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Expert Review of Clinical Pharmacology
ISSN: 1751-2433 (Print) 1751-2441 (Online) Journal homepage: https://www.tandfonline.com/loi/ierj20
The role of xenobiotic-metabolizing enzymes in
the placenta: a growing research field
Ricardo Blanco-Castañeda, Carlos Galaviz-Hernández, Paula C. S. Souto,
Victor Vitorino Lima, Fernanda R. Giachini, Carlos Escudero, Alicia E
Damiano, L. Jazel Barragán-Zúñiga, Gerardo Martínez-Aguilar & Martha
Sosa-MacíasRIVA-TREM
To cite this article: Ricardo Blanco-Castañeda, Carlos Galaviz-Hernández, Paula C. S. Souto,
Victor Vitorino Lima, Fernanda R. Giachini, Carlos Escudero, Alicia E Damiano, L. Jazel Barragán-
Zúñiga, Gerardo Martínez-Aguilar & Martha Sosa-MacíasRIVA-TREM (2020): The role of
xenobiotic-metabolizing enzymes in the placenta: a growing research field, Expert Review of
Clinical Pharmacology, DOI: 10.1080/17512433.2020.1733412
To link to this article: https://doi.org/10.1080/17512433.2020.1733412
Published online: 04 Mar 2020.
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REVIEW
The role of xenobiotic-metabolizing enzymes in the placenta: a growing research
field
Ricardo Blanco-Castañeda
a
, Carlos Galaviz-Hernández
a
, Paula C. S. Souto
b
, Victor Vitorino Lima
b
,
Fernanda R. Giachini
b
, Carlos Escudero
c
, Alicia E Damiano
d,e
, L. Jazel Barragán-Zúñiga
a
, Gerardo Martínez-Aguilar
f
and Martha Sosa-Macías
a
RIVA-REM
†
a
Academia De Genómica, Instituto Politécnico Nacional-CIIDIR Durango, Durango, Mexico;
b
Laboratory of Vascular Biology, Institute of Health
Sciences and Health, Universidad Federal De Mato Grosso, Barra Do Garcas, Brazil;
c
Vascular Physiology Laboratory Group of Investigation in Tumor
Angiogenesis (GIANT) Group of Research and Innovation in Vascular Health (GRIVAS Health) Basic Sciences Department Faculty of Sciences,
Universidad Del Bio-Bio, Chillan, Chile;
d
Laboratorio De Biología De La Reproducción, IFIBIO Houssay-UBA-CONICET, Buenos Aires, Argentina;
e
Departamento De Ciencias Biológicas, Facultad De Farmacia Y Bioquimica, Buenos Aires, UBA, Argentina;
f
Unidad De Investigación Biomédica -
Instituto Mexicano del Seguro Social (IMSS) Durango, Durango, México
ABSTRACT
Introduction: The placenta is a temporary and unique organ that allows for the physical connection
between a mother and fetus; this organ regulates the transport of gases and nutrients mediating the
elimination of waste products contained in the fetal circulation. The placenta performs metabolic and
excretion functions, on the basis of multiple enzymatic systems responsible for the oxidation, reduction,
hydrolysis, and conjugation of xenobiotics. These mechanisms give the placenta a protective role that
limits the fetal exposure to harmful compounds. During pregnancy, some diseases require uninter-
rupted treatment even if it is detrimental to the fetus. Drugs and other xenobiotics alter gene
expression in the placenta with repercussions for the fetus and mother’s well-being.
Areas covered: This review provides a brief description of the human placental structure and function,
the main drug and xenobiotic transporters and metabolizing enzymes, placenta-metabolized sub-
strates, and alterations in gene expression that the exposure to xenobiotics may cause.
Expert opinion: Research should be focused on the identification and validation of biological markers
for the assessment of the harmful effects of some drugs in pregnancy, including the evaluation of
polymorphisms and methylation patterns in chorionic villous samples and/or amniotic fluid.
ARTICLE HISTORY
Received 22 February 2019
Accepted 19 February 2020
KEYWORDS
CYP450 enzyme; drug; gene
expression; placenta;
placental metabolism;
pregnancy; transport protein
1. Introduction
The placenta represents the fusion of fetal membranes to the
uterine mucosa with a blood supply provided by both the
maternal circulatory system and the fetal one.
It is a temporary but vital organ with an essential endocrine
role: to maintain a successful pregnancy. The placenta regu-
lates the transport of oxygen and nutrients from the maternal
to fetal circulation; at the same time, it mediates the removal
of waste products generated on the fetal side; these products
are transported toward the maternal circulation. The transport
in both directions is selective, limiting the entry of compounds
that may adversely affect fetal development; although it is not
a barrier per se, it has been known as the ‘placental barrier’[1].
The placenta performs metabolic and excretion functions
expressing an enzymatic system responsible for the oxidation,
reduction, hydrolysis, and conjugation of drugs, but its enzy-
matic activity and expression is much lower than the one in the
maternal and fetal liver [2]. For example, levels of microsomal
UGT1A extracted from placentas are around 2% of that extracted
from livers, per milligram of tissue, although the UGT1A activities
during first trimester were similar to described in adult liver [3].
Until the 1960s, it had been accepted that the placenta
represents a barrier that protects the fetus against potential
harmful compounds; however, this concept changed after the
discovery of fetal deformities caused by maternal treatment
with thalidomide, a drug indicated for nausea and vomiting
during the first months of pregnancy. In humans, in contrast
to what had been described in animal studies, this drug
crosses the placenta thereby interfering with normal develop-
ment of the fetus. Since then, a warning for potentially pro-
blematic drugs administered during pregnancy is required [4].
Different illnesses such as epilepsy, diabetes, and asthma
require pharmacotherapy most of the time during pregnancy
[4]. It is estimated that 93% of pregnant women take some
medication via physician prescription or self-medication, and
more than 50% up to four drugs [5]. To date, at least 30 drugs
with a teratogenic effect (even at therapeutic doses) have
been identified [6,7]. These harmful effects depend on fetal
gestational age at the time of exposure as well as
CONTACT Martha Sosa-Macías sosa.martha@gmail.com Academia De Genómica, Instituto Politécnico Nacional-CIIDIR Durango,Sigma 119, fracc. 20 de
Noviembre II, Durango C.P. 34220, Mexico
†
Red Iberoamericana de Alteraciones Vasculares asociadas a TRastornos del Embarazo, Chillán, Chile.
EXPERT REVIEW OF CLINICAL PHARMACOLOGY
https://doi.org/10.1080/17512433.2020.1733412
© 2020 Informa UK Limited, trading as Taylor & Francis Group
pharmacological parameters of the drug itself such as the
dose, frequency, route of administration, and time of elimina-
tion [5,8].
Aside from an update on the main xenobiotic-metabolizing
enzymes (XMEs) and exogenous substrates known to be meta-
bolized by the human placenta, the aim of this review is to
describe the effects of xenobiotics on genes engaged in pla-
cental transport and metabolism. Research and continuous
updates in this field will improve the understanding and con-
trol of the administration of medicines during pregnancy to
increase efficiency and safety for both a mother and fetus.
2. Exposure to xenobiotics during pregnancy
The use of drugs during pregnancy represents a challenge due
to the toxicity of the substances and the physiology of
a pregnant woman. It is difficult to determine the exposure
rate of pregnant women to drugs because the methodology is
not uniform. Getting information from sources such as auto-
matic pharmacy registries and interviews with patients during
pregnancy or after delivery may introduce biases and limit the
usefulness of the results. For instance, a study conducted in
France on a cohort of 1,000 women has revealed a frequency
of therapeutic-drug use during pregnancy of up to 99% [8]. It
is worth mentioning that 79% of those women were exposed
to drugs classified as schedule C by the USA FDA, meaning
that the safety of these drugs in pregnancy has not been
evaluated in animal and human studies [9]. Nevertheless,
data from the United States indicate that up to 40% of
women ingest schedule C drugs during pregnancy [10]. In
this regard, during pregnancy, there exist some medical con-
ditions in which stopping treatment carries a risk for both the
mother and fetus; therefore, the drugs must be continuously
ingested, e.g. by women with epilepsy or asthma [11]. In
addition to medicinal drugs, women could be exposed to
substances such as tobacco, alcohol, caffeine, and psychotro-
pic drugs, leading to maternal complications and serious pro-
blems in the development of the fetus [12]. In this regard,
epidemiological studies on pregnant women from several
countries have revealed that alcohol and tobacco are the
most consumed nonprescribed drugs, followed by illicit
drugs such as marijuana and cocaine, whose consumption
frequency has not changed over time [13,14] being similar to
that in the general population.
The exposure to drugs and other xenobiotics during preg-
nancy makes it mandatory to update the information about
the expression and activity of XMEs in the human placenta.
This knowledge is important for evaluating, on the one hand,
the risks of fetal exposure to drugs, and on the other hand, the
maternal dose necessary for the treatment to be effective.
3. An overview of placental structure and function
The placenta is a transient organ that plays important roles
during pregnancy and constitutes the interface between the
mother and fetus.
The anatomo-functional unit of the human placenta is villi.
Placenta villi are composed of extravillous cytotrophoblastic cells
and villous trophoblastic cells. The former is subdivided into
interstitial trophoblast cells and endovascular trophoblast cells;
they participate in the invasion of decidual stroma and spiral
arteries, respectively. Later, the villous trophoblastic cells will fuse
to form the syncytiotrophoblast cell layer (the outermost part of
the placental villi), which is in close contact with maternal blood
[15]. Any given molecule has to cross the ‘placental barrier,’
which means the tissue layers between the fetal circulatory
system and the maternal one, where fetal components include
the placental endothelium, mesenchyme, and trophoblast, while
the maternal tissues include the epithelium, uterine connective
tissue, and endothelium.
In terms of transport of molecules, it is known that oxygen
and carbon dioxide exchange is performed by simple diffusion
that depends on the concentration of those gases in maternal
and fetal blood [16], but both nutrients (such as glucose, amino
acids, and fatty acids) and micronutrients such as vitamins have
to cross the placenta via transporter-mediated mechanisms [17].
Similarly, transport of xenobiotics requires transport systems
present in the ‘placental barrier’(Figure 1)[17]. We will elaborate
on these processes in the sections that follow.
It is important to mention that according to the number of
tissue layers that separate the maternal and fetal blood (and
to the distribution of chorionic villi), the human placenta is
classified as hemomonochorial, meaning that the syncytiotro-
phoblast separates the maternal and fetal circulation [18].
Therefore, the anatomical and histological differences of the
human placental structure from that of other mammalian
species make it difficult to study the transport functions in
animal models.
4. Placental transport
The human placenta performs all known kinds of drug transport,
including active transport, passive transport, facilitated diffusion,
phagocytosis, and pinocytosis. Initially, facilitated diffusion drew
the attention of all researchers, but now that more drugs are
being studied, the key role of active transport has become
evident. Conversely, pinocytosis and phagocytosis seem to par-
ticipate only minimally in the transport of drugs [19,20].
Article Highlights
●The placenta expresses diverse xenobiotic-metabolizing enzymes
(XMEs) involved in the regulation of maternal and fetal exposure to
hormones, dietary compounds, drugs, and environmental chemicals
through biotransformation and elimination. The number and amount
of expressed XMEs varies depending on the period of gestation and
maternal age and health status.
●Apparently, all drugs cross the placenta and are metabolized by it to
a certain extent through different mechanisms. Exposure to these
substances can affect the expression of genes that encode XMEs and
transporter proteins. Consequently, these alterations may provoke
the deregulation of pregnancy and/or of fetal development.
●Advances in new technologies are expected to improve the treat-
ment of maternal and fetal diseases during pregnancy.
2R. BLANCO-CASTAÑEDA ET AL.
4.1. Passive transport
This transport represents one of the main transport systems
for drugs. It does not require energy, and its function and
velocity depend on different characteristics of the drugs
including concentration, liposolubility, and molecular weight.
Concentration: The drugs that are commonly found at
higher concentrations in the maternal circulation tend to
move from this compartment to the fetal circulation.
Liposolubility: Only drugs soluble in lipids can pass through
the cellular membrane in a passive way.
Molecular weight: Compounds smaller than 500 Da pass
easily through the placenta. In addition, lower pH in the fetal
circulation than in the maternal circulation allows alkaline
drugs to passively diffuse to the fetal side [20,21]. Placental
thickness is another important feature; the thicker the mem-
brane, the lower is the amount of a drug able to cross this
membrane. Indeed, placental thickness tends to decrease dur-
ing pregnancy thereby increasing its permeability [19].
4.2. Facilitated diffusion
This type of transport does not require energy either; it is
selective, can be saturated with high concentrations of
a substrate, and requires specific transporters that move the
substrate along the gradient of concentration until the sub-
strate reaches a concentration equilibrium. Several such pro-
teins have been identified in the human placenta, for example,
organic anion transporters (OATs and OATPs), organic cation
transporters (OCTs and OCTNs), multidrug and toxic-
compound extrusion protein 1 (MATE1), and nucleoside trans-
porters (NTs) are related to drug transport [19,22,23].
4.3. Active transport
The aforementioned type of transport does not ensure the
uptake and transfer of all the essential substances required for
an optimal pregnancy.
Some proteins require energy in the form of ATP in order to
move their substratesagainst a concentration gradient. This type
of transport is important in tissues specialized in the metabolism
and elimination of drugs, e.g. the intestine, liver, kidneys, and the
placenta. Most of the time, the transport is substrate-specific, but
overlaps have been demonstrated [20]. Among the transporters
identified in the human placenta, the ABC efflux transporter
superfamily is a good example: P-glycoprotein (P-gp), resistance
protein in breast cancer (BRCP), and the proteins associated with
multidrug resistance (MDRs) have been identified in the human
placenta. The first two confer the principal drug resistance phe-
notypes, and constitute the placental barrier to maternally
derived glucocorticoids, toxins, and drugs [21,24,25].
The degree of fetal exposition to xenobiotics is regulated in
some extent by these transporters in the placenta, as it is
observed with BCRP and MRP1, which extrude pravastatin to
the maternal circulation, once this drug is uptake from maternal
circulation to placenta by OATP1A2, 3A1, 4A1, and 5A1, making
pravastatin undetectable in fetal circulation [26]. On the other
hand, during pregnancy the use of more than one drug that is
P-gp substrate represents a major risk of presenting congenital
cardiac, genitourinary, respiratory, musculoskeletal, and nervous
anomalies (odds ratio [OR] 4.17, 95% CI 1.75–9.91) compared to
use in monotherapy. In addition, if a P-gp inhibitor is used in
combination with other P-gp substrates, the risk increases even
further (OR 13.03, 95% CI 3.37–50.42) [27].
5. Placental metabolism
5.1. Early evidence of human placental metabolism
The first evidence of the metabolismofxenobioticsintheplacenta
was the report about the metabolism of benzo[a]pyrene (BP) by
placental enzymes known as monooxygenases (MOs) in vitro [28].
Later, the involvement of cytochrome P450 (CYP450) isozymes
CYP1A1 and CYP1A2 in the activation of BP by human placental
and liver microsomes, respectively, has been described in vitro
[29]. Moreover, induction of the CYP1A1 gene by maternal cigar-
ette smoking and increased synthesis of the CYP1A1 protein in the
human placenta have been documented [30].
In addition, epoxide hydrolase (EH) activity toward styrene-
7,8-oxide in the microsomal fraction of the human placenta [31]
and glutathione S-transferase (GST) activity toward 1-chloro-
2,4-dinitrobenzene have been identified in the cytosol of human
Figure 1. A schematic cross-section of human placental barrier showing main transporter proteins and xenobiotic-metabolizing enzymes. Drugs and xenobiotics
usually cross the placenta by passive diffusion, transporter-mediated transfer or both. Within the microvillus, drugs can undergo phase I and phase II metabolism.
MATE 1, multidrug and toxin extrusion 1; OCT3, organic cation transporter 3; NET, noradrenalin transporter; SERT, serotonin transporter; OAT4 organic anion
transporter 4; OCTN1 and 2, organic cation/carnitine transporters; OATPs, organic anion transporting polypeptides; CYPs, cytochrome P450 s; EH, epoxide hydrolase;
UGTs, Uridine 5´-diphospho-glucuronosyltransferases; SULTs, sulfotransferases; GSTs, glutathione S-transferases; P-gp, P-glycoprotein; BCRP, breast cancer resistance
protein; MRPs, multidrug resistance-associated proteins.
EXPERT REVIEW OF CLINICAL PHARMACOLOGY 3
placental cells [32]. Neither placental EH or GST activity is increased
by maternal smoking [33]. Besides, the N-acetylation activity of
carcinogenic arylamine 2-aminofluorene in the human placenta
has been observed [34]bymeansofN-acetyltransferase1(NAT1)
[35]. The expression of NAT1 has been confirmed in an early-
pregnancy human placenta [36].
5.2. Placental XMEs
Based on the studies included in this review, it has been
concluded that the human placenta has limited metabolic
activity (lower than liver and kidney) capable of biotrans-
forming compounds of both endogenous and exogenous
origin, through phase I and phase II enzymes. Phase
I enzymes add a chemically reactive functional group (i.e.
hydroxyl, amine, sulfa, or carboxyl) onto its substrate. The
product of this reaction often becomes a substrate for phase
II enzymes, which catalyze conjugating reactions (i.e. glucur-
onidation, glycosidation, sulfation, acetylation, or glutathione
conjugation) and produce metabolites that are generally
highly water-soluble and can be readily excreted [37]. The
placental enzymes are capable of oxidizing, reducing, and
conjugating compounds [2]. Nevertheless, there is still scarce
information about the placental contribution to the conver-
sion of xenobiotics into toxic metabolites. Compared to liver
metabolism, placental metabolism seems to be slower and
does not limit the passage of xenobiotics through the pla-
centa [22].
5.3. Phase I enzymes in the human placenta
5.3.1. Cytochrome P450
CYP450 (CYP) is the most studied enzymatic system in the
liver and is also deeply involved in placental metabolism, with
total microsomal CYP450 content of the human full-term
placenta being approximately 0.1 nmol/(mg protein) [30].
These enzymes are located in the endoplasmic reticulum
and mitochondria of syncytiotrophoblast cells [19]. Most of
the placental CYP enzymes participate in the synthesis and
catabolism of steroid hormones, whereas XMEs represent
a small minority of all CYP450 enzymes [38,39]. The CYPs
expression changes depending on the gestation period [40],
maternal age and health status [38]. The expression and pla-
cental enzymatic activity of CYPs are higher during the first
trimester than at term (Table 1)[41–58], suggesting that the
metabolism of xenobiotics is crucial during embryogenesis
and organogenesis (the first trimester of pregnancy), when
the embryo or fetus is most susceptible to teratogenic effects.
The activities of these enzymes decrease after this period
(Table 1).
5.3.2. The CYP1 family
CYP1A1 mRNA and protein expression and activity have been
demonstrated in the placental trophoblast throughout preg-
nancy [41,42], with significantly higher CYP1A expression in
younger mothers [47]. In placental microsomes from smokers,
CYP1A1 can catalyze the activation of BP into BP-diol epoxide-
DNA adducts both in placental and fetal tissues [29,59].
Recently, it was demonstrated in microsomes from the placen-
tas of smokers that diuron (a broad-spectrum phenylurea-
derived herbicide) can be metabolized by CYP1A1 to a toxic
metabolite [60].
Placental CYP1A1 activity is very low throughout preg-
nancy but is induced by cigarette smoke, polychlorinated
biphenyl exposure, and medications such as glucocorticoids
[61,62]. Besides, cigarette smoke and ethanol synergistically
elevate placental CYP1A1 activity [47]. The induction of
CYP1A1 by cigarette smoke is the greatest at full term, and
high levels persist for weeks after smoking cessation [30].
This induction is consistent with lower methylation levels of
CYP1A1 at a specific CpG site that is adjacent to a xenobiotic
response element (XRE; a transcription factor–binding site) in
the placental tissue of mothers who smoked during preg-
nancy [63].
Table 1. Xenobiotic-metabolizing enzymes detected in human placenta.
First trimester Full term
Enzyme mRNA Protein Function mRNA Protein Function Ref
CYP1A1 + + + + + + [41,42]
CYP1A2 + ND - - + + [41,43]
CYP1B1 + ND ND + ND ND [44]
CYP2 C8/9 + ND ND + + ND [40–42,45]
CYP2D6 + ND ND - ND - [41,42,46]
CYP2E1 + + - + - - [41,42,47]
CYP2F1 + ND ND + ND ND [41,42]
CYP2 J2 + + ND ++ + + [45,48]
CYP3A4 + + - + + + [42,49]
CYP3A5 + + - + + + [42,49]
CYP3A7 + + - + + + [42,49]
CYP4B1 + ND ND + ND ND [42,50]
CYP19A1 ND ND ND ++ + + [50]
sEH/mEH ND ND + + + + [51–53]
GST ND ND + + + + [53,54]
UGT + + ND + + + [53,55,56]
SULT ND + + + + + [57,58]
NAT1 ND ND + + ? ND + [34,36]
+: positive expression, ++: strong positive expression; −: Negative results; ND: no data available; sEH/mEH: soluble and microsomal
epoxide hydrolase; GST: Glutathione S-transferase; UGT: Uridine 5`-diphosphate glucuronyltransferase; SULT: Sulfotransferase; NAT:
N-acetyltransferase.
4R. BLANCO-CASTAÑEDA ET AL.
CYP1A2 mRNA has been identified only in placentas from
the first trimester [42]; however, in these placentas and in term
placentas, functional activity has not been detected [41,42,64].
Converely, Avery et al. (2003) uncovered CYP1A2 expression
and low activity in full-term placentas [43]. Moreover, both
CYP1A2 and CYP1B1 are not induced in the placenta by
maternal cigarette smoking [41,44,65], although constitutive
CYP1B1 expression is low but detectable in first-trimester and
full-term placental samples [44].
5.3.3. The CYP2 family
CYP2C, CYP2D6, CYP2E1, and CYP2F1 mRNAs have been
detected in the human placenta in the first trimester of preg-
nancy [42], but only CYP2E1 and CYP2F1 mRNAs have been
identified in full-term placentas [41]. Immunoreactive CYP2E1
has not been detected, and no CYP2E1 and CYP2D6 enzymatic
activities are present at term [41,46]. Besides, a high level of
CYP2J2 mRNA and low levels of CYP2C mRNA have been
identified in the term placenta [45]. The CYP2J2 expression
has been detected in this pregnancy period by Herse et al.
(2012) and Dalle Vedove et al. (2016), who failed to detect
CYP2C8 [48,51]. Conversely, Cizkova et al. (2018) detected
higher expression of CYP2C8 compared to CYP2C9 and
CYP2J2 in term placenta samples [40].
On the other hand, Rasheed and coworkers (1997) detected
the CYP2E1 protein in third-trimester placentas from heavily
drinking mothers, although with considerable variation among
individuals, whereas placentas from nondrinking women
showed CYP2E1 mRNA but no protein [66]. In contrast,
Collier et al. (2002) during the first trimester of subjects
detected CYP2E1 protein in four of the six placentas sampled,
without detectable activity [47]. The aforementioned evidence
suggests that apparently a negligible amount of CYP2E1 is
present in the human placenta under noninducing conditions.
5.3.4. The CYP3 family
Three main isoforms of CYP3A are found in the human pla-
centa: CYP3A4, CYP3A5, and CYP3A7. Their mRNA and protein
expression have been detected in first-trimester placentas,
whereas CYP3A4 and CYP3A5 mRNAs are present in full-term
placentas [42,49]. Schuetz et al. have detected CYP3A7 mRNA
and protein only in the first- and second-trimester placental
samples [67], whereas Maezawa et al. identified CYP3A4, −5,
and −7 mRNAs in a full-term placenta, with expression levels
very variable among the samples [49]. In these examined
placentas, CYP3A4/5/7 proteins were detected immunologi-
cally by using the same polyclonal antibody. In the same
study, testosterone 6β-hydroxylase activity was detected,
demonstrating the metabolic function of CYP3A isoforms in
the placenta.
5.3.5. CYP4B1 isoform
CYP4B1 mRNA is expressed in both early-gestation and full-
term placentas [42,44,50], and in agreement with CYP1A1,
transcription of CYP4B1 is induced by smoking [68].
Nonetheless, the presence of a functional CYP4B1 enzyme in
the human placenta has not been reported.
5.3.6. CYP19A1 isoform
CYP19A1 (aromatase), an enzyme that is abundantly expressed
in the placenta, is associated with placental physiological func-
tions [2,50]. CYP19A1, in addition to converting androgens to
estrogens, has been involved in the metabolic activation of
aflatoxin B
1
to aflatoxicol [69,70] and in the metabolism of
medications such as glyburide [71], buprenorphine [72], and
methadone [73]. Recently, in full-term placenta samples,
Huuskonen et al. (2016) demonstrated a decrease in CYP19A1
catalytic activity by smoking of mothers, even though protein
levels were not significantly altered. Therefore, CYP19A1 seems
to be the main xenobiotic-metabolizing phase I enzyme in the
placenta [68].
5.3.7. Additional phase I enzymes
An EH activity has been detected in midtrimester and term
placentas [31,52]. Later, in term placentas, microsomal EH
mRNA has been found in higher amounts relative to soluble
EH (sEH) [53]. The sEH protein yields a very weak signal in term
placental villi [51], whereas Cizkova and Tauber (2018)
detected an increased expression of sEH in the cytotropho-
blast as pregnancy progresses and in the syncytiotrophoblast
in term placentas; however, the latter finding was not
observed in all the samples analyzed [40]. The preferred endo-
genous substrate of sEH is epoxyeicosatrienoic acid, which is
hydrolyzed to less active dihydroxyeicosatrienoic acid [74].
Both epoxyeicosatrienoic acid and dihydroxyeicosatrienoic
acid have been detected in the placenta [75].
Other phase I enzymes present at mRNA levels in term
placentas include alcohol dehydrogenase 5, hydroxyacyl-
coenzyme A dehydrogenase type II, NAD(P)H dehydrogenase,
quinone 2 esterase D, lipase A, neuropathy target esterase,
and ubiquitin carboxyl-terminal esterase L3. Besides, the
mRNAs of dehydrogenase/reductase 2, aldehyde dehydrogen-
ase family 3 member B2, and monoamine oxidase A are
expressed at the highest levels in the placenta [53].
5.4. Phase II enzymes in the human placenta
5.4.1. Glutathione S-transferases
These enzymes can conjugate glutathione to a wide range of
hydrophobic and electrophilic molecules thereby making them
less toxic [76]. In mammals, four classes of GSTs have been
identified (α,μ,π,andθ)[19]. GST-πor GSTP1-1 is the main
isozyme of the GST present in the human placenta and is not
normally expressed in adult tissues [53,77,78]. Nishimura and
Naito (2006) detected at term only low quantities of mRNAs of
GSTA3, GSTM1–5, and GSTT1 and −2 and higher mRNA expres-
sion of GSTA4 and GSTZ1 [53]. The GST-πisoform is responsible
for 85% of the metabolic activity of GST. This enzyme is
expressed from the eighth to ninth week of gestation and is
highly expressed during the rest of pregnancy [38]. The GST-π
isoform has been detected in different cellular compartments,
such as the cytosol, mitochondria, and microsomes, as well as the
syncytium´s membrane [54]. In the placenta, GST-πis inhibited
by fluoxetine, thus triggering fetotoxicity [79], and has reduced
activity in overt diabetes [80]. The high expression of GSTs in the
placenta has been linked to the loss of pregnancy, suggesting
EXPERT REVIEW OF CLINICAL PHARMACOLOGY 5
that it is a defense mechanism when pregnancy is under stress
[81]. GST does not seem to be induced significantly by maternal
cigarette smoking [30].
5.4.2. Uridine 5′-diphospho-glucuronosyltransferases
(UGTs)
These enzymes catalyze the attachment of a glucuronic acid
residue to endo- and exogenous compounds. In humans, the
superfamily of UGTs is subdivided into five subfamilies, desig-
nated as UGT1A, UGT2A, UGT2B, UGT3A, and UGT8A. These
subfamilies contain multiple isoforms with independent
expression and regulation [82,83]. UGTs are responsible for
most of phase II metabolism [47], and in the placenta, its
role must be critical, because of the extremely low UGT fetal
activity [3]. The mRNA expression of the UGT1A6 isoform has
been detected in the placenta at term [53], as was that of the
UGT1A4 protein, and it is believed that its activity in the
placenta is responsible for the fast decline of lamotrigine
levels during pregnancy [55]. A recent study revealed mRNA
expression of UGT1A isoforms (UGT1A1, −1A4, −1A6, and
−1A9) in villous cells of the placenta at term [3]. The relative
activity of UGT1A in the placenta is only 2% compared to that
observed in the liver; however, the expression patterns are
similar in the two organs [3]. On the other hand, the mRNA
expression of the UGT2B isoforms (UGT2B4, −2B7, −2B10,
−2B11, −2B15, and −2B17) as well as the presence of proteins
UGT2B4 and −2B7 has been detected in the syncytium of both
first trimester and term placentas [47,84]. The high interindi-
vidual variation in UGT activity negatively correlates with
gestational age and is elevated by maternal smoking, being
even higher in mothers who smoke and drink alcohol [47].
5.4.3. Sulfotransferases (SULTs)
SULTs conjugate sulfate groups to certain compounds (steroids,
catecholamines) using 3′-phosphoadenosine 5′-phosphosulfate
(PAPS) as a cofactor. In human, four gene families have been
identified: SULT1, SULT2, SULT4, and SULT6, but only the first two
express in the placenta, encoding for more than one protein
each [85]. SULT enzymes are involved in the synthesis and meta-
bolism of steroid hormones, and it is thought thatthey represent
one of the main lines of defense against xenobiotics in the
placenta [86]. Substantial SULT activity toward 4-nitro-phenol
(SULT1A1) and dopamine (SULT1A3) has been detected in the
cytosol of cells from cotyledons, with significant activity through-
out the pregnancy starting from the first trimester [57]. SULT1E1
activity toward 17α-ethynylestradiol has also been found in pla-
cental-cell cytosol in considerably lower amounts relative to
SULT1A1 and SULT1A3 activities [57]. Dehydroepiandrosterone
sulfotransferase activity, indicative of SULT2A1 expression, was
also present in the placenta, particularly the cotyledon [57]. In
the same study, isoforms SULT1A1 and −1A3 were detected in
the cytosol of syncytiotrophoblasts, while the expression of
SULT1B1 and −1C2 was essentially undetectable. By contrast,
SULT2B1b mRNA and protein expression and activity have
been uncovered in the nuclei of placental syncytiotrophoblasts
at term [58]. Evidence for SULT1A1, −1A3, −1B1, −1E1, and −2B1
mRNA expression in the placenta at term has also been demon-
strated [53].
Moreover, the placenta expresses other phase II enzymes,
which have been detected at the mRNA level at term, e.g. micro-
somal glutathione S-transferases 1–3(MGST1–3), prostaglandin
Esynthase(PTGES),acetylserotoninO-methyltransferase(ASMT),
nicotinamide N-methyltransferase, and catechol-O-methy-
ltransferase (COMT) [53].
6. Regulation of XMEs and drug transporters in the
placenta
Numerous XMEs and drug transporters are induced in the
human liver and various extrahepatic tissues after being
exposed to a wide variety of xenobiotics [87]. The enzyme
and transporter induction are mediated by nuclear recep-
tors (NRs) that act as environmental-sensor, of which 49
members have been identified in this superfamily.
Nevertheless, a limited number of NRs are expressed in
placenta, such as AhR (aryl hydrocarbon receptor), GR (glu-
cocorticoid receptor, NR3C1), and VDR (vitamin D receptor,
NR1I1) [88].
The AhR activation mediates the metabolism of a wide
variety of xenobiotics besides perform other cellular functions
[89]. In syncytiotrophoblasts, AhR and ARNT (AHR nuclear
translocator) mRNAs and proteins are present abundantly in
the first trimester and at term [90], conversely it has been
detected that the AhRR (AhR repressor) gene expression at
placenta at term is very low [87,91]. It has been demonstrated
that the activation of AHR mediated by tobacco smoke and
other PAHs induce just CYP1A1 expression in the human
placenta [92,93] and it is not dependent of dosage [93]. The
activation of the AHR-dependent CYP1A1 has been associated
with immunosuppression and complications of pregnancy
such as spontaneous abortion, intrauterine growth restriction
(IGR), and premature birth [89].
The placental GR activation mediates the placental metabo-
lism and fetal development [94]. The preterm placenta expresses
eight isoforms of the GRs (GRα,GRβ,GRαC, GR P, GR A, GRαD1-3)
which may vary in relation to gestational age at delivery, mode of
delivery, fetal sex, exogenous glucocorticoids exposure, fetal size,
and receptor location (cytoplasm or nucleus) [94,95]. GRαis the
main isoform identified in the placenta [96], and together with its
phosphorylated form are mainly expressed in cytotrophoblasts,
in term placentas [88]. It has been described that GRαis involved
in up-regulation of P-gp mRNA in JEG3 cells exposed to placental
dexamethasone [97]; although, in full-term placenta explants
treated with dexamethasone, GRαmRNA levels were signifi-
cantly reduced [95].
VDR gene expression and its heterodimer RXRα(NR2B1)
have been identified in the human placenta at term; pre-
dominantly in syncytiotrophoblasts [98], as well as in decid-
ual and placental tissue cell cultures [99]. As occur in other
tissues, no significant induction of XMEs and placental drug
transporters through VDR receptor has been identi-
fied [100].
Other NRs have no activity (or minimal) in human placenta
and in cell cultures, as PXR (NR1I2), CAR (NR1I3), and FXR
(NR1H4) [101]. More studies are needed in order to under-
stand placental gene regulation through of NRs.
6R. BLANCO-CASTAÑEDA ET AL.
Table 2. Effect of xenobiotics on transporters-enzymes in placenta.
Drug/Xenobiotic Model Exp Gene/Protein Ref
Paclitaxel Pre-treated human placenta ↑ABCB1/P-gp [102]
ABCG2/BCRP
Cell culture (Cytotrophoblast) ↓ABCB3 (TAP2)
ABCA9 (ABCA9)
ABCC10 (MRP7)
ABCD1 (ALDP)
SLC10A1 (NTCP)
SLC16A3 (MOT4)
SLC28A3 (S28A3)
SLC29A2 (SL9A2)
SLC7A5 (LAT1)
SLC7A7 (LAT2)
SLC3A1 (OATP3A1)
Thalidomide BeWo Cells ↑CYP3A4 [103]
CYP3A5
CYP2B6
PXR
Rifampicin CYP3A5
PXR
3ʹ-Azido-3ʹ-Deoxythymidine (AZT) JEG-3Cells First-trimester placenta ↑CYP1A1
activity
[104]
β-glucuronidase
activity
CYP reductase activity
GST activity
↓UGT activity
Valproic acid Human trophoblast BeWo cells ↑ABCG2/BRCP/
Activity
[105]
FOLR1 (FRalpha)
↓ABCC2 (MRP2)
SLC19A1/RFC [105,106]
SLCO1A4/OATP1A4
SLC7A5 (LAT1)
Human placenta ↑FOLR1 (FRalpha) [106]
SLC6A4 (SERT)
↓SLC46A1 (PCFT)
SCL19A1 (RFC)
SLC2A1 (GLUT1)
OCTN2 (L-Carnitine Transporter)
SLC44A1 (CTL1)
BeWo Cells
JEG-3
↑SLC46A1 (PCFT) [107]
FOLR1 (FRalpha)
Phenytoine Human trophoblast BeWo cells ↑ABCG2/BCRP [105]
SLC7A5/LAT1
SLCO1A4 (OATP1A4)
↓ABCC2 (MRP2)
Carbamazepine ↑ABCG2 (BCRP)
↕ABCC2 (MRP2)
↓SLCO1A2 (OATP1A2)
SLCO1A4 (OATP1A4)
SCL19A1 (RFC)
Lamotrigine ↑SLC7A5 (LAT1)
↓SLCO1A2/OATP1A2
SLCO1A4 (OATP1A4)
SCL19A1 (RFC)
FOLR1/FRalpha
Levetiracetam SCL19A1/RFC
SLC7A5/LAT1
SLCO1A2/OATP1A2
SLCO1A4/OATP1A4
Buprenorphine JEG3 Cells ↑ABCG2/BCRP/
Activity
[108]
Norbuprenorphine
R-(-).methadona HCl
S-(+)-methadone HCl
Dexametasone Human Placenta (Explants) ↑ABCB1 [25]
Cortisol ABCG2/BCRP
Etravirine Cell Culture (MDKII-ABCG2) ↓ABCG2/BCRP [109]
Ethanol Placental Microsomes ↑CYP2E1 [66]
Cigarrete smoke Human placenta ↑CYP1A, UGT activity [47]
↑CYP1A1, CYP4B1 [68]
↓CYP19A1 activity
Aflatoxin B1 JEG-3 ↑CYP19A1 [70]
Exp: expression, ↑: overexpression, ↓: subexpression, ↕: expression may vary, Italicized: gene expression, Bold: protein expression (alternative
name).
EXPERT REVIEW OF CLINICAL PHARMACOLOGY 7
7. Gene expression altered by the exposure to
xenobiotics
At the gene expression level, xenobiotic exposure during
pregnancy causes significant changes in maternal and fetal
tissues. The impact of this exposure on gene expression has
been clearly demonstrated, affecting particularly genes
involved in metabolism, oxidative stress, inflammation, and
immunity; however, this review focuses only on metabolism-
and transport-related genes. Consequently, these alterations
may provoke the deregulation of pregnancy and/or fetal
development. Table 2 [25,47,66,68,70,102–109] summarizes
the effects of xenobiotics on the expression of transporters
and enzymes in the placenta.
8. Placental metabolism of xenobiotics and its
repercussion on the fetus development
In the course of gestation, the pregnant woman may require
the use of drugs due to an underlying disease or a disease of
recent onset, despite the potential harmful effects on the fetal
development.
These conditions demonstrate that the placenta is not an
absolute protective barrier as it was believed. The way the pla-
centa limits the effects of xenobiotics on the fetus has been
subject of great research interest, so the main drugs used as
treatments for pregnancy complications started to be studied.
Table 3 [31,34–36,56,60,66,70–73,103,104,110–157]summarized
the drugs and other xenobiotics metabolized by placenta.
During the 60s, thalidomide was indicated for the treat-
ment of morning sickness in pregnant women, being with-
drawn by congenital malformations provoked on embryos.
It has been reported that CYP3A4/3A5/3A7 gene cluster
mediates thalidomide 5-hydroxylated metabolite formation
[158]. Recently, it was showed that thalidomide induces limb
abnormalities in mouse embryos treated with the human
CYP3A gene cluster, which was also expressed in mouse pla-
centa [159]. Besides, it was reported that thalidomide signifi-
cantly induced the CYP3A4/5 mRNA expression in the human
placenta and choriocarcinoma BeWo cells [103]. Therefore, this
data suggests that CYP3A in the human placenta may be
involved in the teratogenicity of thalidomide.
Numerous diseases require continuous pharmacological
treatment even during pregnancy such as diabetes, epilepsy,
depression, and infectious (HIV, HCV), among others. In the
case of glyburide (prescript in gestational diabetes), six glybur-
ide metabolites have been identified in human placental
microsomes in amounts significantly lower (~10%) than that
identified in the liver [120,160]. The main metabolite formed
by the placental enzyme CYP19 is ethyl hydroxy glycerol (M5)
[71,160], which is pharmacologically active, affecting fetal
euglycemia [71]. Glyburide administration during pregnancy
has been related to fetal growth restriction, macrosomia,
hypoglycemia, hyperbilirubinemia, polycythemia, hypocalce-
mia, and neonatal intensive care unit admission [161].
In the case of azidothymidine (AZT), for the treatment of
HIV or HCV infections, Patterson et al., (1997) detected AZT
and its glucuronide metabolite (AZT-G) in fetal plasma in
concentrations lower than maternal plasma after infusion
of rhesus macaques [110]. Furthermore, mono-, di-, and
triphosphate AZT metabolites have been detected in the
human placenta [110,111], whose glucuronidation capacity
in human is barely 2% of the therapeutic administered dose
[56]. In perfused placenta, the metabolite AZT-G was prefer-
entially excreted from the fetal compartment out to the
maternal circulation [56], which has been described as
a placental protective clearance mechanism [47]. This obser-
vation was confirmed in a model of pregnant baboons on
which a significant concentration gradient was observed
between amniotic fluid > fetal serum > maternal serum for
AZT (p < 0.019) and AZT-G (p < 0.002) [112].
The higher fetal levels could represent a slower clearance of
AZT in the placenta than in the mother [112]. The administra-
tion of this drug during pregnancy has been associated with
increased mitochondrial failure in the placenta, being the
probable reason of adverse perinatal outcomes [162] such as
preterm very low-birthweight and extremely low-birthweight
infants [163].
In the case of epilepsy;treatment has tobe continued in order
to ensure the maternal and fetal wellbeing, due to the physiolo-
gical changes during pregnancy there is a major risk of presence
of seizures [164]. One of the most studied antiepileptic drugs is
oxcarbazepine. Both in placental perfusion experiments and
human placental microsomes, oxcarbazepine was metabolized
to 10-hydroxy-10,11 dihydrocarbamazepine (10-OH-CBZ)
[126,127], that is as active as oxcarbazepine [165]. In vivo,10-
OH-CBZ has been detected in cord blood in concentrations
similar to maternal serum [166]. However, most of the 10-OH-
CBZ found in cord blood probably does not come entirely from
the placenta due to the low placental metabolism of oxcarbaze-
pine described in the aforementioned studies [126,127].
Moreover, in vivo, the drug and its metabolite are poorly accu-
mulated in both fetal circulation and placental tissue [128]. This
drug as a monotherapy, compared with other antiepileptic drugs
used during pregnancy, does not appear to show an increased
risk of malformations or adverse effects [166].
Overall, alcohol consumption during pregnancy is very
common worldwide. The enzyme alcohol dehydrogenase
(ADH) metabolizes ethanol to acetaldehyde [167,168], that is
the main pathway for the metabolism of ethanol in the liver
[169]. Whereas the remaining of oxidative metabolism is car-
ried out by CYP2E1 (about 10%) [169]. In the human placenta,
CYP2E1 is induced in a variable manner among drinking
mothers [66] and has higher affinity to ethanol than placental
ADH [168]. On the other hand, placental ADH (analogous to
class III ADH enzymes) is not inducible and its contribution in
the ethanol oxidation is minimal [152,153]. Therefore, CYP2E1
could account for ethanol metabolism in the placenta.
Although in perfusion studies it has been showed that the
human placenta oxidizes ethanol to acetaldehyde, the role of
the placenta is considerably lower than the liver one
(45.6 nmol h
−1
g
−1
of tissue vs 178 μmol h
−1
g
−1
of tissue,
respectively) [154,170]. Despite this, the placenta may contri-
bute to augment the amount of acetaldehyde produced,
increasing the fetal exposure to this genotoxic metabolite.
Acetaldehyde has been found in greater concentration in
amniotic fluid than in maternal venous blood, following the
ingestion of 0.3 gm/kg of ethanol in a pregnant woman at 16
8R. BLANCO-CASTAÑEDA ET AL.
Table 3. Xenobiotic metabolism in experimental models of human placenta.
Compounds
Drugs Metabolic pathway Enzyme involved Experimental model Metabolites detection Ref
Azidothymidine (AZT) or
Zidovudine
Glucuronidation
Phosphorylation
UGT Microsomes, JEG-3, perfusion, cultured primary
placental cells, explant, trophoblasts and Hofbauer cells,
baboon, rhesus macaque
ND [56,104,110–112]
Buprenorphine N-dealkylation
Glucuronidation
CYP19 perfusion of placental lobule, in vivo Placenta, meconium, umbilical
cord
[72,113–116]
Bupropion Hydroxylation,
Carbonyl reduction
CYP2B6, CYP19
11β- hydroxysteroid
dehydrogenases
Placental subcellular fractions,
ex vivo placental perfusion, placenta in vivo
Umbilical cord [117–119]
Glyburide Hydroxylation CYP19 Microsomes ND [71,120,121]
Methadone N-demethylation CYP11A1, CYP19 Microsomes, placenta
Mitochondrial and cytosolic fraction
Placenta, umbilical cord,
meconium
[73,122]
Levo-alpha- acetylmethadol N-demethylation CYP19 Microsomas ND [123]
Genistein Glucuronidation
Sulfonation
Perfusion Umbilical cord [124]
Midazolam Hydroxylation Microsomes,
BeWo
ND [103]
Olanzapine Glucuronidation Perfusion ND [125]
Oxcarbazepine Hydroxylation Microsomes, placental perfusion,
placental tissue
Placenta, umbilical cord [126–128]
Phencyclidine Hydroxylation Microsomes ND [129,130]
Fenoterol Sulfonation Perfusion ND [131]
Norepinephrine Hydroxylation Perfusion ND [132]
Ritodrine Sulfonation Baboon ND [133]
Sulfamethazine N-acetylation NAT2 Cytosolic fraction ND [35,36]
Thalidomide Hydroxylation CYP3A4/3A5 Microsomes,
BeWo cells
ND [103]
Warfarin Hydroxylation Aryl hydrocarbon hydroxylase
(CYP1A1)
Microsomes ND [134]
Other compounds
2-acetyl
aminofluorene
Hydroxylation Microsomes ND [135]
Benzo(a)pyrene Hydroxylation
Co-oxidation of a metabolite
Lipoxygenase, CYP1A1 Perfusion, BeWo cells Placenta, umbilical cord [136–139]
7,12-dimethylbenz(a)
anthracene
Hydroxylation Microsomes Placenta [140]
Aflatoxin B
1
Epoxidation
Hydroxylation
Lipoxygenase,
CYP19A1
Microsomes, perfusion, in vitro reaction, JEG-3 Umbilical cord [70,141–144]
2-Aminofluorene N-Acetylation
Oxidation
NAT1
Peroxidase
Placenta ND [34,145]
P-aminobenzoic acid (PABA) N-Acetylation NAT1 Perfusion ND [146]
Bisphenol A Glucuronidationsulfation Placenta Placenta, umbilical cord [147,148]
Cocaine Hydrolisys of ester groups Placenta Placenta, umbilical cord,
meconium
[122,149–151]
Diuron N-demethylation CYP1A1 Perfusion, Microsomes BeWo cells ND [60]
Ethanol Oxidation Alcohol dehydrogenase CYP2E1 Perfusion Amniotic fluid [66,152–155]
Styrene-7,8-Oxide Epoxidation Epoxide hydrolase Microsomes ND [31]
4-Methylnitrosamino-
1-(3-pyridyl)-1-butanone
(NNK)
Carbonyl reduction Carbonyl reductase Placenta, microsomes ND [156,157]
ND: no data available.
EXPERT REVIEW OF CLINICAL PHARMACOLOGY 9
to 18 weeks’gestation [155]. Both ethanol and acetaldehyde
have detrimental effects on placental function, such as
decreasing blood flow and increasing intravascular coagula-
tion, provoking infarctions and hypoxia [171,172]. Therefore,
the fetus may suffer hypoxia or hypoglycemia, conditions that
could provoke IGR [173]. Other reported disturbances are
cardiac malformations [174], kidney defects [175], preterm
birth [176], and stillbirth [177]. All these alterations have
been associated with the fetal alcohol syndrome and fetal
alcohol spectrum disorders [178].
One of the main public health problems worldwide is the
consumption of illegal substances such as cocaine that are harm-
ful to both the mother and fetus. A previous in vitro study with
human placental microsomes suggested that cocaine may be
metabolized by placental cholinesterase [179]. Later, Simone
et al. (1994a) detected butyrylcholinesterase (BChE) activity in
the human placenta, suggesting that this organ has the capacity
to metabolize cocaine [180]. Conversely, Schenker et al. (1993),
did not find evidence for significant cocaine metabolism in
perfusion studies. However, it was described that the placenta
is not a barrier for transferring cocaine and its derivatives
[181,182]. Supporting this, a significant amount of cocaine and
its toxic metabolites benzoylecgonine and cocaethylene are
retained by the placenta, prolonging fetal exposure to these
compounds [180]. Cocaine and its metabolites (predominantly
benzoylecgonine) have been identified in amniotic fluid [183–
185], umbilical cord, placenta [122,149,150,184], and meconium
[122,149–151,185]. Thus, the detection of these compounds in
the biological matrices from the newborn and placenta suggests
that the human placenta has the capacity to metabolize cocaine,
as it has been described in animal studies [186,187]. Cocaine
consumption during pregnancy has been associated with
impaired placental amino acid transport, endocrine disruption
[188], and placental abruption [189]. As a result, the fetus may
suffer from IGR, stillbirth, hypertension, tachycardia, and extreme
vasoconstrictive effects. All these changes could impact on the
global brain development [188].
In order to treat addictions during pregnancy, buprenorphine,
bupropion, and methadone are prescribed for minimizing the
abstinence symptoms and the withdrawsyndrome. At term pla-
centa perfusion study showed that less than 10% of buprenor-
phine (BUP) was transferred to the fetus and ~5% was
metabolized to norbuprenorphine (NBUP) [113]. The concentra-
tions of NBUP are higher in placenta than in maternal plasma and
umbilical cord [113,114] and coincide with the activity of
N-dealkylation of BUP to NBUP by CYP19 in the placenta [72].
The main metabolites detected in placenta were NBUP and
NBUP-glucuronidation (NBUP-Gluc), while in meconium was
NBUP, which presence can predict the neonatal abstinence syn-
drome (NAS) in BUP-maintained women [115]. Moreover,
a significant negative correlation was observed between the
percentage of free BUP in meconium and the neonate’s head
circumference [115]. In contrast, a positive correlation was
described between the metabolites of BUP in placenta and the
neonatal outcomes such as placenta and birth weight, head
circumference, length, gestational age at delivery, Apgar scores
(1 and 5 min), length of hospital stay (days) and the required
ingress to NAS (r > 0.83) [116]. It is worth mentioning that NBUP
is a pharmacologically active metabolite [190] with potential
neonatal adverse effects. Maternal buprenorphine administra-
tion has acute suppressive effects on fetal heart rate and move-
ment, which increases as gestation progresses [191]. In addition,
these effects have been associated with agitation, hypertonia,
hypotonia, somnolence, respiratory distress, and feeding disor-
der in newborns [192].
Reports of in vitro and in placental perfusion studies showed
that the human placenta metabolizes bupropion to erythro- and
threohydrobupropion and in lower amounts to hydroxybupro-
pion [117,118]. These metabolites are pharmacologically less
active than bupropion [193,194]. Data from an in vivo study
demonstrated that the concentrations of bupropion metabolites
in the umbilical cord are higher than those of bupropion [119].
Moreover, higher levels of threohydrobupropion in the amniotic
fluid than those in the umbilical cord are found, suggesting that
this metabolic pathway is very active in the fetus [119]. In micro-
somal fractions, 11B-hydroxysteroid dehydrogenases are the
main placental enzymes involved in the reduction of bupropion
to erythro- and threohydrobupropion, whereas CYP2B6 and, to
a lesser extent, CYP19 are responsible for the formation ofhydro-
xybupropion [117]. Bupropion metabolites increase significantly
(p < 0.01) in the placentas of women who smoked >20 cigarettes
per day compared to metabolites in placentas of nonsmokers
[117]. A placental perfusion study showed that threohydrobu-
propion and bupropion at concentrations 150 ng/mL and
450 ng/mL did not affect the placental tissue viability or the
functional parameters [118]. Bupropion administration during
pregnancy has been related to low risk of teratogenicity but it
is associated with left ventricular outflow tract obstruction when
bupropion is administrated during the first trimester of gesta-
tion [195].
In at term human placenta, the enzyme CYP19 is respon-
sible for the metabolism of methadone to 2-ethylidine-
1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) [73], and of
Levo-α-acetylmethadol (LAAM) to L-α-acetyl-N-normethadol
(norLAAM) [123]. Methadone and EDDP have been identified
in matched placenta and umbilical cord specimens from preg-
nant women receiving methadone daily [122,196]. However,
placental EDDP appears to derive primarily from maternal
methadone metabolism, since less than 1% of methadone is
converted to EDDP in the placenta [197]. Infants born from
mothers receiving methadone have presented lower birth
weight, length, and head circumference [198].
The exposition to xenobiotics during pregnancy is not only
related to drug consumption/prescription, there are a lot of
substances taken from either diet or environment that may
have repercussion on the fetal development and wellbeing.
One of these is bisphenol A (BPA), a xenoestrogen used as
a monomer in the manufacture of plastic products [199]. BPA
has been detected in measurable levels in umbilical cord
serum both in mid-gestation and close to delivery [147,148].
In these studies, BPA and sulfated BPA levels in cord serum
were higher than glucuronided BPA ones [147,148]. This could
reflect the metabolic activity of conjugation in placenta, since
several studies have reported higher sulfotransferase activity
and lower UGT activity in the human placenta compared with
liver [200–202]. Further, Liu et al. (2017) detected higher con-
centrations of conjugated BPA metabolites in cord serum than
in paired maternal one, which could be the result of the
10 R. BLANCO-CASTAÑEDA ET AL.
placental and fetal metabolism at least at the end of preg-
nancy [148]. It has been found a limited placental permeability
of BPA-glucuronide in a human placenta perfusion study [203],
and a slower clearance of conjugated BPA in feto-placental
compartment in animal studies [204,205]. The BPA exposure
in-utero may provoke fewer parenchymal tissue development
in endocrine pancreas, kidney, and uterus; triggering diabeto-
genic and atherogenic effects [199]. Besides, BPA exposure
increases the risk of developing either attention-deficit/hyper-
activity and/or autism spectrum disorders [206] and may be
associated with adverse reproductive outcomes [207,208].
Aflatoxin B1 (AFB1), a fungal toxin produced by Aspergillus
species, is a common dietary contaminant usually found in low-
and middle-income countries [209]. Several studies have reported
AFB1 and aflatoxin-albumin adducts both in maternal and in cord
serum [141,142,210–212]. However, the cord adduct levels were
up to 10-fold lower than maternal levels, probably as a result of
lower passage through placenta and/or lower efficiency of fetal
metabolism [210]. Two studies have demonstrated the capacity of
human placental tissue to activateAFB1.Thefirststudyreveals
activation by CYP1A and CYP19 enzymes [213], while the second
through epoxidation of AFB1 by a purified lipoxygenase from
human term placenta and of intrauterine conceptual tissue at
8–10 weeks of gestation [143]. The best-known metabolites of
AFB1 responsible for its carcinogenicity are AFB-8,9-epoxide and
aflatoxicol (AFL). Nonetheless, AFL has been the only metabolite
detected in both perfusion models and in vitro incubations with
placental cytosolic fractions [144]. This last result is supported by
Storvik et al., (2011) who reported the AFB1 biotransformation to
AFL by JEG-3 cells and by recombinant CYP19A1 [70]. Exposure to
AFB1 during pregnancy has been linked to poor child growth and
development, particularly lowerbirthweightandsmallerhead
circumference [209,212], as well as with reduced IgA levels [212].
Pregnant mothers are exposed to polycyclic aromatic hydro-
carbons (PAH) from sources such as diet and air pollution. The
best-known PAH is benzo(a)pyrene (BP). The effects on preg-
nancy have also became one of the main research fields in the
late years. Perfusion placental experiments have demonstrated
that maternal exposure to BP reaches fetus and that the placenta
can activate BP to diol-epoxides that bind covalently to DNA
(DNA adduct) [136]. In the same study, the authors confirmed
this result in trophoblastic BeWo cells. Although CYP1A1 is the
key enzyme in BP activation in the human placenta [29,59], it has
been described that a cytosolic lipoxygenase (LO) purified from
the human term placenta mediate co-oxidation of BP to several
reactive metabolites [213]. DNA adducts have been found in
placentas from both cigarette smokers and nonsmokers
[137,214], and in cord blood [138,215,216].
Aprotectiveeffectoftheplacentainnewbornsbornto
mothers exposed to tobacco smoke was demonstrated by
asignificantdecreaseofDNAadductlevelsinnewbornscom-
pared with mothers [139]. However, prenatal exposure to BP and
other PAHs has been significantly associated with stillbirths, con-
genital abnormalities, fetal growth reduction, and smaller head
circumference and reabsorption (animal model) [215,217–219].
The detection of metabolites in specimens of newborn,
placenta, and amniotic fluid highlights the role of the placenta
in the metabolism of xenobiotics in pregnant women.
However, the expression and activity of the XMEs that perform
this function in the placenta is by far much lower compared
with organs specialized in the biotransformation of xenobio-
tics, such as liver or kidney. Furthermore, the XMEs and trans-
porters function as a set in the placenta, that in some cases
could represent a protective mechanism for the fetus against
harmful endogenous and exogenous compounds.
9. Conclusion
The placenta is an organ that contributes in the biotransforma-
tion of several xenobiotics, which has the potential to modify the
expression of enzymes and transporters involved in its physiol-
ogy and in the fetus development. Better knowledge about the
effects exerted by xenobiotics and their impact on the placental
systems of metabolism and transport will elucidate the patho-
physiology of pregnancy complications and the alterations in
fetal development. This expanded knowledge will also help to
select the best and safest therapies both for the treatment of
diseases during pregnancy and for the protection of the fetus.
10. Expert opinion
10.1. How could the advances or research discussed may
impact on real-world outcomes?
Many factors are involved in the high variability of the expression
profile and activity of XMEs in the placenta. The identification of
polymorphisms and methylation patterns in XME-encoding
genes could be useful as predictors of fetal toxicity. This informa-
tion is expected to allow for better and safer selection of phar-
macotherapy in pregnancy, thereby limiting the potential
adverse events and decreasing the expenses associated with
medical care. At present, knowledge in this field is scarce and
has little or no clinical applicability in the short term; however, it
lays the foundation for the development of new lines of research.
10.2. What are the key areas for improvement in the
area being discussed?
To determine the net effect of a drug in pregnancy, future studies
must guarantee evaluation of global gene expression in the pla-
centa, placental metabolism, gene polymorphisms in both the
placenta and mother, and drug monitoring in maternal plasma.
Despite their deleterious effects, some drugs cannot be
discontinued in pregnant women. Therefore, it is advisable
to find markers that can predict such adverse events at the
early stages of pregnancy. The latter suggestion implies the
evaluation of polymorphisms and methylation patterns in
chorionic villous samples and/or amniotic fluid. Nevertheless,
their accessibility is limited because they are not involved in
standard diagnostic procedures.
10.3. What potential does further research hold?
Additional studies in this field hold promise to identify pre-
dictive biomarkers of fetotoxicity, in order to optimize phar-
macotherapy in pregnancy.
Continuous scientific advances make it hard to determine
a final point in this research field.
EXPERT REVIEW OF CLINICAL PHARMACOLOGY 11
10.4. Does the future of study lie in this area? Are there
other more promising areas in the field which could be
progressed?
It is important to evaluate the many factors to which a pregnant
woman is exposed, and they could influence the expression of
genes involved in the transport and metabolism of drugs in the
placenta. The above data are needed for a better understanding
of the pharmacological effects on both a mother and fetus.
New technologies have been focused on the development of
strategies to administer drugsinamorerationalwayduring
pregnancy. Among such technologies is elastin-like polypeptides,
which reduce transplacental drugtransferandnanoparticlesthat
serve as transplacental delivery vehicles for drugs.
10.5. How will the field evolve in the future?
This field will evolve together with scientific and technological
advances in molecular and developmental biology. Current knowl-
edge on pharmacotherapy in pregnancy is mainly based on the
adverse effects observed in animal models and clinical case
reports. Research in basic science such as that described in the
present review, together with scientific and technological
advances, will allow for the adoption of individualized treatment
guidelines, ensuring therapeutic effects and minimizing adverse
events.
Funding
This work was supported by Instituto Politecnico Nacional-Mexico, SIP-
20196451 and SIP-20196043.
Declaration of Interest
The authors have no relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial conflict with
the subject matter or materials discussed in the manuscript. This includes
employment, consultancies, honoraria, stock ownership or options, expert
testimony, grants or patents received or pending, or royalties.
Reviewer Disclosures
Peer reviewers on this manuscript have no relevant financial or other
relationships to disclose.
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