present in interaction models for both response
and toxicity (Table 5). Thus, higher order gene–gene interaction along with
confounding factors plays a significant role in determination of
pharmacogenetic-based treatment outcomes in these patients.
6.1.3 Docetaxel
Docetaxel (Taxotere) is an antimitotic chemotherapy drug that interferes
with cell division. This drug has a wide spectrum of antitumor activity
Table 5 GMDR Analysis of Gene–Gene Interaction Models for Treatment Response and
Toxicity in Breast Cancer Patients Undergoing Chemotherapy
Treatment
Outcomes
Best Interaction
Model
CV
Testing
Accuracy
a
CV
Consistency pvalue OR (95% CI)
a
Treatment
response
CYP3A5*3,
NQO1 609C>T,
ABCB1 1236C>T
0.62 9/10 0.0001 12.15
(3.09–47.79)
Grade 2–4
toxicity
CYP2C19*2,
ABCB1 3435C>T
0.57 8/10 0.0049 3.00
(1.38–6.53)
Grade 2–4
anemia
CYP2C19*2,
ABCB1 3435C>T,
ABCB1
2677G>T/A
0.63 10/10 <0.0001 5.43
(2.42–12.16)
Grade 2–4
leucopenia
CYP2B6*9,
UGT2B15
253A>C, ABCB1
2677G>T/A
0.45 6/10 0.0004 5.14
(2.01–13.10)
CV, cross-validation.
Total of 234 patients undergoing CP-based chemotherapy were included in the study and followed for
chemotoxicity (NCI-CTCAE, ver. 3), Out of 234, 111 patients receiving neoadjuvant chemotherapy
were followed for treatment response (RECIST). GMDR analysis was carried out to determine the
higher order gene–gene interaction of phase I, II, and III drug-metabolizing genes along with con-
founding factors like age, tumor size, pathological lymph node, hormone receptors, and her 2 neu status
with breast cancer treatment outcomes.
a
Values rounded up to two decimal places, significant pvalues <0.05.
108 Balraj Mittal et al.
Author's personal copy
and is given to treat locally advanced or metastatic breast cancer, HNC,
gastric cancer, hormone-refractory prostate cancer, and nonsmall cell lung
cancer (NSCLC) (http://www.cancer.gov/cancertopics/druginfo/fda-
docetaxel). Use is accompanied by significant adverse effects including grade
3/4 neutropenia, alopecia, asthenia, dermatologic reactions, fluid retention,
hypersensitivity reaction, motor and sensory neuropathies, stomatitis, and
diarrhea [264]. In addition, there is large interindividual variation in treat-
ment response [265–268].
Docetaxel is extensively metabolized by CYP3A4 and CYP3A5 [216]
(Fig. 5) via oxidation to t-butylhydroxy docetaxel (M2), which is further
metabolized to (M1, M3, and M4). M1 and M3 are two diastereomeric
hydroxyoxazolidinones and M4 is an oxazolidinedione [269]. Biotransfor-
mation is the main route for elimination which makes this drug of interest
with respect to genetic polymorphisms in CYP450. In fact, a few studies
have correlated its clearance with CYP3A4*1B and CYP3A5*3polymor-
phisms [64,265,270–272]. A recent study demonstrated that *1/*3 geno-
type as well as *3 allele of CYP3A5*3was significantly associated with
responders in treatment response group along with the haplotype combina-
tion A
CYP3A4
–A
CYP3A5
[191]. Other studies explored the role of *1/*1
genotype of CYP3A5*3and found it associated with decreased clearance
in different ethnicities [273,274]. Another study reported that CYP3A5
*1/*3genotype was significantly associated with febrile neutropenia in
docetaxel-treated breast cancer patients [275].
6.1.4 Paclitaxel
Paclitaxel (Taxol), an antimicrotubule agent, is used to treat malignant solid
tumors such as breast, lung, head and neck, and ovarian cancer [276]. Com-
mon side effects include myelosuppression, when administered three times
weekly, and peripheral neuropathy, when administered weekly [277].
Oxidation
CYP3A4 CYP3A5 t-Butyl hydroxy
docetaxel [M2]
M1
M3
M4
Docetaxel
M1 & M3 = diasteromeric h
y
drox
y
oxazolidinones; M2 = An alcohol docetaxel; M4 = An oxazolidinedione
Figure 5 Metabolism of docetaxel.
109CYP450 in Cancer Treatment
Author's personal copy
Substantial interindividual variation was also noted in efficacy and toxicity.
Therefore, identification of factors that predict paclitaxel clearance and/or
toxicity could aid in personalizing therapy.
Paclitaxel is converted to its main metabolite 6α-OH paclitaxel by
CYP2C8 (85%) and to 30-p-OH-paclitaxel (15%) by CYP3A4 [124]. The
30-p-OH and 6α-OH forms are converted to inactive dihydroxypaclitaxel
by CYP2C8 and CYP3A4, respectively (Fig. 6). However, 10 variant alleles
(*1to*10) of CYP2C8 have been described so far (www.cypalleles.ki.se)in
which the *2,*3,*5,*7, and *8alleles have decreased enzyme activ-
ity [34,217,218]. The CYP2C8*2(805A>T; Ile269Phe) allele is found pre-
dominantly in African-Americans [276] and rarely in Caucasians
[217,218,278]. Contrary to this, the CYP2C8*3(416G>A, 1196A>G;
Arg139Lys, Lys399Arg) allele was found in 2% of African-Americans and
8–13% of Caucasians [217,218,278]. The CYP2C8*2allele demonstrated
reduced clearance (50%) when compared to the wild-type CYP2C8*1
allele [217,218]. Similarly, CYP2C8*3and CYP2C8*4(792C>G, Ile264-
Met) allele also exhibited decreased enzyme activity [217,278]. The
CYP2C8*3polymorphism was associated with altered paclitaxel turnover
in vitro [217,218]. Therefore, analysis of the CYP2C8*2,*3, and *4alleles
is necessary to assess efficacy and side effects.
6.1.5 Ifosfamide
Ifosfamide (IFO), also marketed as Ifex, is a nitrogen mustard alkylating anti-
tumor prodrug used to treat lung, cervical, ovarian, breast, lymphoma, bone,
and testicular cancer [241]. Common side effects (20% of patients) include
encephalopathy as well as uro-, nephro-, cardio-, and neurotoxicity [279,280].
IFO is pharmacologically activated to 4-hydroxyifosfamide by CYP3A4
and CYP2B6 with minor contributions from CYP2A6, CYP2C8,
Paclitaxel metabolism
6-OH paclitaxel
3⬘-p-OH
paclitaxel
Paclitaxel Dihydroxy paclitaxel
CYP2C8
CYP2C8
CYP3A4
CYP3A4
Figure 6 Metabolism of paclitaxel.
110 Balraj Mittal et al.
Author's personal copy
CYP2C9, and CYP2C19 [219,220]. Although IFO requires CYP3A4 and
CYP2B6 for bioactivation and metabolism, CYP3A5 is mainly respon-
sible for IFO activation via autoinduction [281]. Once formed,
4-hydroxyifosfamide is highly unstable and rapidly interconverts with its
tautomer, aldoifosfamide, or is oxidized by alcohol dehydrogenase to
4-keto-4-hydroxyifosfamide. It is likely that both 4-hydroxyifosfamide
and its tautomer passively diffuse out of hepatic cells, circulate, and then
passively enter other cells [282]. Aldoifosfamide partitions between aldehyde
dehydrogenase (ALDH1A1)-mediated detoxification and the inactive
metabolite carboxyifosfamide, catalyzed conversion to aldoifosfamide. More
importantly, a spontaneous (nonenzymatic) elimination ultimately yields the
therapeutically active metabolite-cytotoxic nitrogen mustards [ifosforamide
mustard or isophosphoramide mustard (IPM)] and an equimolar amount
of byproduct acrolein, which is highly electrophilic and responsible for
its urotoxicity [281] (Fig. 7). 4-Hydroxylation is a major oxidative
detoxification pathway that results in both the detoxified 2- or
3-dechloroethylifosfamide (DCE) and the formation of chloroacetaldehyde
(CAA-toxic) [219,283]. Both pathways are primarily mediated by hepatic
CYP2B6 and CYP3A4. IPM contains a highly reactive alkyl group which
covalently links specific nucleophilic sites in DNA resulting in tumor cell
apoptosis.
Polymorphisms in IFO-metabolizing genes may play a significant role
in drug efficacy [284]. Similar to CP, IFO is metabolized via N-
dechloroethylation to chloroacetaldehyde. However, N-dechloroethylation
accounts for only 10% of CP metabolism [284]. CYP3A4 is the main
AldoIfosfamide
2-Dechloroethyl ifosfamide
3-Dechloroethyl ifosfamide
Chloroacetaldehyde
Ifosfamide
Ifosfamide
4-Hydroxycyclophosphamide
CYP3A5
CYP3A5
CYP2C8
Liver
via transporter
CYP3A4
CYP3A4
CYP2C9
CYP2B6
CYP2B6
CYP2A6
Figure 7 Metabolism of ifosfamide.
111CYP450 in Cancer Treatment
Author's personal copy
enzyme responsible IFO activation (70%) with the remainder catalyzed by
CYP2B6 [215,285]. An extensive study also showed that 4-hydroxylation of
IFO is mainly catalyzed by CYP3A4, with minor contributions by
CYP2B6, CYP1A1, CYP2A6, and CYP2C19 [215]. The CYP2B6*1/*6
and *6/*6 genotypes have been linked with lower catalytic activity and pro-
tein expression in liver, increased plasma IFO, and higher rates of CAA-
associated toxicity [283]. Carriers of CYP3A5*1catalyzed the detoxification
pathway to DCE at a faster rate leading to a increased CAA and higher risk of
nephrotoxicity due to its ability to rapidly degrade in blood [286].
Genetic variations in CYP3A4 are relatively few with a very low allele
frequency. As such, it is difficult to assess the contribution of CYP3A4
genotyping in predicting IFO therapy outcome in the absence of well-
defined and well-characterized pharmacogenetic and pharmacodynamic
studies.
6.1.6 Irinotecan
IRI, a semisynthetic analogue of the natural alkaloid camptothecin, is used
for treatment of metastatic colorectal cancer.
IRI is hepatically metabolized via hydrolysis and converted to SN-38,
the active metabolite, by carboxyl esterases (CES) [287]. Only a small
percentage, however, is converted to active SN-38 (<3%) due to low
CES substrate affinity [288,289] (Fig. 8). SN-38 prevents DNA unwinding
by inhibition of DNA topoisomerase I [290] which results in irreversible
double strand breaks and ultimately cell death. SN-38 is then conjugated
to SN-38 glucoronic acid and detoxified in the liver. The UGT1A1*28
genetic polymorphism causes decreased conversion of the active metabolite
Irinotecan
CYP3A4
CYP3A4
CYP3A4
CYP3A5
CYP3A5
APC
M4
NPC
APC = 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino] carbonyloxycamptothecin
NPC = 7-ethyl-10-[4-(1-piperidino)-1-amino] carbonyloxycamptothecin
M4 = Metabolite 4
Figure 8 Metabolism of irinotecan.
112 Balraj Mittal et al.
Author's personal copy
and toxic substance SN-38 to SN-38 glucuronide [291]. However, the role
of CYP3A4 is restricted to IRI conversion to inactive compounds APC
(7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino] carbonyl
oxycamptothecin) and NPC (7-ethyl-10-[4-(1-piperidino)-1-amino]
carbonyl oxycamptothecin). Recently, an in vitro study showed that the
decreased activity of CYP3A4*16 (661G>C) variant resulted in decreased
APC. Similarly, it was found that CYP3A4*18 allele leads to reduced catal-
ysis because of a higher V
max
[221].In vitro studies have also shown minor
role for CYP3A5 in IRI metabolism [292–294].CYP3A5*3allele
undergoes alternative splicing that results in null CYP3A5 enzyme expres-
sion which severely decreased oxidative metabolism thus leading to
decreased APC and NPC production [295].
Few studies have demonstrated the interindividual variability in IRI and
SN-38 pharmacokinetics with treatment outcome [296,297]. Moreover,
there is no clear clinical use for determining CYP3A4 or CYP3A5 genetic
polymorphisms to improve IRI metabolism. CYP3A4 genes play little role
in its metabolism and the frequency of genetic variants is quite low.
6.1.7 Imatinib
Imatinib(Gleevec) is a tyrosine kinase inhibitor (TKI) usedin the treatment of
Philadelphia chromosome-positive (Ph
+
) chronic myeloid leukemia (CML)
or metastatic malignant gastrointestinal stromal tumors (GIST) [298].
In normal cells, tyrosine kinase enzymes are turned on and off as
required. In Ph
+
CML cells, one tyrosine kinase enzyme, BCR-Abl, is
always on. Imatinib blocks this BCR-Abl enzyme. As a result, these cells
stop dividing. Because the BCR-Abl tyrosine kinase enzyme exists only
in cancer cells and not healthy cells, imatinib works as a form of targeted
therapy, i.e., only cancer cells are killed [299]. However, the action of
imatinib is a bit different in case of GIST. These harbor KIT mutations
and produce ligand-independent constitutive activation of KIT [300,301].
Imatinib interrupts KIT-mediated signal transduction in a manner similar
to inhibition of BCR-Abl and thus stops cancer cell proliferation [302–304].
Unfortunately, not much data are available on the metabolism of
imatinib and enzymes involved therein. CYP3A4/5 has been implicated
in the demethylation of imatinib to N-demethyl-imatinib [222] (Fig. 9).
The importance of CYP3A4 activity in imatinib treatment was demon-
strated using co-administered phenytoin (a CYP3A4 inducer) or ketocona-
zole (a CYP3A4 inhibitor). These resulted in a reduced AUC (increased
metabolism) and a significantly increased AUC (decreased metabolism),
113CYP450 in Cancer Treatment
Author's personal copy
respectively. Other studies showed that ketoconazole co-administration
caused a significantly reduced imatinib exposure (AUC) of 40% due to
reduced clearance. Conversely, co-administration of rifampin and St John’s
Wort (potent inducers of CYP3A4) decreased the AUC of imatinib due to
increased metabolism [305–307]. In addition, CYP1A2, CYP2C8,
CYP2C9, CYP2C19, and CYP2D6 can hydroxylate imatinib [298,303].
Due to the rarity of genetic polymorphisms in CYP3A4, their role is limited
pharmacogenetically for this compound.
6.1.8 Flutamide
Flutamide (Drogenil) is an oral, nonsteroidal antiandrogen drug primarily
used to treat prostate cancer. It prevents proliferation of prostate cancer cells
by binding to androgen receptors.
Studies have shown that CYP1A2 plays a major role in metabolism of
flutamide to 2-hydroxyflutamide [223,224]. This metabolite is subsequently
hydrolyzed to 30-trifluoromethyl-40-nitroaniline and excreted in urine
[224]. Flutamide metabolism is inhibited by a-naphthoflavone and ketoco-
nazole at low concentration. Biologic activity of this compound is due to its
metabolite, 2-hydroxyflutamide (Fig. 10)[308].
GIST
CML
Excretion
Inactive metaboliteCGP 74588
Phosphorylation
Substrates
Phosphorylation
Substrates
Signal transduction
Signal transduction
Imatinib
KIT
BCR-ABL
CYP3A5
CYP3A4
CYP2C19
CYP2D6
CYP1A2
CYP2C9
Figure 9 Metabolism of imatinib.
Flutamide
CYP1A2
2-Hydroxyflutamide
CYP1A2 3¢-Trifluoromethyl
-4¢-nitroaniline Excreted in urine
Figure 10 Metabolism of offlutamide.
114 Balraj Mittal et al.
Author's personal copy
CYP1A2 is highly polymorphic, where ∗1C,∗1K,∗7, and ∗11 alleles
account for decreased enzyme activity (www.imm.ki.se/CYPalleles; August
1, 2005). The frequency of these alleles between populations varies widely.
The *1C variant has an allele frequency of 23% [309], the ∗7allele has an
allele frequency below 0.5% [310], and the ∗11 allele has an allele frequency
of 0.2% [311] in Japanese. However, the ∗1K variant has an allele frequency
of 3% in Ethiopians, 3.6% in Saudi Arabians, and 0.5% in Spaniards [312].
As such, it likely that individuals with alleles resulting in decreased activ-
ity may not benefit as much from flutamide. Further studies are clearly
needed to ascertain the role of CYP1A2 polymorphisms in antiandrogenic
therapy.
6.1.9 Tegafur
Tegafur is a chemotherapeutic fluorouracil (5-FU) prodrug used primarily
in treatment of bowel cancer. Bioactivation is catalyzed by CYP2A6 via
50-hydroxylation (Fig. 11)[313,314]. At present, there are 26 known allelic
variants of the CYP2A6 gene. CYP2A6∗2,∗4,∗5, and ∗20 alleles encode
enzymes of null activity, while the ∗6,∗7,∗9,∗10,∗11,∗12,∗17,∗18A/
B, and ∗19 alleles encode enzymes of reduced activity (www.imm.ki.se/
CYPalleles). A study on CYP2A6*11 showed that ∗11 allele was present
in an individual with a poor metabolic phenotype. However, a compound
heterozygote CYP2A6∗4C/∗11 had fourfold higher AUC versus other
patients [225]. As such, it is likely that CYP2A6 PMs would respond less
to Tegafur therapy. Large-scale studies are required to come to a definitive
conclusion.
6.1.10 Gefitinib
Gefitinib (Iressa
®
) is a drug used in the treatment of locally advanced or
metastatic NSCLC. Gefitinib belongs to a class of TKIs that compete with
ATP for its binding pocket in mutated or overexpressed EGFR receptors
[315]. This drug inhibits tyrosine kinase activity and prevents cancer cell
proliferation.
In vitro studies have revealed that gefitinib is primarily metabolized by
CYP3A4 and also by CYP3A5, CYP2D6, and the extrahepatic CYP1A1
Tegafur 5⬘Hydroxytegafur
CYP2A6
5FU
Figure 11 Metabolism of tefagur. Prodrug conversion to active form 5-FU.
115CYP450 in Cancer Treatment
Author's personal copy
[226]. Metabolites M387783, M537194, and M608236O are produced
by CYP3A4/5 via O- and N-dealkylation and defluorination, whereas
N-desmethyl-derivative (M523595), major plasma metabolite in humans,
is produced from CYP2D6 (Fig. 12).
Polymorphism in CYP3A4, CYP3A5, and CYP2D6 has previously
been reported. A recent study observed no significant difference between
CYP3A5 expressers and nonexpressers in gefitinib clearance or half-life
[316]. CYP2D6 comparison of extensive versus PMs showed twofold
higher gefitinib exposure in the former (AUC ¼3060 ng h/mL; range
215–8840) versus the latter (AUC ¼1430 ng h/mL; range 406–5830)
[316]. Unfortunately, it is difficult to assess clinical utility of CYP3A4 and
CYP2D6 polymorphisms in individualized therapy due to limited number
of published studies. Acquired resistance is another complication of gefitinib
treatment, a finding which has led to the development of second-
generation TKI.
6.1.11 Etoposide and Teniposide
Etoposide (VP16) and teniposide (VM26) are topoisomerase II inhibitors
widely used as cytotoxic anticancer drugs in small cell lung, acute lympho-
blastic leukemia (ALL), lymphoma and testicular germ cell cancer. Both
undergo O-demethylation to form a catechol metabolite (Fig. 13) which
displays antitumor activity [317,318]. CYP3A4 is an important enzyme in
this conversion with a minor role noted for CYP3A5 [227,228], CYP2E1,
and CYP1A2 [151].
M387783
M537194
M523595
M387783
M537194
M523595
CYP2D6
CYP3A5 Gefitinib
CYP3A4
Secondar
y
route Primary route
CYP2C9
CYP1A1
CYP2C19
CYP2D6
Figure 12 Metabolism of gefitinib.
116 Balraj Mittal et al.
Author's personal copy
In a study involving 109 ALL children, etoposide clearance was corre-
lated with CYP3A5*3/*3genotype in African ethnicity, but this correlation
was not found in Caucasians [319]. Further studies are needed to confirm
and clarify these findings.
6.1.12 Thalidomide
Thalidomide (Immunoprin) is an immunomodulatory drug effective in the
treatment of multiple myeloma and prostate cancer due to its inhibition on
angiogenesis [320–322]. Thalidomide is hydroxylated by CYP2C19 to
5-OH thalidomide [229]. The 5,6-dOH metabolite is subsequently formed
via CYP2C19 and CYP2C9 (Fig. 14).
CYP2C19 is highly polymorphic which can impact therapeutic out-
come. For example, in a case-controlled study of prostate cancer patients
on thalidomide monotherapy, CYP2C19 PMs showed decreased produc-
tion of 5-OH thalidomide [323].
6.1.13 Vincristine
Vincristine (Oncovin), a mitotic drug, is commonly used as combination
chemotherapy in the treatment of pediatric ALL. Genetics may play a major
Thalidomide
Nonenzymatic
hydrolysis
CYP2C19
CYP2B6
CYP2C19
CYP2C19
Nonactive Components
cis-5 OH-thalidomide
5 OH-thalidomide
CYP2C9
5,6-dOH-thalidomide
Figure 14 Metabolism of thalidomide. Active form of drug*.
Etoposide catechol
CYP3A4
Etoposide
Figure 13 O-Demethylation of etoposide.
117CYP450 in Cancer Treatment
Author's personal copy
role in outcome because large interracial differences in response have been
reported. In fact, higher survival was noted for Caucasians versus African-
Americans in clinical trials [324,325]. Vincristine is metabolized by both
CYP3A4 and CYP3A5 to its major metabolite M1 (Fig. 15). However,
the contribution of CYP3A5 in its metabolism is seven- to ninefold higher
than CYP3A4 [230]. Thus, for 20% of Caucasian and 70% of African
CYP3A5 expressers, CYP3A5 may contribute significantly (55–95%) to
total vincristine metabolism [326], making it a major determinant in
predicting outcome.
6.2 CYP450 Inhibitors in Anticancer Therapy
Various studies have been performed on CYP450 isozyme inhibitors
[327–331]. Although isozymes vary in their substrate specificity, there is sig-
nificant overlap. In addition, there are specific inhibitors of each isozyme
which compete for the substrate-binding site [332,333].
Unfortunately, only few inhibitors enter into clinical trials and fewer still
are ultimately developed as an anticancer therapy. Anticancer drugs with
narrow therapeutic index suffer from the problem of bioavailability. Studies
attempting to increase the bioavailability of orally administered drugs have
been performed in several preclinical and clinical settings with several anti-
cancer drugs including the cytotoxic taxanes (paclitaxel and docetaxel), vin-
orelbine, and topoisomerase I inhibitors (IRI). Examples of CYP450
inhibitors in anticancer therapies are shown in Table 6.
6.2.1 Taxanes
Oral anticancer treatment is preferred over intravenous administration due
to its cost effectiveness and convenience. Taxanes (paclitaxel and docetaxel)
are administered intravenously at different dosages and schedules [345] due
Vincristine CYP3A4
CYP3A5
Metabolite M1
(major)
Metabolite M2
(minor)
Metabolite M4
(minor)
Figure 15 Metabolism of vincristine.
118 Balraj Mittal et al.
Author's personal copy
to poor oral bioavailability (10%) [345–347]. Taxanes are poorly soluble in
water and do not sufficiently dissolve when administered in crystalline form.
Paclitaxel has great affinity for drug transporters like P-glycoprotein (P-gp,
ABCB1) in the gastrointestinal tract and is rapidly eliminated. Docetaxel is
extensively metabolized by hepatic CYP450 (especially CYP3A4) further
limiting oral usefulness.
Studies with CYP4503A knockout mice showed a significantly
improved bioavailability for oral docetaxel [336]. Co-administration of rito-
navir, a CYP3A4 inhibitor, enhanced the plasma concentration of oral
docetaxel without affecting relative brain accumulation. Similar results were
reported by others. One study showed that CYP3A4 inhibition boosted the
effect of ritonavir on oral paclitaxel bioavailability in humans [337].In
another study, oral administration of docetaxel to mice lacking all Cyp3a
and P-gp genes showed a significantly improved bioavailability (>70-fold)
[338]. However, it also resulted in severe intestinal lesions. These findings
indicate that inhibition of CYP3A4/P-gp might be a highly effective strat-
egy to improve oral drug bioavailability, but with concomitant risks.
Table 6 CYP450 Inhibitors in Anticancer Therapies
Drug CYP450 Enzymes Inhibitors References
Cisplatin CYP1A1, CYP1A2,
CYP2D6, CYP3A4,
and CYP3A5
Ondansetron [334]
Cyclophosphamide CYP1A1, CYP1A2,
CYP2D6, CYP3A4,
and CYP3A5
Ondansetron [335]
Docetaxel CYP3A4 Ritonavir, cyclosporin
A
[336–338]
Erolitinib CY3A4 Ketoconazole [339]
Gefitinib CYP3A4 Itraconazole [340]
Irinotecan CYP3A4 Ketoconazole,
cyclosporin A, St.
John’s Wort (SJW)
[341]
Imatinib CYP3A Erythromycin,
ketoconazole, SJW
[305]
Tamoxifen CYP2D6 Paroxetine [238,342]
Vinorelbine CYP3A4 Paclitaxel [343,344]
119CYP450 in Cancer Treatment
Author's personal copy
Cyclosporin A (CsA) co-administration with docetaxal or paclitaxel
resulted in 90% and 50% oral bioavailability [348]. Interpatient variability
was similar to that obtained by intravenous drug administration. Another
study in which ritonavir was co-administered with docetaxel showed signif-
icantly increased bioavailability (4–183%). Extensive first-pass metabolism
likely contributes to low bioavailability of oral docetaxel in mice [349].
A clinical study showed that one course of oral docetaxel 75 mg/m
2
with
or without a single oral dose of CsA 15 mg/kg resulted in a 7.3-fold increase
in systemic exposure. The apparent bioavailability of oral docetaxel
increased from 8% to 90% in the absence or presence of CsA, respectively.
However, the effect of CsA on the bioavailability of docetaxel was less pro-
nounced in mice [349] compared with humans [350].
A phase II study in advanced breast cancer with weekly oral docetaxel
plus CsA showed that patients suffered from less hematologic toxicity with
an overall response rate of 52% (n¼25) [351–354]. Inter- and intra-AUC
variability after oral docetaxel were comparable to intravenous administra-
tion (29–53%) [355,356].
Based on the intravenous dosages, solutions for oral administration of
taxanes were formulated. These solutions had several disadvantages and solid
formulations of paclitaxel and docetaxel were subsequently developed. Clin-
ical studies using these novel formulations in combination with ritonavir are
currently in progress [357].
6.2.2 Vinorelbine
Vinorelbine, another anticancer drug, is used intravenously despite the avail-
ability of an oral formulation which has been approved in several European
countries. Unfortunately, large interindividual bioavailability variation was
observed in these studies [358–361].
Recently, interactions of the anticancer drug vinorelbine with CYP450
3A were investigated using P-gp/Cyp3a knockout mice [362]. The absence
of Cyp3a alone or the combined absence of P-gp and Cyp3a resulted in
increased plasma concentration of 2.2- and 3.4-fold, respectively. Similar
results were obtained by others [363].
6.2.3 Irinotecan
IRI is an anticancer drug widely used to treat colorectal cancer. Some studies
have shown the administration of IRI along with CYP3A4 inhibitors
affected clearance and altered the plasma concentration of its active metab-
olite, SN-38. One study demonstrated that concomitant administration of
120 Balraj Mittal et al.
Author's personal copy
IRI with ketoconazole, an inhibitor of CYP3A4, caused increased plasma
SN-38 [364]. CsA, a CYP3A4 inhibitor, resulted in significantly reduced
clearance of IRI and led to serious side effects in humans [365]. Another
study showed that combination of IRI, St. John’s Wort, a CYP3A4 inducer,
resulted in decreased SN-38 [366]. Based on these preliminary findings, it is
likely that co-administration of drugs that are substrates for CYP3A4 will
influence treatment outcome. These studies are needed.
7. CONCLUSION
CYP450 plays very important role in the etiology of various cancers
due to their involvement in detoxification of potential carcinogens and syn-
thesis of steroids. Although various studies have shown the association of
CYP450 polymorphisms with several cancers, results are inconsistent due
to lack of study power. Therefore, multicentric studies with large sample size
are clearly required to more effectively elucidate the genetic predisposition
of various cancers.
The majority of anticancer drugs are metabolized by CYP450. CYP450
genes are highly polymorphic thus leading to large interindividual variations
in therapeutic response and toxicity; genetic profiling is clearly needed to
tailor personalized therapy.
In addition, a large number of CYP450 inducers and inhibitors are
known. These are under current evaluation to increase bioavailability,
decrease toxicity, and improve outcome.
ACKNOWLEDGMENTS
The authors acknowledge the contribution of Dr. Punita Lal, Dr. Sushma Agrawal, and Dr.
Pankaj Chaturvedi, Sanjay Gandhi Post Graduate Institute of Medical Sciences (SGPGIMS),
Lucknow, for their contribution in various studies carried out in our laboratory. The grants
from Department of Science and Technology (DST) and Indian Council of Medical
Research (ICMR), Government of India, New Delhi are gratefully acknowledged.
REFERENCES
[1] K.N. Degtyarenko, Structural domains of P450-containing monooxygenase systems,
Protein Eng. 8 (8) (1995) 737–747.
[2] http://minf.vub.ac.be/~fabi/edu/3degraad/HIV/cytochrome.html
[3] M.L. Buck, The cytochrome P450 enzyme system and its effect on drug metabolism,
Pediatr. Pharmacother. 3 (5) (1997).
[4] D.C. Lamb, et al., The first virally encoded cytochrome p450, J. Virol. 83 (16) (2009)
8266–8269.
[5] P.B. Danielson, The cytochrome P450 superfamily: biochemistry, evolution and drug
metabolism in humans, Curr. Drug Metab. 3 (6) (2002) 561–597.
121CYP450 in Cancer Treatment
Author's personal copy
[6] A. Sigel, H. Sigel, R.K.O. Sigel, The ubiquitous roles of cytochrome P450 proteins,
Met. Ions Life Sci. 3 (2007) 678.
[7] D.R. Nelson, Comparison of P450s from human and fugu: 420 million years of ver-
tebrate P450 evolution, Arch. Biochem. Biophys. 409 (1) (2003) 18–24.
[8] D.R. Nelson, The cytochrome p450 homepage, Hum. Genomics 4 (1) (2009) 59–65.
[9] D.W. Nebert, F.J. Gonzalez, P450 genes: structure, evolution, and regulation, Annu.
Rev. Biochem. 56 (1987) 945–993.
[10] I. Hanukoglu, Electron transfer proteins of cytochrome P450 systems, Adv. Mol. Cell
Biol. 14 (1996) 29–55.
[11] G.C. Smith, D.G. Tew, C.R. Wolf, Dissection of NADPH-cytochrome P450 oxido-
reductase into distinct functional domains, Proc. Natl. Acad. Sci. U.S.A. 91 (18) (1994)
8710–8714.
[12] K.J. McLean, et al., Biodiversity of cytochrome P450 redox systems, Biochem. Soc.
Trans. 33 (Pt 4) (2005) 796–801.
[13] D.R. Nelson, et al., Comparison of cytochrome P450 (CYP) genes from the mouse
and human genomes, including nomenclature recommendations for genes,
pseudogenes and alternative-splice variants, Pharmacogenetics 14 (1) (2004) 1–18.
[14] J.G. Slatter, et al., Bioactivation of the anticancer agent CPT-11 to SN-38 by human
hepatic microsomal carboxylesterases and the in vitro assessment of potential drug inter-
actions, Drug Metab. Dispos. 25 (10) (1997) 1157–1164.
[15] M. Ingelman-Sundberg, Human drug metabolising cytochrome P450 enzymes: prop-
erties and polymorphisms, Naunyn Schmiedebergs Arch. Pharmacol. 369 (1) (2004)
89–104.
[16] S.J. London, et al., CYP1A1 I462V genetic polymorphism and lung cancer risk in a
cohort of men in Shanghai, China, Cancer Epidemiol. Biomarkers Prev. 9 (9)
(2000) 987–991.
[17] S. Chen, et al., Polymorphisms of the CYP1A1 and GSTM1 genes in relation to indi-
vidual susceptibility to lung carcinoma in Chinese population, Mutat. Res. 458 (1–2)
(2001) 41–47.
[18] M. Garcia-Closas, et al., A case-control study of cytochrome P450 1A1, glutathione
S-transferase M1, cigarette smoking and lung cancer susceptibility (Massachusetts,
United States), Cancer Causes Control 8 (4) (1997) 544–553.
[19] S. Ohshima, Y. Xu, p53 gene mutations, and CYP1A1 and GSTM1 genotypes in pul-
monary squamous cell carcinomas, Mol. Pathol. 50 (2) (1997) 108–110.
[20] K. Kawajiri, et al., Germ line polymorphisms of p53 and CYP1A1 genes involved in
human lung cancer, Carcinogenesis 14 (6) (1993) 1085–1089.
[21] T. Tefre, et al., Human CYP1A1 (cytochrome P(1)450) gene: lack of association
between the Msp I restriction fragment length polymorphism and incidence of lung
cancer in a Norwegian population, Pharmacogenetics 1 (1) (1991) 20–25.
[22] V. Malaiyandi, E.M. Sellers, R.F. Tyndale, Implications of CYP2A6 genetic variation
for smoking behaviors and nicotine dependence, Clin. Pharmacol. Ther. 77 (3) (2005)
145–158.
[23] P. Vineis, N. Malats, Strategic issues in the design and interpretation of studies on met-
abolic polymorphisms and cancer, IARC Sci. Publ. 148 (1999) 51–61.
[24] J.S. Mandel, et al., Reducing mortality from colorectal cancer by screening for fecal
occult blood. Minnesota Colon Cancer Control Study, N. Engl. J. Med. 328 (19)
(1993) 1365–1371.
[25] C. Xu, et al., CYP2A6 genetic variation and potential consequences, Adv. Drug Deliv.
Rev. 54 (10) (2002) 1245–1256.
[26] T. Kamataki, et al., Genetic polymorphism of CYP2A6 as one of the potential deter-
minants of tobacco-related cancer risk, Biochem. Biophys. Res. Commun. 338 (1)
(2005) 306–310.
122 Balraj Mittal et al.
Author's personal copy
[27] M. Fujieda, et al., Evaluation of CYP2A6 genetic polymorphisms as determinants of
smoking behavior and tobacco-related lung cancer risk in male Japanese smokers,
Carcinogenesis 25 (12) (2004) 2451–2458.
[28] N. Ariyoshi, et al., Genetic polymorphism of CYP2A6 gene and tobacco-induced
lung cancer risk in male smokers, Cancer Epidemiol. Biomarkers Prev. 11 (9)
(2002) 890–894.
[29] R.F. Tyndale, E.M. Sellers, Genetic variation in CYP2A6-mediated nicotine metab-
olism alters smoking behavior, Ther. Drug Monit. 24 (1) (2002) 163–171.
[30] M. Rotger, et al., Predictive value of known and novel alleles of CYP2B6 for efavirenz
plasma concentrations in HIV-infected individuals, Clin. Pharmacol. Ther. 81 (4)
(2007) 557–566.
[31] J. Wang, et al., Identification of a novel specific CYP2B6 allele in Africans causing
impaired metabolism of the HIV drug efavirenz, Pharmacogenet. Genomics 16 (3)
(2006) 191–198.
[32] K. Tsuchiya, et al., Homozygous CYP2B6 *6 (Q172H and K262R) correlates with high
plasma efavirenz concentrations in HIV-1 patients treated with standard efavirenz-
containing regimens, Biochem. Biophys. Res. Commun. 319 (4) (2004) 1322–1326.
[33] I. Cavaco, et al., CYP2C8 polymorphism frequencies among malaria patients in
Zanzibar, Eur. J. Clin. Pharmacol. 61 (1) (2005) 15–18.
[34] A. Soyama, et al., Five novel single nucleotide polymorphisms in the CYP2C8 gene, one
of which induces a frame-shift, Drug Metab. Pharmacokinet. 17 (4) (2002) 374–377.
[35] A. Weise, et al., Development and evaluation of a rapid and reliable method for cyto-
chrome P450 2C8 genotyping, Clin. Lab. 50 (3–4) (2004) 141–148.
[36] A.K. Daly, et al., Genetic susceptibility to diclofenac-induced hepatotoxicity: contri-
bution of UGT2B7, CYP2C8, and ABCC2 genotypes, Gastroenterology 132 (1)
(2007) 272–281.
[37] R. Taniguchi, et al., Utilization of human liver microsomes to explain individual dif-
ferences in paclitaxel metabolism by CYP2C8 and CYP3A4, J. Pharmacol. Sci. 97 (1)
(2005) 83–90.
[38] S.S. Rathore, et al., Frequencies of VKORC1 -1639 G>A, CYP2C9*2 and
CYP2C9*3 genetic variants in the Northern Indian population, Biosci. Trends
4 (6) (2010) 333–337.
[39] J. Blaisdell, et al., Identification and functional characterization of new potentially
defective alleles of human CYP2C19, Pharmacogenetics 12 (9) (2002) 703–711.
[40] P.P. Maliakal, P.F. Coville, S. Wanwimolruk, Decreased hepatic drug metabolising
enzyme activity in rats with nitrosamine-induced tumours, Drug Metabol. Drug Inter-
act. 19 (1) (2002) 13–27.
[41] S. Gulati, et al., Frequency distribution of high risk alleles of CYP2C19, CYP2E1,
CYP3A4 genes in Haryana population, Environ. Toxicol. Pharmacol. 37 (3) (2014)
1186–1193.
[42] M. Eichelbaum, M. Ingelman-Sundberg, W.E. Evans, Pharmacogenomics and indi-
vidualized drug therapy, Annu. Rev. Med. 57 (2006) 119–137.
[43] W.E. Evans, M.V. Relling, Pharmacogenomics: translating functional genomics into
rational therapeutics, Science 286 (5439) (1999) 487–491.
[44] S. Bernard, et al., Interethnic differences in genetic polymorphisms of CYP2D6 in the
U.S. population: clinical implications, Oncologist 11 (2) (2006) 126–135.
[45] M. Ingelman-Sundberg, Genetic polymorphisms of cytochrome P450 2D6
(CYP2D6): clinical consequences, evolutionary aspects and functional diversity, Phar-
macogenomics J. 5 (1) (2005) 6–13.
[46] J. Kirchheiner, et al., Pharmacogenetics of antidepressants and antipsychotics: the con-
tribution of allelic variations to the phenotype of drug response, Mol. Psychiatry 9 (5)
(2004) 442–473.
123CYP450 in Cancer Treatment
Author's personal copy
[47] U.M. Zanger, S. Raimundo, M. Eichelbaum, Cytochrome P450 2D6: overview and
update on pharmacology, genetics, biochemistry, Naunyn Schmiedebergs Arch.
Pharmacol. 369 (1) (2004) 23–37.
[48] ALFRED: The Allele Frequency Database (ALFRED). http://alfred.med.yale.edu/
alfred/AboutALFRED.asp (accessed June 2015).
[49] M. Ingelman-Sundberg, Pharmacogenetics of cytochrome P450 and its applications in
drug therapy: the past, present and future, Trends Pharmacol. Sci. 25 (4) (2004)
193–200.
[50] M. Ingelman-Sundberg, M. Oscarson, R.A. McLellan, Polymorphic human cyto-
chrome P450 enzymes: an opportunity for individualized drug treatment, Trends
Pharmacol. Sci. 20 (8) (1999) 342–349.
[51] L. Bertilsson, et al., Pronounced differences between native Chinese and Swedish
populations in the polymorphic hydroxylations of debrisoquin and S-mephenytoin,
Clin. Pharmacol. Ther. 51 (4) (1992) 388–397.
[52] M.V. Relling, et al., Lower prevalence of the debrisoquin oxidative poor metabolizer
phenotype in American black versus white subjects, Clin. Pharmacol. Ther. 50 (3)
(1991) 308–313.
[53] E. Steiner, et al., Polymorphic debrisoquin hydroxylation in 757 Swedish subjects,
Clin. Pharmacol. Ther. 44 (4) (1988) 431–435.
[54] A. Gaedigk, et al., Cytochrome P4502D6 (CYP2D6) gene locus heterogeneity:
characterization of gene duplication events, Clin. Pharmacol. Ther. 81 (2) (2007)
242–251.
[55] S.M. Wang, et al., Frequencies of genotypes and alleles of the functional SNPs in
CYP2C19 and CYP2E1 in mainland Chinese Kazakh, Uygur and Han populations,
J. Hum. Genet. 54 (6) (2009) 372–375.
[56] S. Kato, et al., Analysis of cytochrome P450 2E1 genetic polymorphisms in relation to
human lung cancer, Cancer Epidemiol. Biomarkers Prev. 3 (6) (1994) 515–518.
[57] G.W. Chang, P.C. Kam, The physiological and pharmacological roles of cytochrome
P450 isoenzymes, Anaesthesia 54 (1) (1999) 42–50.
[58] D.A. Garteiz, et al., Pharmacokinetics and biotransformation studies of terfenadine in
man, Arzneimittelforschung 32 (9a) (1982) 1185–1190.
[59] L.J. Marnett, Aspirin and the potential role of prostaglandins in colon cancer, Cancer
Res. 52 (20) (1992) 5575–5589.
[60] K. Gellner, et al., Genomic organization of the human CYP3A locus: identification of
a new, inducible CYP3A gene, Pharmacogenetics 11 (2) (2001) 111–121.
[61] C. Finta, P.G. Zaphiropoulos, The human cytochrome P450 3A locus. Gene evolu-
tion by capture of downstream exons, Gene 260 (1–2) (2000) 13–23.
[62] S.J. Plummer, et al., CYP3A4 and CYP3A5 genotypes, haplotypes, and risk of prostate
cancer, Cancer Epidemiol. Biomarkers Prev. 12 (9) (2003) 928–932.
[63] R.H. van Schaik, Cancer treatment and pharmacogenetics of cytochrome P450
enzymes, Investig. New Drugs 23 (6) (2005) 513–522.
[64] B. Amirimani, et al., RESPONSE: re: modification of clinical presentation of prostate
tumors by a novel genetic variant in CYP3A4, J. Natl. Cancer Inst. 91 (18) (1999)
1588–1590.
[65] C.S. Huang, et al., Cytochrome P4501A1 polymorphism as a susceptibility factor for
breast cancer in postmenopausal Chinese women in Taiwan, Br. J. Cancer 80 (11)
(1999) 1838–1843.
[66] N. Ishibe, et al., Cigarette smoking, cytochrome P450 1A1 polymorphisms, and breast
cancer risk in the Nurses’ Health Study, Cancer Res. 58 (4) (1998) 667–671.
[67] E. Taioli, et al., A CYP1A1 restriction fragment length polymorphism is associated
with breast cancer in African-American women, Cancer Res. 55 (17) (1995)
3757–3758.
124 Balraj Mittal et al.
Author's personal copy
[68] L.A. Hefler, et al., Estrogen-metabolizing gene polymorphisms in the assessment of
breast carcinoma risk and fibroadenoma risk in Caucasian women, Cancer 101 (2)
(2004) 264–269.
[69] L. da Fonte de Amorim, et al., CYP1A1, GSTM1, and GSTT1 polymorphisms and
breast cancer risk in Brazilian women, Cancer Lett. 181 (2) (2002) 179–186.
[70] C.B. Ambrosone, et al., Cytochrome P4501A1 and glutathione S-transferase
(M1) genetic polymorphisms and postmenopausal breast cancer risk, Cancer Res.
55 (16) (1995) 3483–3485.
[71] Y. Miyoshi, et al., Breast cancer risk associated with CYP1A1 genetic polymorphisms
in Japanese women, Breast J. 8 (4) (2002) 209–215.
[72] L.R. Bailey, et al., Breast cancer and CYPIA1, GSTM1, and GSTT1 polymorphisms:
evidence of a lack of association in Caucasians and African Americans, Cancer Res.
58 (1) (1998) 65–70.
[73] M. Krajinovic, et al., Genetic susceptibility to breast cancer in French-Canadians: role
of carcinogen-metabolizing enzymes and gene-environment interactions, Int. J. Can-
cer 92 (2) (2001) 220–225.
[74] V.M. Basham, et al., Polymorphisms in CYP1A1 and smoking: no association with
breast cancer risk, Carcinogenesis 22 (11) (2001) 1797–1800.
[75] L.F. Masson, et al., Cytochrome P-450 1A1 gene polymorphisms and risk of breast
cancer: a HuGE review, Am. J. Epidemiol. 161 (10) (2005) 901–915.
[76] W. Zheng, et al., Genetic polymorphism of cytochrome P450-1B1 and risk of breast
cancer, Cancer Epidemiol. Biomarkers Prev. 9 (2) (2000) 147–150.
[77] N.A. Kocabas, et al., Cytochrome P450 CYP1B1 and catechol O-methyltransferase
(COMT) genetic polymorphisms and breast cancer susceptibility in a Turkish popu-
lation, Arch. Toxicol. 76 (11) (2002) 643–649.
[78] K.P. Economopoulos, T.N. Sergentanis, Three polymorphisms in cytochrome P450
1B1 (CYP1B1) gene and breast cancer risk: a meta-analysis, Breast Cancer Res. Treat.
122 (2) (2010) 545–551.
[79] L. Yao, et al., No association between CYP1B1 Val432Leu polymorphism and breast
cancer risk: a meta-analysis involving 40,303 subjects, Breast Cancer Res. Treat.
122 (1) (2010) 237–242.
[80] E. Floriano-Sanchez, et al., CYP3A4 expression in breast cancer and its association with
risk factors in Mexican women, Asian Pac. J. Cancer Prev. 15 (8) (2014) 3805–3809.
[81] Z. Huang, et al., Expression of cytochromes P450 in human breast tissue and tumors,
Drug Metab. Dispos. 24 (8) (1996) 899–905.
[82] R. Mitra, et al., CYP3A4 mediates growth of estrogen receptor-positive breast cancer
cells in part by inducing nuclear translocation of phospho-Stat3 through biosynthesis
of (+/)-14,15-epoxyeicosatrienoic acid (EET), J. Biol. Chem. 286 (20) (2011)
17543–17559.
[83] A. Tervasmaki, et al., Recurrent CYP2C19 deletion allele is associated with triple-
negative breast cancer, BMC Cancer 14 (2014) 902.
[84] C. Justenhoven, et al., CYP2C19*17 is associated with decreased breast cancer risk,
Breast Cancer Res. Treat. 115 (2) (2009) 391–396.
[85] A. Abbas, et al., GSTM1, GSTT1, GSTP1 and CYP1A1 genetic polymorphisms and
susceptibility to esophageal cancer in a French population: different pattern of squa-
mous cell carcinoma and adenocarcinoma, World J. Gastroenterol. 10 (23) (2004)
3389–3393.
[86] A.H. Wang, et al., Genetic susceptibility and environmental factors of esophageal can-
cer in Xi’an, World J. Gastroenterol. 10 (7) (2004) 940–944.
[87] L.D. Wang, et al., CYP1A1, GSTs and mEH polymorphisms and susceptibility to
esophageal carcinoma: study of population from a high-incidence area in north China,
World J. Gastroenterol. 9 (7) (2003) 1394–1397.
125CYP450 in Cancer Treatment
Author's personal copy
[88] M.T. Wu, et al., Genetic polymorphisms of cytochrome P4501A1 and oesophageal
squamous-cell carcinoma in Taiwan, Br. J. Cancer 87 (5) (2002) 529–532.
[89] A.H. Wang, et al., Relationship of tobacco smoking CYP1A1 GSTM1 gene
polymorphism and esophageal cancer in Xi’an, World J. Gastroenterol. 8 (1) (2002)
49–53.
[90] S. Morita, et al., CYP1A1, CYP2E1 and GSTM1 polymorphisms are not associated
with susceptibility to squamous-cell carcinoma of the esophagus, Int. J. Cancer
71 (2) (1997) 192–195.
[91] M. Jain, et al., CYP1A1 Msp1 T/C polymorphism in esophageal cancer: no association
and risk modulation, Oncol. Res. 16 (9) (2007) 437–443.
[92] F.F. Shen, et al., Association between CYP1A1 polymorphisms and esophageal cancer:
a meta-analysis, Mol. Biol. Rep. 40 (10) (2013) 6035–6042.
[93] F.F. Gong, et al., Cytochrome P450 1A1 (CYP1A1) polymorphism and susceptibility
to esophageal cancer: an updated meta-analysis of 27 studies, Tumour Biol. 35 (10)
(2014) 10351–10361.
[94] W.X. Shi, S.Q. Chen, Frequencies of poor metabolizers of cytochrome P450 2C19 in
esophagus cancer, stomach cancer, lung cancer and bladder cancer in Chinese popu-
lation, World J. Gastroenterol. 10 (13) (2004) 1961–1963.
[95] L. Yao, et al., Quantitative assessment of the influence of cytochrome P450 2C19
gene polymorphisms and digestive tract cancer risk, Tumour Biol. 34 (5) (2013)
3083–3091.
[96] D. Lin, Y. Tang, Q. Peng, Genetic polymorphisms of cytochrome P450 2E1 and glu-
tathione S-transferase P1 and susceptibility to esophageal cancer, Zhonghua Zhong Liu
Za Zhi 20 (2) (1998) 94–97.
[97] D. Li, C. Dandara, M.I. Parker, Association of cytochrome P450 2E1 genetic poly-
morphisms with squamous cell carcinoma of the oesophagus, Clin. Chem. Lab.
Med. 43 (4) (2005) 370–375.
[98] S. Itoga, et al., Tandem repeat polymorphism of the CYP2E1 gene: an association
study with esophageal cancer and lung cancer, Alcohol. Clin. Exp. Res. 26 (8 Suppl.)
(2002) 15S–19S.
[99] C. Dandara, R. Ballo, M.I. Parker, CYP3A5 genotypes and risk of oesophageal cancer
in two South African populations, Cancer Lett. 225 (2) (2005) 275–282.
[100] M.L. Slattery, et al., CYP1A1, cigarette smoking, and colon and rectal cancer, Am. J.
Epidemiol. 160 (9) (2004) 842–852.
[101] C. Sachse, et al., A pharmacogenetic study to investigate the role of dietary carcinogens
in the etiology of colorectal cancer, Carcinogenesis 23 (11) (2002) 1839–1849.
[102] S. Landi, et al., A comprehensive analysis of phase I and phase II metabolism gene poly-
morphisms and risk of colorectal cancer, Pharmacogenet. Genomics 15 (8) (2005)
535–546.
[103] G.J. Tranah, et al., Epoxide hydrolase and CYP2C9 polymorphisms, cigarette
smoking, and risk of colorectal carcinoma in the Nurses’ Health Study and the Phy-
sicians’ Health Study, Mol. Carcinog. 44 (1) (2005) 21–30.
[104] C. Martinez, et al., Association of CYP2C9 genotypes leading to high enzyme activity
and colorectal cancer risk, Carcinogenesis 22 (8) (2001) 1323–1326.
[105] L.E. McGreavey, et al., No evidence that polymorphisms in CYP2C8, CYP2C9,
UGT1A6, PPARdelta and PPARgamma act as modifiers of the protective effect of
regular NSAID use on the risk of colorectal carcinoma, Pharmacogenet. Genomics
15 (10) (2005) 713–721.
[106] H. Wang, et al., Association between cytochrome P450 2C9 gene polymorphisms and
colorectal cancer susceptibility: evidence from 16 case-control studies, Tumour Biol.
35 (5) (2014) 4317–4322.
126 Balraj Mittal et al.
Author's personal copy
[107] I. Kiss, et al., Colorectal cancer risk in relation to genetic polymorphism of cytochrome
P450 1A1, 2E1, and glutathione-S-transferase M1 enzymes, Anticancer Res. 20 (1B)
(2000) 519–522.
[108] E.M. van der Logt, et al., Role of epoxide hydrolase, NAD(P)H:quinone oxidoreduc-
tase, cytochrome P450 2E1 or alcohol dehydrogenase genotypes in susceptibility to
colorectal cancer, Mutat. Res. 593 (1–2) (2006) 39–49.
[109] O. Jiang, et al., CYP2E1 polymorphisms and colorectal cancer risk: a HuGE systematic
review and meta-analysis, Tumour Biol. 34 (2) (2013) 1215–1224.
[110] A. Srivastava, et al., Role of genetic variant A-204C of cholesterol 7alpha-hydroxylase
(CYP7A1) in susceptibility to gallbladder cancer, Mol. Genet. Metab. 94 (1) (2008)
83–89.
[111] S.N. Pandey, G. Choudhuri, B. Mittal, Association of CYP1A1 Msp1 polymorphism
with tobacco-related risk of gallbladder cancer in a north Indian population, Eur. J.
Cancer Prev. 17 (2) (2008) 77–81.
[112] K.L. Sharma, et al., Association of genetic variants of xenobiotic and estrogen metab-
olism pathway (CYP1A1 and CYP1B1) with gallbladder cancer susceptibility,
Tumour Biol. 35 (6) (2014) 5431–5439.
[113] Y. Tsuchiya, et al., Evidence that genetic variants of metabolic detoxication and cell
cycle control are not related to gallbladder cancer risk in Chilean women, Int. J. Biol.
Markers 25 (2) (2010) 75–78.
[114] A. Kimura, et al., Effect of genetic predisposition on the risk of gallbladder cancer in
Hungary, Asian Pac. J. Cancer Prev. 9 (3) (2008) 391–396.
[115] Y. Tsuchiya, et al., Polymorphisms of cytochrome P450 1A1, glutathione S-transferase
class mu, and tumour protein p53 genes and the risk of developing gallbladder cancer in
Japanese, Clin. Biochem. 40 (12) (2007) 881–886.
[116] K. Srivastava, et al., Candidate gene studies in gallbladder cancer: a systematic review
and meta-analysis, Mutat. Res. 728 (1–2) (2011) 67–79.
[117] R. Rai, et al., CYP17 polymorphism (rs743572) is associated with increased risk of
gallbladder cancer in tobacco users, Tumour Biol. 35 (7) (2014) 6531–6537.
[118] M.W. Yu, et al., Cytochrome P450 1A1 genetic polymorphisms and risk of hepato-
cellular carcinoma among chronic hepatitis B carriers, Br. J. Cancer 80 (3–4) (1999)
598–603.
[119] L. Silvestri, et al., CYP enzyme polymorphisms and susceptibility to HCV-related
chronic liver disease and liver cancer, Int. J. Cancer 104 (3) (2003) 310–317.
[120] J.A. Agundez, et al., CYP2D6 genes and risk of liver cancer, Lancet 345 (8953) (1995)
830–831.
[121] M. Munaka, et al., Genetic polymorphisms of tobacco- and alcohol-related metabo-
lizing enzymes and the risk of hepatocellular carcinoma, J. Cancer Res. Clin. Oncol.
129 (6) (2003) 355–360.
[122] M.W. Yu, et al., Cytochrome P450 2E1 and glutathione S-transferase M1 polymor-
phisms and susceptibility to hepatocellular carcinoma, Gastroenterology 109 (4) (1995)
1266–1273.
[123] H.E. Blum, Hepatocellular carcinoma: susceptibility markers, IARC Sci. Publ.
154 (2001) 241–244.
[124] T.T. Sreelekha, et al., Genetic polymorphism of CYP1A1, GSTM1 and GSTT1 genes
in Indian oral cancer, Oral Oncol. 37 (7) (2001) 593–598.
[125] M. Sato, et al., Genetically high susceptibility to oral squamous cell carcinoma in terms
of combined genotyping of CYP1A1 and GSTM1 genes, Oral Oncol. 36 (3) (2000)
267–271.
[126] J.Y. Park, et al., CYP1A1 and GSTM1 polymorphisms and oral cancer risk, Cancer
Epidemiol. Biomarkers Prev. 6 (10) (1997) 791–797.
127CYP450 in Cancer Treatment
Author's personal copy
[127] A.F. Olshan, et al., GSTM1, GSTT1, GSTP1, CYP1A1, and NAT1 polymorphisms,
tobacco use, and the risk of head and neck cancer, Cancer Epidemiol. Biomarkers
Prev. 9 (2) (2000) 185–191.
[128] M. Gajecka, et al., CYP1A1, CYP2D6, CYP2E1, NAT2, GSTM1 and GSTT1 poly-
morphisms or their combinations are associated with the increased risk of the laryngeal
squamous cell carcinoma, Mutat. Res. 574 (1–2) (2005) 112–123.
[129] E. Reszka, et al., Relevance of glutathione S-transferase M1 and cytochrome P450
1A1 genetic polymorphisms to the development of head and neck cancers, Clin.
Chem. Lab. Med. 46 (8) (2008) 1090–1096.
[130] L. Liu, et al., Functional CYP1A1 genetic variants, alone and in combination with
smoking, contribute to development of head and neck cancers, Eur. J. Cancer
49 (9) (2013) 2143–2151.
[131] X. Zhuo, et al., Cytochrome P450 1A1 Ile462Val polymorphism and oral carcinoma
risk: an updated meta-analysis including 1,515 cases and 2,233 controls, Tumour Biol.
33 (6) (2012) 2079–2089.
[132] A.P. Singh, et al., Polymorphism in cytochrome P4501A1 is significantly associated
with head and neck cancer risk, Cancer Investig. 27 (8) (2009) 869–876.
[133] E.H. Olivieri, et al., CYP1A2*1C, CYP2E1*5B, and GSTM1 polymorphisms are
predictors of risk and poor outcome in head and neck squamous cell carcinoma
patients, Oral Oncol. 45 (9) (2009) e73–e79.
[134] G.J. Gattas, et al., Genetic polymorphisms of CYP1A1, CYP2E1, GSTM1, and
GSTT1 associated with head and neck cancer, Head Neck 28 (9) (2006) 819–826.
[135] K. Tanimoto, et al., Polymorphisms of the CYP1A1 and GSTM1 gene involved in
oral squamous cell carcinoma in association with a cigarette dose, Oral Oncol.
35 (2) (1999) 191–196.
[136] A.P. Singh, et al., Genetic polymorphisms in cytochrome P4501B1 and susceptibility
to head and neck cancer, Mutat. Res. 639 (1–2) (2008) 11–19.
[137] Y. Ko, et al., Association of CYP1B1 codon 432 mutant allele in head and neck squa-
mous cell cancer is reflected by somatic mutations of p53 in tumor tissue, Cancer Res.
61 (11) (2001) 4398–4404.
[138] G. Li, et al., CYP2E1 G1532C, NQO1 Pro187Ser, and CYP1B1 Val432Leu poly-
morphisms are not associated with risk of squamous cell carcinoma of the head and
neck, Cancer Epidemiol. Biomarkers Prev. 14 (4) (2005) 1034–1036.
[139] C. Matthias, et al., Polymorphism in cytochrome P450 CYP2D6, CYP1A1, CYP2E1
and glutathione S-transferase, GSTM1, GSTM3, GSTT1 and susceptibility to
tobacco-related cancers: studies in upper aerodigestive tract cancers,
Pharmacogenetics 8 (2) (1998) 91–100.
[140] C. Matthias, et al., Cyclin D1, glutathione S-transferase, and cytochrome P450 geno-
types and outcome in patients with upper aerodigestive tract cancers: assessment of the
importance of individual genes using multivariate analysis, Cancer Epidemiol. Bio-
markers Prev. 8 (9) (1999) 815–823.
[141] M.V. Gonzalez, et al., Genetic polymorphism of N-acetyltransferase-2, glutathione
S-transferase-M1, and cytochromes P450IIE1 and P450IID6 in the susceptibility to
head and neck cancer, J. Clin. Pathol. 51 (4) (1998) 294–298.
[142] S.S. Yadav, et al., Interaction of drug metabolizing cytochrome P450 2D6 poor
metabolizers with cytochrome P450 2C9 and 2C19 genotypes modify the susceptibil-
ity to head and neck cancer and treatment response, Mutat. Res. 684 (1–2) (2010)
49–55.
[143] J.A. Agundez, et al., Functionally active duplications of the CYP2D6 gene are more
prevalent among larynx and lung cancer patients, Oncology 61 (1) (2001) 59–63.
[144] V. Jahnke, et al., Glutathione S-transferase and cytochrome-P-450 polymorphism as
risk factors for squamous cell carcinoma of the larynx, Am. J. Surg. 172 (6) (1996)
671–673.
128 Balraj Mittal et al.
Author's personal copy
[145] N.M. Cury, et al., Polymorphisms of the CYP1A1 and CYP2E1 genes in head and
neck squamous cell carcinoma risk, Mol. Biol. Rep. 39 (2) (2012) 1055–1063.
[146] L. Balaji, K.B. Singh, L.V. Bhaskar, Genetic polymorphisms of the CYP2E1 gene do
not contribute to oral cancer susceptibility in south Indians, Asian Pac. J. Cancer Prev.
12 (6) (2011) 1523–1527.
[147] J. Tai, et al., Genetic polymorphisms in cytochrome P450 genes are associated with an
increased risk of squamous cell carcinoma of the larynx and hypopharynx in a Chinese
population, Cancer Genet. Cytogenet. 196 (1) (2010) 76–82.
[148] T. Ho, Q. Wei, E.M. Sturgis, Epidemiology of carcinogen metabolism genes and risk
of squamous cell carcinoma of the head and neck, Head Neck 29 (7) (2007) 682–699.
[149] C.F. Marques, et al., Influence of CYP1A1, CYP2E1, GSTM3 and NAT2 genetic
polymorphisms in oral cancer susceptibility: results from a case–control study in
Rio de Janeiro, Oral Oncol. 42 (6) (2006) 632–637.
[150] S. Morita, et al., Genetic polymorphisms of drug-metabolizing enzymes and suscep-
tibility to head-and-neck squamous-cell carcinoma, Int. J. Cancer 80 (5) (1999)
685–688.
[151] T. Kawashiro, et al., A study on the metabolism of etoposide and possible interactions
with antitumor or supporting agents by human liver microsomes, J. Pharmacol. Exp.
Ther. 286 (3) (1998) 1294–1300.
[152] D. Lu, X. Yu, Y. Du, Meta-analyses of the effect of cytochrome P450 2E1 gene poly-
morphism on the risk of head and neck cancer, Mol. Biol. Rep. 38 (4) (2011)
2409–2416.
[153] X.R. Yang, et al., CYP1A1 and GSTM1 polymorphisms in relation to lung cancer risk
in Chinese women, Cancer Lett. 214 (2) (2004) 197–204.
[154] O. Ozturk, et al., GST M1 and CYP1A1 gene polymorphism and daily fruit consump-
tion in Turkish patients with non-small cell lung carcinomas, In Vivo 17 (6) (2003)
625–632.
[155] N. Song, et al., CYP 1A1 polymorphism and risk of lung cancer in relation to tobacco
smoking: a case–control study in China, Carcinogenesis 22 (1) (2001) 11–16.
[156] X. Xu, et al., Cytochrome P450 CYP1A1 MspI polymorphism and lung cancer sus-
ceptibility, Cancer Epidemiol. Biomarkers Prev. 5 (9) (1996) 687–692.
[157] K. Nakachi, et al., Association of cigarette smoking and CYP1A1 polymorphisms with
adenocarcinoma of the lung by grades of differentiation, Carcinogenesis 16 (9) (1995)
2209–2213.
[158] H. Sugimura, et al., CYP1A1 and CYP2E1 polymorphism and lung cancer, case–
control study in Rio de Janeiro, Brazil, Pharmacogenetics 5 (Spec No) (1995)
S145–S148.
[159] K. Nakachi, et al., Polymorphisms of the CYP1A1 and glutathione S-transferase genes
associated with susceptibility to lung cancer in relation to cigarette dose in a Japanese
population, Cancer Res. 53 (13) (1993) 2994–2999.
[160] X. Shi, et al., CYP1A1 and GSTM1 polymorphisms and lung cancer risk in Chinese
populations: a meta-analysis, Lung Cancer 59 (2) (2008) 155–163.
[161] M. Kumar, S.K. Agarwal, S.K. Goel, Lung cancer risk in north Indian population:
role of genetic polymorphisms and smoking, Mol. Cell. Biochem. 322 (1–2) (2009)
73–79.
[162] W. Tan, et al., Frequency of CYP2A6 gene deletion and its relation to risk of lung and
esophageal cancer in the Chinese population, Int. J. Cancer 95 (2) (2001) 96–101.
[163] T. Kamataki, et al., Genetic polymorphism of CYP2A6 in relation to cancer, Mutat.
Res. 428 (1–2) (1999) 125–130.
[164] M. Miyamoto, et al., CYP2A6 gene deletion reduces susceptibility to lung cancer,
Biochem. Biophys. Res. Commun. 261 (3) (1999) 658–660.
[165] G.S. Hamada, et al., The heme-binding region polymorphism of cytochrome
P450IA1 (CypIA1), rather than the RsaI polymorphism of IIE1 (CypIIE1), is
129CYP450 in Cancer Treatment
Author's personal copy
associated with lung cancer in Rio de Janeiro, Cancer Epidemiol. Biomarkers Prev.
4 (1) (1995) 63–67.
[166] A. Hirvonen, et al., The human CYP2E1 gene and lung cancer: DraI and RsaI restric-
tion fragment length polymorphisms in a Finnish study population, Carcinogenesis
14 (1) (1993) 85–88.
[167] S. Kato, et al., Cytochrome P450IIE1 genetic polymorphisms, racial variation, and
lung cancer risk, Cancer Res. 52 (23) (1992) 6712–6715.
[168] R.C. Sobti, et al., Genetic polymorphism of the CYP1A1, CYP2E1, GSTM1 and
GSTT1 genes and lung cancer susceptibility in a north Indian population, Mol. Cell.
Biochem. 266 (1–2) (2004) 1–9.
[169] J. Watanabe, et al., An Rsa I polymorphism in the CYP2E1 gene does not
affect lung cancer risk in a Japanese population, Jpn. J. Cancer Res. 86 (3) (1995)
245–248.
[170] X. Wu, et al., Cytochrome P450 2E1 DraI polymorphisms in lung cancer in minority
populations, Cancer Epidemiol. Biomarkers Prev. 7 (1) (1998) 13–18.
[171] F. Uematsu, et al., Human cytochrome P450IIE1 gene: DraI polymorphism and sus-
ceptibility to cancer, Tohoku J. Exp. Med. 168 (2) (1992) 113–117.
[172] H. Dally, et al., The CYP3A4*1B allele increases risk for small cell lung cancer: effect
of gender and smoking dose, Pharmacogenetics 13 (10) (2003) 607–618.
[173] K.T. Yeh, et al., CYP3A5*1 is an inhibitory factor for lung cancer in Taiwanese,
Kaohsiung J. Med. Sci. 19 (5) (2003) 201–207.
[174] J. Jakobsson, et al., A functional C-G polymorphism in the CYP7B1 promoter region
and its different distribution in Orientals and Caucasians, Pharmacogenomics J. 4 (4)
(2004) 245–250.
[175] A. Gsur, E. Feik, S. Madersbacher, Genetic polymorphisms and prostate cancer risk,
World J. Urol. 21 (6) (2004) 414–423.
[176] B.L. Chang, et al., Polymorphisms in the CYP1B1 gene are associated with increased
risk of prostate cancer, Br. J. Cancer 89 (8) (2003) 1524–1529.
[177] K. Suzuki, et al., Genetic polymorphisms of estrogen receptor alpha, CYP19,
catechol-O-methyltransferase are associated with familial prostate carcinoma risk in
a Japanese population, Cancer 98 (7) (2003) 1411–1416.
[178] Y. Tanaka, et al., Polymorphisms of the CYP1B1 gene have higher risk for prostate
cancer, Biochem. Biophys. Res. Commun. 296 (4) (2002) 820–826.
[179] M. Wadelius, et al., Prostate cancer associated with CYP17 genotype,
Pharmacogenetics 9 (5) (1999) 635–639.
[180] K. Suzuki, et al., Association of the genetic polymorphism in cytochrome P450 (CYP)
1A1 with risk of familial prostate cancer in a Japanese population: a case–control study,
Cancer Lett. 195 (2) (2003) 177–183.
[181] M. Murata, et al., Genetic polymorphisms in cytochrome P450 (CYP) 1A1, CYP1A2,
CYP2E1, glutathione S-transferase (GST) M1 and GSTT1 and susceptibility to pros-
tate cancer in the Japanese population, Cancer Lett. 165 (2) (2001) 171–177.
[182] M. Wadelius, et al., Polymorphisms in NAT2, CYP2D6, CYP2C19 and GSTP1 and
their association with prostate cancer, Pharmacogenetics 9 (3) (1999) 333–340.
[183] C. Li, et al., Cytochrome P1B1 (CYP1B1) polymorphisms and cancer risk: a meta-
analysis of 52 studies, Toxicology 327 (2015) 77–86.
[184] A. Loukola, et al., Comprehensive evaluation of the association between prostate can-
cer and genotypes/haplotypes in CYP17A1, CYP3A4, and SRD5A2, Eur. J. Hum.
Genet. 12 (4) (2004) 321–332.
[185] M.T. Tayeb, et al., CYP3A4 promoter variant is associated with prostate cancer risk in
men with benign prostate hyperplasia, Oncol. Rep. 9 (3) (2002) 653–655.
[186] L.P. Zhou, et al., CYP3A4*1B polymorphism and cancer risk: a HuGE review and
meta-analysis, Tumour Biol. 34 (2) (2013) 649–660.
130 Balraj Mittal et al.
Author's personal copy
[187] C. Zeigler-Johnson, et al., CYP3A4, CYP3A5, and CYP3A43 genotypes and haplo-
types in the etiology and severity of prostate cancer, Cancer Res. 64 (22) (2004)
8461–8467.
[188] R.A. Kittles, et al., Cyp17 promoter variant associated with prostate cancer aggressive-
ness in African Americans, Cancer Epidemiol. Biomarkers Prev. 10 (9) (2001) 943–947.
[189] Y. Yamada, et al., Impact of genetic polymorphisms of 17-hydroxylase cytochrome
P-450 (CYP17) and steroid 5alpha-reductase type II (SRD5A2) genes on prostate-
cancer risk among the Japanese population, Int. J. Cancer 92 (5) (2001) 683–686.
[190] A. Gsur, et al., A polymorphism in the CYP17 gene is associated with prostate cancer
risk, Int. J. Cancer 87 (3) (2000) 434–437.
[191] R.M. Lunn, et al., Prostate cancer risk and polymorphism in 17 hydroxylase (CYP17)
and steroid reductase (SRD5A2), Carcinogenesis 20 (9) (1999) 1727–1731.
[192] T. Habuchi, et al., Increased risk of prostate cancer and benign prostatic hyperplasia
associated with a CYP17 gene polymorphism with a gene dosage effect, Cancer
Res. 60 (20) (2000) 5710–5713.
[193] C. Ntais, A. Polycarpou, J.P. Ioannidis, Association of the CYP17 gene polymorphism
with the risk of prostate cancer: a meta-analysis, Cancer Epidemiol. Biomarkers Prev.
12 (2) (2003) 120–126.
[194] K. Suzuki, et al., Association of the genetic polymorphism of the CYP19 intron
4[TTTA]n repeat with familial prostate cancer risk in a Japanese population, Anticancer
Res. 23 (6D) (2003) 4941–4946.
[195] S. Yao, et al., Gene polymorphisms in cyclophosphamide metabolism pathway,
treatment-related toxicity, and disease-free survival in SWOG 8897 clinical trial for
breast cancer, Clin. Cancer Res. 16 (24) (2010) 6169–6176.
[196] S. Boccia, et al., CYP2E1PstI/RsaI polymorphism and interaction with tobacco, alco-
hol and GSTs in gastric cancer susceptibility: A meta-analysis of the literature,
Carcinogenesis 28 (1) (2007) 101–106.
[197] M.S. Wu, et al., Genetic polymorphisms of cytochrome p450 2E1, glutathione
S-transferase M1 and T1, and susceptibility to gastric carcinoma in Taiwan, Int. J.
Color. Dis. 17 (5) (2002) 338–343.
[198] G.T. Park, et al., Analysis of CYP2E1 polymorphism for the determination of genetic
susceptibility to gastric cancer in Koreans, J. Gastroenterol. Hepatol. 18 (11) (2003)
1257–1263.
[199] I.N. Nishimoto, et al., Cytochrome P450 2E1 polymorphism in gastric cancer in Bra-
zil: case–control studies of Japanese Brazilians and non-Japanese Brazilians, Cancer
Epidemiol. Biomarkers Prev. 9 (7) (2000) 675–680.
[200] S. Kato, et al., Cytochrome P4502E1 (CYP2E1) genetic polymorphism in a case–
control study of gastric cancer and liver disease, Pharmacogenetics 5 (Spec No)
(1995) S141–S144.
[201] M. Malakar, et al., CYP2E1 genetic polymorphism with dietary, tobacco, alcohol
habits, H. pylori infection status and susceptibility to stomach cancer in Mizoram, India,
Asian Pac. J. Cancer Prev. 15 (20) (2014) 8815–8822.
[202] W. Zhuo, et al., CYP2E1 RsaI/PstI polymorphism and gastric cancer susceptibility:
meta-analyses based on 24 case–control studies, PLoS One 7 (11) (2012) e48265.
[203] M.J. Roth, et al., Polymorphic variation of Cyp1A1 is associated with the risk of gastric
cardia cancer: a prospective case-cohort study of cytochrome P-450 1A1 and GST
enzymes, Cancer Causes Control 15 (10) (2004) 1077–1083.
[204] H. Xue, et al., The effect of CYP1A1 and CYP1A2 polymorphisms on gastric cancer
risk among different ethnicities: a systematic review and meta-analysis, Tumour Biol.
35 (5) (2014) 4741–4756.
[205] H. Tsukino, et al., Effects of cytochrome P450 (CYP) 2A6 gene deletion and CYP2E1
genotypes on gastric adenocarcinoma, Int. J. Cancer 100 (4) (2002) 425–428.
131CYP450 in Cancer Treatment
Author's personal copy
[206] U. Ghoshal, et al., Genetic polymorphism of cytochrome P450 (CYP) 1A1, CYP1A2,
and CYP2E1 genes modulate susceptibility to gastric cancer in patients with
Helicobacter pylori infection, Gastric Cancer 17 (2) (2014) 226–234.
[207] M. Sankhwar, S.N. Sankhwar, Variations in CYP isoforms and bladder cancer: a
superfamily paradigm, Urol. Oncol. 32 (1) (2014) 28.e33–28.e40.
[208] X.D. Deng, et al., Functional RsaI/PstI polymorphism in cytochrome P450 2E1 con-
tributes to bladder cancer susceptibility: evidence from a meta-analysis, Asian Pac. J.
Cancer Prev. 15 (12) (2014) 4977–4982.
[209] Y. Lu, et al., Lack of association between CYP1A1 polymorphisms and risk of bladder
cancer: a meta-analysis, Asian Pac. J. Cancer Prev. 15 (9) (2014) 4071–4077.
[210] W. Jiang, et al., Association of CYP1B1 L432V polymorphism with urinary cancer
susceptibility: a meta-analysis, Diagn. Pathol. 9 (2014) 113.
[211] W. Wen, et al., Cytochrome P450 1B1 and catechol-O-methyltransferase genetic
polymorphisms and breast cancer risk in Chinese women: results from the shanghai
breast cancer study and a meta-analysis, Cancer Epidemiol. Biomarkers Prev. 14 (2)
(2005) 329–335.
[212] F. Hidalgo, et al., Gigantic diverticulum of the colon. A complication of diverticulosis?
Rev. Esp. Enferm. Dig. 80 (2) (1991) 115–118.
[213] J.K. Coller, et al., The influence of CYP2B6, CYP2C9 and CYP2D6 genotypes on
the formation of the potent antioestrogen Z-4-hydroxy-tamoxifen in human liver, Br.
J. Clin. Pharmacol. 54 (2) (2002) 157–167.
[214] Z. Desta, et al., Comprehensive evaluation of tamoxifen sequential biotransformation
by the human cytochrome P450 system in vitro: prominent roles for CYP3A and
CYP2D6, J. Pharmacol. Exp. Ther. 310 (3) (2004) 1062–1075.
[215] Z. Huang, P. Roy, D.J. Waxman, Role of human liver microsomal CYP3A4 and
CYP2B6 in catalyzing N-dechloroethylation of cyclophosphamide and ifosfamide,
Biochem. Pharmacol. 59 (8) (2000) 961–972.
[216] M. Shou, et al., Role of human cytochrome P450 3A4 and 3A5 in the metabolism of
taxotere and its derivatives: enzyme specificity, interindividual distribution and met-
abolic contribution in human liver, Pharmacogenetics 8 (5) (1998) 391–401.
[217] N. Bahadur, et al., CYP2C8 polymorphisms in Caucasians and their relationship with
paclitaxel 6alpha-hydroxylase activity in human liver microsomes, Biochem.
Pharmacol. 64 (11) (2002) 1579–1589.
[218] D. Dai, et al., Polymorphisms in human CYP2C8 decrease metabolism of the antican-
cer drug paclitaxel and arachidonic acid, Pharmacogenetics 11 (7) (2001) 597–607.
[219] R. Chugh, et al., Assessment of ifosfamide pharmacokinetics, toxicity, and relation to
CYP3A4 activity as measured by the erythromycin breath test in patients with sarcoma,
Cancer 109 (11) (2007) 2315–2322.
[220] J. Zhang, et al., Metabolism and transport of oxazaphosphorines and the clinical impli-
cations, Drug Metab. Rev. 37 (4) (2005) 611–703.
[221] K. Maekawa, et al., CYP3A4*16 and CYP3A4*18 alleles found in East Asians exhibit
differential catalytic activities for seven CYP3A4 substrate drugs, Drug Metab. Dispos.
38 (12) (2010) 2100–2104.
[222] M.H. Cohen, et al., Approval summary for imatinib mesylate capsules in the treatment
of chronic myelogenous leukemia, Clin. Cancer Res. 8 (5) (2002) 935–942.
[223] M.S. Shet, et al., Metabolism of the antiandrogenic drug (Flutamide) by human
CYP1A2, Drug Metab. Dispos. 25 (11) (1997) 1298–1303.
[224] M. Schulz, et al., The pharmacokinetics of flutamide and its major metabolites after a
single oral dose and during chronic treatment, Eur. J. Clin. Pharmacol. 34 (6) (1988)
633–636.
[225] S. Daigo, et al., A novel mutant allele of the CYP2A6 gene (CYP2A6*11) found in a
cancer patient who showed poor metabolic phenotype towards tegafur,
Pharmacogenetics 12 (4) (2002) 299–306.
132 Balraj Mittal et al.
Author's personal copy
[226] D. McKillop, et al., Cytochrome P450-dependent metabolism of gefitinib,
Xenobiotica 35 (1) (2005) 39–50.
[227] X. Zhuo, et al., Kinetics and regulation of cytochrome P450-mediated etoposide
metabolism, Drug Metab. Dispos. 32 (9) (2004) 993–1000.
[228] M.V. Relling, et al., O-demethylation of epipodophyllotoxins is catalyzed by human
cytochrome P450 3A4, Mol. Pharmacol. 45 (2) (1994) 352–358.
[229] Y. Ando, E. Fuse, W.D. Figg, Thalidomide metabolism by the CYP2C subfamily,
Clin. Cancer Res. 8 (6) (2002) 1964–1973.
[230] J.B. Dennison, et al., Selective metabolism of vincristine in vitro by CYP3A5, Drug
Metab. Dispos. 34 (8) (2006) 1317–1327.
[231] I.N. White, Tamoxifen: is it safe? Comparison of activation and detoxication mech-
anisms in rodents and in humans, Curr. Drug Metab. 4 (3) (2003) 223–239.
[232] S.S. Dehal, D. Kupfer, CYP2D6 catalyzes tamoxifen 4-hydroxylation in human liver,
Cancer Res. 57 (16) (1997) 3402–3406.
[233] V. Stearns, et al., Active tamoxifen metabolite plasma concentrations after
coadministration of tamoxifen and the selective serotonin reuptake inhibitor paroxe-
tine, J. Natl. Cancer Inst. 95 (23) (2003) 1758–1764.
[234] W. Schroth, et al., Breast cancer treatment outcome with adjuvant tamoxifen relative
to patient CYP2D6 and CYP2C19 genotypes, J. Clin. Oncol. 25 (33) (2007)
5187–5193.
[235] M.P. Goetz, et al., The impact of cytochrome P450 2D6 metabolism in women
receiving adjuvant tamoxifen, Breast Cancer Res. Treat. 101 (1) (2007) 113–121.
[236] M.P. Goetz, et al., Pharmacogenetics of tamoxifen biotransformation is associated
with clinical outcomes of efficacy and hot flashes, J. Clin. Oncol. 23 (36) (2005)
9312–9318.
[237] P. Wegman, et al., Genotype of metabolic enzymes and the benefit of tamo-
xifen in postmenopausal breast cancer patients, Breast Cancer Res. 7 (3) (2005)
R284–R290.
[238] Y. Jin, et al., CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during
adjuvant breast cancer treatment, J. Natl. Cancer Inst. 97 (1) (2005) 30–39.
[239] D. Serrano, et al., Efficacy of tamoxifen based on cytochrome P450 2D6, CYP2C19
and SULT1A1 genotype in the Italian Tamoxifen Prevention Trial, Pharmaco-
genomics J. 11 (2) (2011) 100–107.
[240] J.E. Abraham, et al., CYP2D6 gene variants: association with breast cancer specific sur-
vival in a cohort of breast cancer patients from the United Kingdom treated with adju-
vant tamoxifen, Breast Cancer Res. 12 (4) (2010) R64.
[241] C.H. Takimoto, E. Cavlo, Principles of oncologic pharmacotherapy, in: R. Pazdur,
L.R. Coia, W.J. Hoskins, et al. (Eds.), Cancer Management: A Multidisciplinary
Approach, 11th ed., CMP Healthcare Media, Lawrence, KS, 2005, pp. 11–22.
[242] J. Zhang, et al., Insights into oxazaphosphorine resistance and possible approaches to its
circumvention, Drug Resist. Updat. 8 (5) (2005) 271–297.
[243] S. Ren, et al., Oxidation of cyclophosphamide to 4-hydroxycyclophosphamide and
deschloroethylcyclophosphamide
in human liver microsomes, Cancer Res. 57 (19) (1997) 4229–4235.
[244] P. Roy, et al., Development of a substrate-activity based approach to identify the major
human liver P-450 catalysts of cyclophosphamide and ifosfamide activation based on
cDNA-expressed activities and liver microsomal P-450 profiles, Drug Metab. Dispos.
27 (6) (1999) 655–666.
[245] T.K. Chang, et al., Differential activation of cyclophosphamide and ifosphamide by
cytochromes P-450 2B and 3A in human liver microsomes, Cancer Res. 53 (23)
(1993) 5629–5637.
[246] M. Whirl-Carrillo, et al., Pharmacogenomics knowledge for personalized medicine,
Clin. Pharmacol. Ther. 92 (4) (2012) 414–417.
133CYP450 in Cancer Treatment
Author's personal copy
[247] T.K. Chang, et al., Identification of the polymorphically expressed CYP2C19 and the
wild-type CYP2C9-ILE359 allele as low-Km catalysts of cyclophosphamide and
ifosfamide activation, Pharmacogenetics 7 (3) (1997) 211–221.
[248] C. Rodriguez-Antona, M. Ingelman-Sundberg, Cytochrome P450 pharmacogenetics
and cancer, Oncogene 25 (11) (2006) 1679–1691.
[249] N.E. Sladek, Metabolism of oxazaphosphorines, Pharmacol. Ther. 37 (3) (1988)
301–355.
[250] V.L. Boyd, et al., 31P nuclear magnetic resonance spectroscopic observation of the
intracellular transformations of oncostatic cyclophosphamide metabolites, J. Med.
Chem. 29 (7) (1986) 1206–1210.
[251] A.D. Huitema, et al., The clinical pharmacology of alkylating agents in high-dose che-
motherapy, Anti-Cancer Drugs 11 (7) (2000) 515–533.
[252] A. DeMichele, et al., In response to “Drug metabolizing enzyme polymorphisms
predict clinical outcome in a node-positive breast cancer cohort”, J. Clin. Oncol.
25 (35) (2007) 5675–5677.
[253] W.P. Petros, et al., Associations between drug metabolism genotype, chemotherapy
pharmacokinetics, and overall survival in patients with breast cancer, J. Clin. Oncol.
23 (25) (2005) 6117–6125.
[254] P.P. Gor, et al., Cyclophosphamide-metabolizing enzyme polymorphisms and survival
outcomes after adjuvant chemotherapy for node-positive breast cancer: a retrospective
cohort study, Breast Cancer Res. 12 (3) (2010) R26.
[255] J. Bray, et al., Influence of pharmacogenetics on response and toxicity in breast cancer
patients treated with doxorubicin and cyclophosphamide, Br. J. Cancer 102 (6) (2010)
1003–1009.
[256] H.J. Xie, et al., Role of polymorphic human CYP2B6 in cyclophosphamide
bioactivation, Pharmacogenomics J. 3 (1) (2003) 53–61.
[257] T. Lang, et al., Extensive genetic polymorphism in the human CYP2B6 gene with
impact on expression and function in human liver, Pharmacogenetics 11 (5) (2001)
399–415.
[258] J. Kirchheiner, et al., Bupropion and 4-OH-bupropion pharmacokinetics in relation
to genetic polymorphisms in CYP2B6, Pharmacogenetics 13 (10) (2003) 619–626.
[259] M. Rotger, et al., Influence of CYP2B6 polymorphism on plasma and intracellular
concentrations and toxicity of efavirenz and nevirapine in HIV-infected patients,
Pharmacogenet. Genomics 15 (1) (2005) 1–5.
[260] S. Rodriguez-Novoa, et al., Influence of 516G>T polymorphisms at the gene
encoding the CYP450-2B6 isoenzyme on efavirenz plasma concentrations in HIV-
infected subjects, Clin. Infect. Dis. 40 (9) (2005) 1358–1361.
[261] R. Timm, et al., Association of cyclophosphamide pharmacokinetics to polymorphic
cytochrome P450 2C19, Pharmacogenomics J. 5 (6) (2005) 365–373.
[262] L. Griskevicius, et al., Bioactivation of cyclophosphamide: the role of polymorphic
CYP2C enzymes, Eur. J. Clin. Pharmacol. 59 (2) (2003) 103–109.
[263] S. Tulsyan, et al., Significant role of CYP450 genetic variants in cyclophosphamide
based breast cancer treatment outcomes: a multi-analytical strategy, Clin. Chim. Acta
434 (2014) 21–28.
[264] S.D. Baker, A. Sparreboom, J. Verweij, Clinical pharmacokinetics of docetaxel: recent
developments, Clin. Pharmacokinet. 45 (3) (2006) 235–252.
[265] A. Tran, et al., Pharmacokinetics and toxicity of docetaxel: role of CYP3A, MDR1,
and GST polymorphisms, Clin. Pharmacol. Ther. 79 (6) (2006) 570–580.
[266] N. Yamamoto, et al., Randomized pharmacokinetic and pharmacodynamic study of
docetaxel: dosing based on body-surface area compared with individualized dosing
based on cytochrome P450 activity estimated using a urinary metabolite of exogenous
cortisol, J. Clin. Oncol. 23 (6) (2005) 1061–1069.
134 Balraj Mittal et al.
Author's personal copy
[267] S.D. Baker, et al., Relationship of systemic exposure to unbound docetaxel and neu-
tropenia, Clin. Pharmacol. Ther. 77 (1) (2005) 43–53.
[268] B.C. Goh, et al., Explaining interindividual variability of docetaxel pharmacokinetics
and pharmacodynamics in Asians through phenotyping and genotyping strategies,
J. Clin. Oncol. 20 (17) (2002) 3683–3690.
[269] S.D. Baker, et al., Comparative pharmacokinetics of weekly and every-three-weeks
docetaxel, Clin. Cancer Res. 10 (6) (2004) 1976–1983.
[270] S.D. Baker, et al., Pharmacogenetic pathway analysis of docetaxel elimination, Clin.
Pharmacol. Ther. 85 (2) (2009) 155–163.
[271] T.M. Bosch, et al., Pharmacogenetic screening of CYP3A and ABCB1 in relation to
population pharmacokinetics of docetaxel, Clin. Cancer Res. 12 (19) (2006)
5786–5793.
[272] M. Schirmer, et al., Genetic signature consistent with selection against the
CYP3A4*1B allele in non-African populations, Pharmacogenet. Genomics 16 (1)
(2006) 59–71.
[273] E. Hustert, et al., The genetic determinants of the CYP3A5 polymorphism,
Pharmacogenetics 11 (9) (2001) 773–779.
[274] P. Kuehl, et al., Sequence diversity in CYP3A promoters and characterization of the
genetic basis of polymorphic CYP3A5 expression, Nat. Genet. 27 (4) (2001) 383–391.
[275] S.M. Tsai, et al., Side effects after docetaxel treatment in Taiwanese breast cancer
patients with CYP3A4, CYP3A5, and ABCB1 gene polymorphisms, Clin. Chim.
Acta 404 (2) (2009) 160–165.
[276] J. Spratlin, M.B. Sawyer, Pharmacogenetics of paclitaxel metabolism, Crit. Rev.
Oncol. Hematol. 61 (3) (2007) 222–229.
[277] M. Markman, Managing taxane toxicities, Support. Care Cancer 11 (3) (2003)
144–147.
[278] A. Henningsson, et al., Association of CYP2C8, CYP3A4, CYP3A5, and ABCB1
polymorphisms with the pharmacokinetics of paclitaxel, Clin. Cancer Res. 11 (22)
(2005) 8097–8104.
[279] T. Ajithkumar, et al., Ifosfamide encephalopathy, Clin. Oncol. (R. Coll. Radiol.)
19 (2) (2007) 108–114.
[280] Y.J. Shin, et al., Fatal Ifosfamide-induced metabolic encephalopathy in patients with
recurrent epithelial ovarian cancer: report of two cases, Cancer Res. Treat. 43 (4)
(2011) 260–263.
[281] D. Wang, et al., The role of constitutive androstane receptor in oxazaphosphorine-
mediated induction of drug-metabolizing enzymes in human hepatocytes, Pharm.
Res. 28 (8) (2011) 2034–2044.
[282] P. Hingorani, et al., Preclinical activity of palifosfamide lysine (ZIO-201) in pediatric
sarcomas including oxazaphosphorine-resistant osteosarcoma, Cancer Chemother.
Pharmacol. 64 (4) (2009) 733–740.
[283] H. Wang, L.M. Tompkins, CYP2B6: new insights into a historically overlooked cyto-
chrome P450 isozyme, Curr. Drug Metab. 9 (7) (2008) 598–610.
[284] E.L. Zaki, J.E. Springate, M. Taub, Comparative toxicity of ifosfamide metabolites and
protective effect of mesna and amifostine in cultured renal tubule cells, Toxicol. In
Vitro 17 (4) (2003) 397–402.
[285] D. Walker, et al., Identification of the major human hepatic cytochrome P450
involved in activation and N-dechloroethylation of ifosfamide, Biochem. Pharmacol.
47 (7) (1994) 1157–1163.
[286] J.S. McCune, et al., Contribution of CYP3A5 to hepatic and renal ifosfamide
N-dechloroethylation, Drug Metab. Dispos. 33 (7) (2005) 1074–1081.
[287] N.F. Smith, W.D. Figg, A. Sparreboom, Pharmacogenetics of irinotecan metabolism
and transport: an update, Toxicol. In Vitro 20 (2) (2006) 163–175.
135CYP450 in Cancer Treatment
Author's personal copy
[288] E. Levesque, et al., Refining the UGT1A haplotype associated with irinotecan-
induced hematological toxicity in metastatic colorectal cancer patients treated with
5-fluorouracil/irinotecan-based regimens, J. Pharmacol. Exp. Ther. 345 (1) (2013)
95–101.
[289] X. Liu, et al., Association between UGT1A1*28 polymorphisms and clinical outcomes
of irinotecan-based chemotherapies in colorectal cancer: a meta-analysis in Caucasians,
PLoS One 8 (3) (2013) e58489.
[290] Y. Pommier, et al., DNA topoisomerases and their poisoning by anticancer and
antibacterial drugs, Chem. Biol. 17 (5) (2010) 421–433.
[291] R.H. Mathijssen, et al., Clinical pharmacokinetics and metabolism of irinotecan
(CPT-11), Clin. Cancer Res. 7 (8) (2001) 2182–2194.
[292] A. Santos, et al., Metabolism of irinotecan (CPT-11) by CYP3A4 and CYP3A5 in
humans, Clin. Cancer Res. 6 (5) (2000) 2012–2020.
[293] M.C. Haaz, et al., Biosynthesis of an aminopiperidino metabolite of irinotecan
[7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecine] by human
hepatic microsomes, Drug Metab. Dispos. 26 (8) (1998) 769–774.
[294] M.C. Haaz, et al., Metabolism of irinotecan (CPT-11) by human hepatic microsomes:
participation of cytochrome P-450 3A and drug interactions, Cancer Res. 58 (3)
(1998) 468–472.
[295] J.Y. Han, et al., Integrated pharmacogenetic prediction of irinotecan pharmacokinetics
and toxicity in patients with advanced non-small cell lung cancer, Lung Cancer 63 (1)
(2009) 115–120.
[296] F.A. de Jong, et al., ABCG2 pharmacogenetics: ethnic differences in allele frequency
and assessment of influence on irinotecan disposition, Clin. Cancer Res. 10 (17) (2004)
5889–5894.
[297] R.H. Mathijssen, et al., Impact of body-size measures on irinotecan clearance: alter-
native dosing recommendations, J. Clin. Oncol. 20 (1) (2002) 81–87.
[298] Anon, Drugs of choice for cancer, Treat. Guidel. Med. Lett. 1 (7) (2003) 41–52.
[299] J.M. Goldman, J.V. Melo, Chronic myeloid leukemia—advances in biology and new
approaches to treatment, N. Engl. J. Med. 349 (15) (2003) 1451–1464.
[300] K. Isozaki, S. Hirota, Gain-of-function mutations of receptor tyrosine kinases in gas-
trointestinal stromal tumors, Curr. Genomics 7 (8) (2006) 469–475.
[301] S. Hirota, et al., Gain-of-function mutations of c-kit in human gastrointestinal stromal
tumors, Science 279 (5350) (1998) 577–580.
[302] M.A. Siddiqui, L.J. Scott, Imatinib: a review of its use in the management of gastro-
intestinal stromal tumours, Drugs 67 (5) (2007) 805–820.
[303] B. Peng, P. Lloyd, H. Schran, Clinical pharmacokinetics of imatinib, Clin. Pharma-
cokinet. 44 (9) (2005) 879–894.
[304] D.G. Savage, K.H. Antman, Imatinib mesylate—a new oral targeted therapy, N. Engl.
J. Med. 346 (9) (2002) 683–693.
[305] R.F. Frye, et al., Effect of St John’s wort on imatinib mesylate pharmacokinetics, Clin.
Pharmacol. Ther. 76 (4) (2004) 323–329.
[306] P.F. Smith, et al., Induction of imatinib metabolism by hypericum perforatum, Blood
104 (4) (2004) 1229–1230.
[307] A.E. Bolton, et al., Effect of rifampicin on the pharmacokinetics of imatinib mesylate
(Gleevec, STI571) in healthy subjects, Cancer Chemother. Pharmacol. 53 (2) (2004)
102–106.
[308] B. Katchen, S. Buxbaum, Disposition of a new, nonsteroid, antiandrogen, alpha, alpha,
alpha-trifluoro-2-methyl-40-nitro-m-propionotoluidide (Flutamide), in men follow-
ing a single oral 200 mg dose, J. Clin. Endocrinol. Metab. 41 (2) (1975) 373–379.
[309] M. Nakajima, et al., Genetic polymorphism in the 50-flanking region of human
CYP1A2 gene: effect on the CYP1A2 inducibility in humans, J. Biochem. 125 (4)
(1999) 803–808.
136 Balraj Mittal et al.
Author's personal copy
[310] D. Allorge, et al., Identification of a novel splice-site mutation in the CYP1A2 gene,
Br. J. Clin. Pharmacol. 56 (3) (2003) 341–344.
[311] N. Murayama, et al., Six novel nonsynonymous CYP1A2 gene polymorphisms: cat-
alytic activities of the naturally occurring variant enzymes, J. Pharmacol. Exp. Ther.
308 (1) (2004) 300–306.
[312] E. Aklillu, et al., Genetic polymorphism of CYP1A2 in Ethiopians affecting induction
and expression: characterization of novel haplotypes with single-nucleotide polymor-
phisms in intron 1, Mol. Pharmacol. 64 (3) (2003) 659–669.
[313] J. Kajita, et al., The contribution of cytochrome P450 to the metabolism of tegafur in
human liver, Drug Metab. Pharmacokinet. 18 (5) (2003) 303–309.
[314] K. Ikeda, et al., Bioactivation of tegafur to 5-fluorouracil is catalyzed by cytochrome
P-450 2A6 in human liver microsomes in vitro, Clin. Cancer Res. 6 (11) (2000)
4409–4415.
[315] G. Tortora, et al., Overcoming resistance to molecularly targeted anticancer therapies:
rational drug combinations based on EGFR and MAPK inhibition for solid tumours
and haematologic malignancies, Drug Resist. Updat. 10 (3) (2007) 81–100.
[316] H.C. Swaisland, et al., Exploring the relationship between expression of cytochrome
P450 enzymes and gefitinib pharmacokinetics, Clin. Pharmacokinet. 45 (6) (2006)
633–644.
[317] J.M. van Maanen, et al., Cytochrome P-450-mediated O-demethylation: a route in the
metabolic activation of etoposide (VP-16-213), Cancer Res. 47 (17) (1987) 4658–4662.
[318] J.M. van Maanen, et al., The role of metabolic activation by cytochrome P-450 in
covalent binding of VP 16–213 to rat liver and HeLa cell microsomal proteins, Eur.
J. Cancer Clin. Oncol. 21 (9) (1985) 1099–1106.
[319] S. Kishi, et al., Effects of prednisone and genetic polymorphisms on etoposide
disposition in children with acute lymphoblastic leukemia, Blood 103 (1) (2004)
67–72.
[320] W.D. Figg, et al., A randomized phase II trial of thalidomide, an angiogenesis inhibitor,
in patients with androgen-independent prostate cancer, Clin. Cancer Res. 7 (7) (2001)
1888–1893.
[321] S. Singhal, et al., Antitumor activity of thalidomide in refractory multiple myeloma,
N. Engl. J. Med. 341 (21) (1999) 1565–1571.
[322] R.J. D’Amato, et al., Thalidomide is an inhibitor of angiogenesis, Proc. Natl. Acad.
Sci. U.S.A. 91 (9) (1994) 4082–4085.
[323] Y. Ando, et al., Pharmacogenetic associations of CYP2C19 genotype with in vivo
metabolisms and pharmacological effects of thalidomide, Cancer Biol. Ther. 1 (6)
(2002) 669–673.
[324] B.J. Lange, et al., Double-delayed intensification improves event-free survival for chil-
dren with intermediate-risk acute lymphoblastic leukemia: a report from the Chil-
dren’s Cancer Group, Blood 99 (3) (2002) 825–833.
[325] B.H. Pollock, et al., Racial differences in the survival of childhood B-precursor acute
lymphoblastic leukemia: a Pediatric Oncology Group Study, J. Clin. Oncol. 18 (4)
(2000) 813–823.
[326] J.B. Dennison, et al., Effect of CYP3A5 expression on vincristine metabolism with
human liver microsomes, J. Pharmacol. Exp. Ther. 321 (2) (2007) 553–563.
[327] A. Bogacz, et al., The influence of soybean extract on the expression level of selected
drug transporters, transcription factors and cytochrome P450 genes encoding phase
I drug-metabolizing enzymes, Ginekol. Pol. 85 (5) (2014) 348–353.
[328] G. Kumar, et al., Isothiocyanates: a class of bioactive metabolites with chemopreven-
tive potential, Tumour Biol. (2015) 1–12 (April 3, 2015; Ahead of print).
[329] S.M. Lim, et al., Combination of CYP inhibitor with MEK/ERK inhibitor enhances
the inhibitory effect on ERK in BRAF mutant colon cancer cells, Anticancer Res.
33 (6) (2013) 2499–2508.
137CYP450 in Cancer Treatment
Author's personal copy
[330] S.V. Singh, K. Singh, Cancer chemoprevention with dietary isothiocyanates mature
for clinical translational research, Carcinogenesis 33 (10) (2012) 1833–1842.
[331] C.J. Wen, et al., Preferential induction of CYP1A1 over CYP1B1 in human breast
cancer MCF-7 cells after exposure to berberine, Asian Pac. J. Cancer Prev. 15 (1)
(2014) 495–499.
[332] M. Murray, G.F. Reidy, Selectivity in the inhibition of mammalian cytochromes
P-450 by chemical agents, Pharmacol. Rev. 42 (2) (1990) 85–101.
[333] M. Dossing, et al., Time course of phenobarbital and cimetidine mediated changes in
hepatic drug metabolism, Eur. J. Clin. Pharmacol. 25 (2) (1983) 215–222.
[334] P.J. Cagnoni, et al., Modification of the pharmacokinetics of high-dose cyclophospha-
mide and cisplatin by antiemetics, Bone Marrow Transplant. 24 (1) (1999) 1–4.
[335] C.J. Gilbert, et al., Pharmacokinetic interaction between ondansetron and cyclophos-
phamide during high-dose chemotherapy for breast cancer, Cancer Chemother.
Pharmacol. 42 (6) (1998) 497–503.
[336] J.J. Hendrikx, et al., Oral co-administration of elacridar and ritonavir enhances plasma
levels of oral paclitaxel and docetaxel without affecting relative brain accumulation, Br.
J. Cancer 110 (11) (2014) 2669–2676.
[337] J.J. Hendrikx, et al., P-glycoprotein and cytochrome P450 3A act together in
restricting the oral bioavailability of paclitaxel, Int. J. Cancer 132 (10) (2013)
2439–2447.
[338] R.A. van Waterschoot, et al., Absence of both cytochrome P450 3A and
P-glycoprotein dramatically increases docetaxel oral bioavailability and risk of intesti-
nal toxicity, Cancer Res. 69 (23) (2009) 8996–9002.
[339] C.D. Scripture, W.D. Figg, Drug interactions in cancer therapy, Nat. Rev. Cancer
6 (7) (2006) 546–558.
[340] H. Swaisland, R.P. Smith, J. Farebrother, A. Laight, The effect of the induction and
inhibition of CYP3A4 on the pharmacokinetics of single oral doses of ZD1839
(‘Iressa’), a selective epidermal growth factor receptor tyrosine kinase inhibitor
(EGFR-TKI), in healthy male volunteers, Proc. Am. Soc. Clin. Oncol. 21 (2002) 83a.
[341] R.H. Mathijssen, et al., Effects of St. John’s wort on irinotecan metabolism, J. Natl.
Cancer Inst. 94 (16) (2002) 1247–1249.
[342] V. Stearns, et al., Hot flushes, Lancet 360 (9348) (2002) 1851–1861.
[343] S. Scalone, et al., Vinorelbine-induced acute reversible peripheral neuropathy in a
patient with ovarian carcinoma pretreated with carboplatin and paclitaxel, Acta Oncol.
43 (2) (2004) 209–211.
[344] D. Parimoo, S. Jeffers, F.M. Muggia, Severe neurotoxicity from vinorelbine-paclitaxel
combinations, J. Natl. Cancer Inst. 88 (15) (1996) 1079–1080.
[345] M.T. Huizing, et al., Taxanes: a new class of antitumor agents, Cancer Investig. 13 (4)
(1995) 381–404.
[346] J.M. Meerum Terwogt, et al., Co-administration of cyclosporin enables oral therapy
with paclitaxel, Lancet 352 (9124) (1998) 285.
[347] A. Sparreboom, et al., Limited oral bioavailability and active epithelial excretion of
paclitaxel (Taxol) caused by P-glycoprotein in the intestine, Proc. Natl. Acad. Sci.
U.S.A. 94 (5) (1997) 2031–2035.
[348] M.M. Malingre, J.H. Beijnen, J.H. Schellens, Oral delivery of taxanes, Investig. New
Drugs 19 (2) (2001) 155–162.
[349] H.A. Bardelmeijer, et al., Low systemic exposure of oral docetaxel in mice resulting
from extensive first-pass metabolism is boosted by ritonavir, Cancer Res. 62 (21)
(2002) 6158–6164.
[350] M.M. Malingre, et al., Coadministration of cyclosporine strongly enhances the oral
bioavailability of docetaxel, J. Clin. Oncol. 19 (4) (2001) 1160–1166.
138 Balraj Mittal et al.
Author's personal copy
[351] C.M.F. Kruijtzer, M.M. Malingre
´, J.H. Schornagel, et al., A phase II study with
weekly oral docetaxel and cyclosporin A in patients with metastatic breast cancer, Proc.
Am. Soc. Clin. Oncol. 20 (2001) 1941.
[352] H.J. Lu
¨ck, S. Donne
`, M. Glaubitz, et al., Phase I study of weekly docetaxel
(Taxotere
®
) in heavily pretreated breast cancer patients, Eur. J. Cancer 33 (Suppl.)
(1997) 158.
[353] J.D. Hainsworth, et al., Weekly docetaxel in the treatment of elderly patients with
advanced breast cancer: a Minnie Pearl Cancer Research Network phase II trial,
J. Clin. Oncol. 19 (15) (2001) 3500–3505.
[354] H.J. Burstein, et al., Docetaxel administered on a weekly basis for metastatic breast can-
cer, J. Clin. Oncol. 18 (6) (2000) 1212–1219.
[355] H. Rosing, et al., Pharmacokinetics and metabolism of docetaxel administered as a 1-h
intravenous infusion, Cancer Chemother. Pharmacol. 45 (3) (2000) 213–218.
[356] R. Bruno, et al., Population pharmacokinetics/pharmacodynamics of docetaxel in
phase II studies in patients with cancer, J. Clin. Oncol. 16 (1) (1998) 187–196.
[357] R.A. Jibodh, et al., Taxanes: old drugs, new oral formulations, Eur. J. Pharmacol.
717 (1–3) (2013) 40–46.
[358] J.P. Delord, et al., Combination chemotherapy of vinorelbine and cisplatin: a phase
I pharmacokinetic study in patients with metastatic solid tumors, Anticancer Res.
29 (2) (2009) 553–560.
[359] R.J. Gralla, et al., Oral vinorelbine in the treatment of non-small cell lung cancer:
rationale and implications for patient management, Drugs 67 (10) (2007) 1403–1410.
[360] D. Rossi, et al., A phase II study of single-agent oral vinorelbine in patients with
pretreated advanced non-small-cell lung cancer, Clin. Lung Cancer 8 (6) (2007)
382–385.
[361] V. Hirsh, et al., Oral versus intravenous administration of vinorelbine as a single agent
for the first-line treatment of metastatic nonsmall cell lung carcinoma (NSCLC): a ran-
domized phase II trial, Am. J. Clin. Oncol. 30 (3) (2007) 245–251.
[362] J.S. Lagas, et al., P-glycoprotein, multidrug-resistance associated protein 2, Cyp3a, and
carboxylesterase affect the oral availability and metabolism of vinorelbine, Mol.
Pharmacol. 82 (4) (2012) 636–644.
[363] R.R. Press, et al., The effect of P-glycoprotein and cytochrome P450 3a on the oral
bioavailability of vinorelbine in mice, Cancer Chemother. Pharmacol. 57 (6) (2006)
819–825.
[364] D.F. Kehrer, et al., Modulation of irinotecan metabolism by ketoconazole, J. Clin.
Oncol. 20 (14) (2002) 3122–3129.
[365] G.B. Ratain MJ, L. Iyer, et al., A phase I study of irinotecan (CPT-11) with pharma-
cokinetic modulation by cyclosporin A (CsA) and phenobarbital (PB), Proc. Am. Soc.
Clin. Oncol. 18 (1999) 202a.
[366] R.H. Mathijssen, et al., Modulation of irinotecan (CPT-11) metabolism by St. John’s
wort in cancer patients, Proc. Am. Assoc. Cancer Res. 43 (2002) 2443a.
139CYP450 in Cancer Treatment
Author's personal copy
ResearchGate has not been able to resolve any citations for this publication.
View
View
View
View
Thalidomide is an inhibitor of angiogenesis
Article
  • Apr 1994
Thalidomide is a potent teratogen causing dysmelia (stunted limb growth) in humans. We have demonstrated that orally administered thalidomide is an inhibitor of angiogenesis induced by basic fibroblast growth factor in a rabbit cornea micropocket assay. Experiments including the analysis of thalidomide analogs revealed that the antiangiogenic activity correlated with the teratogenicity but not with the sedative or the mild immunosuppressive properties of thalidomide. Electron microscopic examination of the corneal neovascularization of thalidomide-treated rabbits revealed specific ultrastructural changes similar to those seen in the deformed limb bud vasculature of thalidomide-treated embryos. These experiments shed light on the mechanism of thalidomide's teratogenicity and hold promise for the potential use of thalidomide as an orally administered drug for the treatment of many diverse diseases dependent on angiogenesis.
View
View
View
Effects of St. John's Wort on Irinotecan Metabolism
Article
  • Aug 2002
  • J NATL CANCER I
St. John's wort (SJW), a widely used herbal product, has been implicated in drug interactions resulting from the induced expression of the cytochrome P450 CYP3A4 isoform. In this study, we determined the effect of SJW on the metabolism of irinotecan, a pro-drug of SN-38 and a known substrate for CYP3A4. Five cancer patients were treated with irinotecan (350 mg/m2, intravenously) in the presence and absence of SJW (900 mg daily, orally for 18 days) in an unblinded, randomized crossover study design. The plasma levels of the active metabolite SN-38 decreased by 42% (95% confidence interval [CI] = 14% to 70%) following SJW cotreatment with 1.0 μM × h (95% CI = 0.34 μM × h to 1.7 μM × h) versus 1.7 μM × h (95% CI = 0.83 μM × h to 2.6 μM × h) (P = .033, two-sided paired Student's t test). Consequently, the degree of myelosuppression was substantially worse in the absence of SJW. These findings indicate that patients on irinotecan treatment should refrain from taking SJW because plasma levels of SN-38 were dramatically reduced, which may have a deleterious impact on treatment outcome.
View
View
Active Tamoxifen Metabolite Plasma Concentrations After Coadministration of Tamoxifen and the Selective Serotonin Reuptake Inhibitor Paroxetine
Article
  • Dec 2003
  • J NATL CANCER I
Background: Tamoxifen, a selective estrogen receptor modulator (SERM), is converted to 4-hydroxy-tamoxifen and other active metabolites by cytochrome P450 (CYP) enzymes. Selective serotonin reuptake inhibitors (SSRIs), which are often prescribed to alleviate tamoxifen-associated hot flashes, can inhibit CYPs. In a prospective clinical trial, we tested the effects of coadministration of tamoxifen and the SSRI paroxetine, an inhibitor of CYP2D6, on tamoxifen metabolism. Methods: Tamoxifen and its metabolites were measured in the plasma of 12 women of known CYP2D6 genotype with breast cancer who were taking adjuvant tamoxifen before and after 4 weeks of coadministered paroxetine. We assessed the inhibitory activity of pure tamoxifen metabolites in an estradiol-stimulated MCF7 cell proliferation assay. To determine which CYP isoforms were involved in the metabolism of tamoxifen to specific metabolites, we used CYP isoform-specific inhibitors. All statistical tests were two-sided. Results: We separated, purified, and identified the metabolite 4-hydroxy-N-desmethyl-tamoxifen, which we named endoxifen. Plasma concentrations of endoxifen statistically significantly decreased from a mean of 12.4 ng/mL before paroxetine coadministration to 5.5 ng/mL afterward (difference = 6.9 ng/mL, 95% confidence interval [CI] = 2.7 to 11.2 ng/mL) (P = .004). Endoxifen concentrations decreased by 64% (95% CI = 39% to 89%) in women with a wild-type CYP2D6 genotype but by only 24% (95% CI = 23% to 71%) in women with a variant CYP2D6 genotype (P = .03). Endoxifen and 4-hydroxy-tamoxifen inhibited estradiol-stimulated MCF7 cell proliferation with equal potency. In vitro, troleandomycin, an inhibitor of CYP3A4, inhibited the demethylation of tamoxifen to N-desmethyl-tamoxifen by 78% (95% CI = 65% to 91%), and quinidine, an inhibitor of CYP2D6, reduced the subsequent hydroxylation of N-desmethyl-tamoxifen to endoxifen by 79% (95% CI = 50% to 108%). Conclusions: Endoxifen is an active tamoxifen metabolite that is generated via CYP3A4-mediated N-demethylation and CYP2D6-mediated hydroxylation. Coadministration of paroxetine decreased the plasma concentration of endoxifen. Our data suggest that CYP2D6 genotype and drug interactions should be considered in women treated with tamoxifen.
View