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R E S E A R C H Open Access
Genetic polymorphisms of glutathione
S-transferase M1 and T1, and evaluation of
oxidative stress in patients with non-small cell
lung cancer
Hongyan Zhang
1
, Xuwei Wu
1
, Yi Xiao
1
, Mei Chen
1
, Zhidong Li
1
, Xing Wei
1
and Kaifa Tang
2*
Abstract
Background: Our objective is to investigate the genetic polymorphisms of the glutathione S-transferase M1 and T1
genes (GSTM1 and GSTT1) and evaluate oxidative damage in patients with non-small lung cancer (N-SCLC).
Methods: One hundred and ten patients with N-SCLC and 100 controls are included in this case-control study. Multiplex
polymerase chain reaction (PCR) analyses were used to identify the genotypes. The activities of malondialdehyde (MDA)
and nitric oxide (NO) and total antioxidant capacity (T-AOC) were detected by spectroscopic analysis.
Results: The frequencies of the GSTM1, T1, and GSTM1/T1 null genotypes in the patient group were significantly higher
than that in the control group (OR = 2.071, P= 0.009; OR = 1.900, P= 0.024; OR = 3.258, P= 0.003). The activities of MDA
and NO were significantly higher in the patient group than that in the control group (P<0.001), and T-AOC was
significantly lower in patient group than that in control group (P<0.001). The activities of MDA, and NO were
higher but the T-AOC was lower in patients with the GSTM1, T1 and M1/T1 null genotypes than those in patients
with GSTM1, T1 and M1/T1 present genotypes (P<0.001).
Conclusions: Our results suggest that oxidative damage may be play a important role in patients with N-SCLC, and
that GSTM1 and GSTT1 null genotypes may predispose the cells of patients with N-SCLC to increased oxidative
damage.
Keywords: Glutathione S-transferases, Polymorphism, Oxidative stress, Non-small lung cancer
Background
Lung cancer remains the leading cause of cancer death
in the United States and in European countries, as well
as in Asian countries, mainly due to late presentation
[1]. Among various histological types of lung cancers,
non-small cell lung cancer (N-SCLC) accounts for ap-
proximately 80%. However, knowledge on early detec-
tion, therapeutic progress, and the prognosis of N-SCLC
patients remain poor [2].
Lung is a primary organ with large surface area that is dir-
ectly exposed to ambient air, and therefore higher oxygen
tensions, and is known to regulate reactive oxygen species
(ROS) production [3]. The lung cells experience enhanced
oxidative stress (OS) by exogenous free radical-generating
environmental irritants and pollutants, including oxidants
such as cigarette smoke, ozone, and endogenous factors like
inflammation and activation of inflammatory cells [4]. Previ-
ous study has shown that oxidative stress and free radicals
have been associated with an increased risk of various can-
cers [5]. Others studies have suggested that exposure to OS
leads to single and clustered damage to cellular DNA and is
involved in mutations and genomic instability, which even-
tually results in malignant transformation [6,7]. Ito et a1.
demonstrated that low antioxidant capacity (AOC) in those
who never smoked but that have N-SCLC may have con-
tributed to excessive oxidative DNA damage in the lung
* Correspondence: doc.tangkf@hotmail.com
2
Affiliated Hospital of Guiyang Medical College, No. 9 Beijing Road, Guiyang
550004, China
Full list of author information is available at the end of the article
EUROPEAN JOURNAL
OF MEDICAL RESEARC
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© 2014 Zhang et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain
Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article,
unless otherwise stated.
Zhang et al. European Journal of Medical Research 2014, 19:67
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tissues [8]. Peddireddy et al. showed that an evidence-
based increased rate of oxidativestressplaysarolein
the pathogenesis of N-SCLC because a failure in the
oxidant/antioxidant balance favors lipid peroxidation
and DNA damage [9].
Glutathione S-transferases (GST) are a family of phase
II enzymes, which uses reduced glutathione in a conju-
gation and in a reduction reaction to eliminate many
different toxic electrophiles and products of oxidative
stress [10,11]. Glutathione S-transferases (GSTM1) are
able to detoxify benzopyrene diolepoxide, whereas gluta-
thione S-transferases T1 (GSTT1) can conjugate oxidized
lipids and halogenated compounds [12]. GSTM1 and
GSTT1 are expressed in lung tissues [13]. GSTM1 (1p13)
and GSTT1 (22q 11.2) genes, encoding for a μ-GST isoen-
zyme and a θ-GST isoenzyme, respectively, can be deleted,
thereby causing a lack of the respective enzyme function
[14]. Some previous studies suggested that GSTM1 and
GSTT1 null genotypes may be associated with increased
susceptibility to lung cancer [15,16], but other studies have
shown that there no association between GSTM1 and T1
null genotypes for lung cancer risk [17,18].
However, few reports have investigated the relation-
ship between GSTM1 and T1 genotypes and the level of
oxidative stress (OS) in patients with N-SCLC. In this
study, our intention is to determine the genotypic fre-
quencies of the GSTM1 and T1 polymorphisms, and to
evaluate the OS in patients with N-SCLC from Yunnan
Province of China. The genotypes of GSTM1 and T1
and oxidative biochemical markers such as malondialde-
hyde (MDA), nitric oxide (NO) and total antioxidant
capacity (T-AOC) were detected in each sample.
Methods
Participants
This case-control study consisted of 110 patients with
primary N-SCLC and 100 healthy controls from Yunnan
Province of China. The mean age, sex, performance status
(PS), and smoking habits are shown in Table 1. N-SCLC
was histologically confirmed in all patients, and all
N-SCLC patients were evaluated and staged at their
first visit according to medical history, physical examin-
ation including PS by Eastern Cooperative Oncology
Group stage, complete blood count, serum biochemis-
try analyses, chest X-ray, and computed tomography
scans. The controls were selected from a pool of healthy
volunteers who visited the general health checkup center
during the same period. A detailed questionnaire was
completed for each case and control by a trained inter-
viewer. All controls had no known medical illness or
hereditary disorders and were taking no medications.
The protocol was approved by the Ethics Committee
of the Affiliated Yan’an Hospital of Kunming Medical
University.
Glutathione S-transferase gene polymorphisms
An AxyPrep TM Genomic DNA Miniprep Kit (Axygen
Biosciences, Union City, CA, USA) was used to isolate gen-
omic DNA from peripheral blood samples. The GSTM1
and GSTT1 genotypes were identified by multiplex poly-
merase chain reaction (PCR) using published primer se-
quences as follows: GSTM1 gene, 5′-GAA CTC CCT
GAAAAGCTAAAGC-3′(forward) and 5′-GTT GGG
CTC AAA TAT ACG GTG G-3′(reverse); GSTT1 gene,
5′-TTC CTT ACT GGT CCT CAC ATC TC-3′(forward)
and 5′-TCA CCG GAT CAT GGC CAG CA-3′(reverse);
Table 1 The descriptive statistics for the demographic
and clinical characteristics of all participants
N-SCLC
(n = 110)
Controls
(n =100)
Pvalue
Mean age ± SD (Age range) 60.18 ± 8.64 59.23 ± 11.12 0.493
Sex
Female (%) 16 (14.55) 13 (13.00) -
Male (%) 94 (85.45) 87 (87.00) 0.746
Smoking history
a
Mean pack-years ± SD 50.38 ± 20.25 48.02 ± 20.76 0.405
Performance status
b
0 to 1 (%) 83 (75.45) - -
2 to 4 (%) 27 (24.55) - -
N-SCLC, non-small cell lung cancer; SD, standard deviation.
a
Smoking history in pack-years.
b
Eastern Cooperative Oncology Group performance status.
Figure 1 A representative image of multiplex polymerase chain
reaction (PCR) analysis of glutathione S-transferase M1 and T1
(GSTM1/T1), and β-actin gene polymorphisms. Lane M, 50-bp
DNA marker; Lane 1, GSTM1/T1 (+/+) genotype; Lane 2, GSTM1/T1 (+/-)
genotype; Lane 3, GSTM1/T1 (-/+) genotype; Lane 4, GSTM1/T1 (-/-)
genotype and Lane 5, negative control.
Zhang et al. European Journal of Medical Research 2014, 19:67 Page 2 of 6
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and a 400-bp fragment for the β-actin gene 5′-ACT CCC
CAT CCC AAG ACC-3′(forward) and 5’-CCT TAA TGT
CAC GCA CGA T-3’(reverse) was used as an internal con-
trol for DNA amplification [19] (Figure 1).
Measurement of malondialdehyde, total antioxidant
capability and nitric oxide
The contents of malondialdehyde (MDA), total antioxi-
dant capability (T-AOC) and nitric oxide (NO) in plasma
were assayed using colorimetric methods with a spectro-
photometer (Biomate 5, Thermo Electron Corporation,
Rochester, NY, USA). The assays were conducted using
the assay kits purchased from Nanjing Jiancheng Institute
of Bioengineering (Nanjing, China) and used according to
the manufacturer’sinstructions.
Statistical analysis
The χ
2
test was used to compare sex and cigarette smoke
between patients and controls. All data are expressed as
the mean ± standard deviation (SD). Age, smoking index
expressed as pack-years (number of cigarettes smoked per
day × number of years smoked/20) were compared using
the unpaired Student’sttest. The differences in the
frequencies of the GST genotypes between groups were
analyzed using the χ
2
test, and the odds ratios (OR)
with95%confidenceintervals(CI)arereported.The
difference between the two groups was analyzed by un-
paired ttest with two-tailed values, and P<0.05 was
considered statistically significant. All analyses were per-
formed using SPSS software version 16.0 (SPSS, Inc.,
Chicago, IL, USA).
Results and discussion
No statistically significant differences were found be-
tween patients and controls with respect to age, sex and
smoking history. The frequencies of the GSTM1 and T1
genotypes in cases and controls are shown in Table 2.
The frequency of the GSTM1 null genotype was 42.0%
in the control group and 60.0% in the patient group
(OR = 2.071; CI 95%, 1.194 to 3.593; P= 0.009), and
34.0% and 78.0% (OR = 4.132; CI 95%, 1.957 to 8.724;
P<0.001) in only GSTT1 null genotype cases, and 51.1%
and 52.9% (OR = 0.719; CI 95%, 0.298 to 1.734; P=0.462)
in only GSTT1 present genotype cases. The frequency of
the GSTT1 null genotype was 53.0% in the control group
and 69.2% in the patient group (OR = 1.900; CI 95%, 1.084
Table 2 The distribution of glutathione S-transferase (GST) M1 and T1 genotypes in study groups
Group N-SCLC (%) (n = 110) Control (%) (n = 100) χ
2
Pvalue OR (CI 95%)
GSTT1 total (n = 110) (n = 100)
GSTM1(+) 44 (40.0) 58 (58.0) - - -
(-) 66 (60.0) 42 (42.0) 6.794 0.009 2.071 (1.194 to 3.593)
GSTT1(-) (n = 75) (n = 53)
GSTM1(+) 24 (32.0) 35 (66.0) - - -
(-) 51 (78.0) 18 (34.0) 14.480 <0.001 4.132 (1.957 to 8.724)
GSTT1(+) (n = 35) (n = 47)
GSTM1(+) 20 (57.1) 23 (48.9) - - -
(-) 15 (52.9) 24 (51.1) 0.542 0.462 0.719 (0.298 to 1.734)
GSTM1 total (n = 110) (n = 100)
GSTT1(+) 35 (31.8) 47 (47.0) - - -
(-) 75 (69.2) 53 (53.0) 5.073 0.024 1.900 (1.084-3.331)
GSTM1(-) (n = 66) (n = 42)
GSTT1(+) 15 (22.7) 24 (57.1) - - -
(-) 51 (77.3) 18 (52.9) 13.177 <0.001 4.533 (1.958-10.496)
GSTM1(+) (n = 44) (n = 58)
GSTT1(+) 20 (45.5) 23 (39.7) - - -
(-) 24 (54.5) 35 (60.3) 2.233 0.135 1.826 (0.826-4.036)
GSTM1/T1
(+/+) 20 (18.2) 23 (23.0) - - -
(+/-) 24 (21.8) 35 (35.0) 0.345 0.557 0.789 (0.357-1.743)
(-/+) 15 (13.6) 24 (24.0) 0.542 0.462 0.719 (0.298-1.734)
(-/-) 51 (46.4) 18 (18.0) 8.571 0.003 3.258 (1.457-7.287)
+, present genotype; -, null genotype; OR, odds ratio; CI, confidence intervals.
Zhang et al. European Journal of Medical Research 2014, 19:67 Page 3 of 6
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to 3.331; P= 0.024), and 52.9% and 77.3% (OR = 4.533; CI
95%, 1.958 to 10.496; P<0.001) in only GSTM1 null geno-
type cases, and 60.3% and 54.5% (OR= 1.826; CI 95%,
0.826 to 4.036; P= 0.135) in only GSTM1 present geno-
type cases. The frequency of the GSTM1/T1 null geno-
type was 18.0% in the control group and 46.4% in the
patient (OR = 3.258; CI 95%, 1.457 to 7.287; P=0.003).
There were significant differences between the control
group and patient group with respect to the frequencies of
the GSTM1 and T1 genotypes in this study.
Glutathione S-transferase M1 and T1 polymorphisms
with respect to MDA, NO, and T-AOC in the plasma are
displayed in Table 3. The data of MDA, NO and T-AOC
were distributed in a nearly normal fashion. The activity
of MDA and NO were significantly higher in the patient
group than in the control group (P<0.001), and T-AOC
was significantly lower in the patient group than in the
control group (P<0.001). Furthermore, the activities of
MDA and NO in the GSTM1, T1 and M1/T1 null geno-
type groups were statistically significantly higher than that
with the GSTM1, T1 and M1/T1 present genotypes
(P<0.001). However, the levels of T-AOC in the GSTM1,
T1 and M1/T1 null genotypes groups were statistically
significantly lower than that with the GSTM1, T1 and
M1/T1 present genotypes (P<0.001). In addition, we
found that the GSTM1 and GSTT1 genotypes also
affect the levels of MDA, NO and T-AOC in the control
group. The levels of MDA and NO in the GSTM1 and
GSTT1 null genotype groups were higher than that in
present genotype group, and T-AOC was lower in present
genotype group (P<0.05).
Oxidative stress (OS) is defined as an imbalance be-
tween production of free radicals and reactive metabo-
lites, which are called reactive oxygen species (ROS),
and ROS elimination by protective mechanisms which
are referred to as antioxidants, and this imbalance leads
to damage of important molecules and cells, with poten-
tial impact on the whole organism [20]. In addition, can-
cer initiation and progression have been shown to be
associated with oxidative stress by increasing DNA mu-
tations or inducing DNA damage, genome instability,
and cell proliferation [21]. Previous studies showed that
an increased rate of oxidative stress plays an important
role in the pathogenesis of N-SCLC [8,9]. In the current
study, our results suggest that the levels of MDA and
NO were higher in the patient group than that in the
control group, but the level of T-AOC was lower in the
patient group than that in the control group.
Glutathione S-transferases (GSTs), an important super
family of phase II drug-metabolizing enzymes that re-
spond to oxidative stress, include at least seven distinct
classes, namely, α(A), μ(M), π(P), σ(Sigma), ζ(Zeta), ω
(Omega) and θ(T), and play an important role in cell
protection by catalyzing the conjugation of a large variety
Table 3 Genetic polymorphisms of glutathione S-transferase (GST) M1 and T1 in relation to plasma MDA, NO and T-AOC
Group N MDA (nmo/lmL) NO (nmol/mL) T-AOC (units/mL)
Control 100 8.49 ± 3.30 16.79 ± 5.37 13.69 ± 4.56
Case 110 11.67 ± 4.31 19.68 ± 4.11 9.88 ± 3.58
P<0.001 <0.001 <0.001
GSTM1
(+) 44 10.18 ± 4.23 18.01 ± 3.56 11.11 ± 2.67
(-) 66 12.67 ± 4.09 20.80 ± 4.09 9.07 ± 3.88
P<0.001
a
; 0.003
b
<0.001
a
; <0.001
b
<0.001
a
; 0.001
b
GSTT1
(+) 35 9.29 ± 2.84 17.98 ± 3.99 11.73 ± 2.82
(-) 75 12.78 ± 4.44 20.48 ± 3.94 9.03 ± 3.58
P<0.001
a
; <0.001
c
<0.001
a
; 0.003
c
<0.001
a
; <0.001
c
GSTM1/T1 Control Case PControl Case PControl Case P
(+/+) 23 7.81 ± 2.97 20 8.56 ± 2.86 0.047 23 15.74 ± 4.38 20 17.68 ± 3.57 0.049 23 14.71 ± 4.29 23 11.97 ± 2.28 0.046
(+/-) 35 8.45 ± 3.01 24 11.52 ± 4.76 0.018 35 16.05 ± 5.13 24 18.28 ± 3.60 0.032 35 13.68 ± 4.79 35 10.39 ± 2.80 0.028
(-/+) 24 8.47 ± 2.98 15 10.27 ± 2.60 0.021 24 16.23 ± 4.90 15 18.37 ± 4.59 0.027 24 13.59 ± 4.92 24 11.40 ± 3.47 0.024
(-/-) 18 8.81 ± 3.12 51 13.38 ± 4.20 0.008 18 18.02 ± 4.29 51 21.51 ± 3.68 0.004 18 10.27± 5.01 18 8.39 ± 3.75 0.003
P<0.001
a
; <0.001
d
<0.001
a
; <0.001
d
<0.001
a
; <0.001
d
+, present genotype; -, null genotype; MDA, malondialdehyde; NO, nitric oxide; T-AOC, total antioxidant capacity.
a
compared with control.
b
compared with GSTM1 (+).
c
compared with GSTT1 (+).
d
compared with GSTM1/T1 (+/+).
Zhang et al. European Journal of Medical Research 2014, 19:67 Page 4 of 6
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of endogenous and exogenous compounds, including ROS
and carcinogenic compounds and their metabolites. Hu-
man cytosolic GST genes exhibit genetic polymorphisms,
and many genetic polymorphisms lead to altered GST ac-
tivities, which may be partially responsible for the individ-
ual host’s susceptibility to oxidative damage. Previous
studies suggested that GSTM1 and GSTT1 null genotypes
may be associated with increased susceptibility to lung
cancer [15,16], but other studies have shown no associa-
tions between GSTM1 and T1 null genotypes for lung
cancer risk [17,18]. In our results, we found that the fre-
quencies of the GSTM1, T1, and M1/T1 null genotypes
were significantly higher in the patient group than that in
the control group. Moreover, we found that OR for
GSTM1 (null/present) in T1 null genotype (OR = 4,132)
and present genotype (OR = 0,719) groups, and OR for
GSTT1 (null/present) in M1 null genotype (OR = 4.533)
and present genotype (OR = 1.826) groups are heteroge-
neous. It was shown that a significant susceptibility to oxi-
dative damage is not attributable to the presence of either
the M1 or T1 gene. Both genes must be positive for the
significance of OR.
Furthermore, the association between the GSTM1 and
T1 genotypes and level of oxidative stress in the patient
group was analyzed in the current study. We found that
the activities of MDA and NO in the GSTM1, T1 and
M1/T1 null genotype groups were statistically signifi-
cantly higher than that in the GSTM1, T1 and M1/T1
present genotype groups. The level of T-AOC in the
GSTM1, GSTT1 and GSTM1/T1 null genotype groups
were statistically significantly lower than that in the
GSTM1, T1 and M1/T1 present genotype groups. More-
over, we found that for one of the genes of M1 and T1
to be positive is not sufficient for susceptibility to oxida-
tive damages. Both genes must be positive for an import-
ant increase in susceptibility to oxidative damages.
Conclusions
Our results suggest that oxidative damage may play an
important role in patients with N-SCLC and that the
GSTM1 and GSTT1 null genotypes may predispose the
tissues of patients with N-SCLC to increased oxidative
damage. Both null genotypes must be positive for an im-
portant increase in the susceptibility to oxidative damages.
Therefore, more attention should be paid to oxidative
stress-related pathological manifestations in patients with
N-SCLC who bear the GSTM1 and GSTT1 null genotypes.
Furthermore, studies on glutathione S-transferases gene
polymorphisms and levels of oxidative stress should be
done in a multicenter, multi-ethnic population and with a
large number of patients with N-SCLC in the future.
Abbreviations
GSTM1: glutathione S-transferase M1; GST T1: glutathione S-transferase T1;
N-SCLC: non-small lung cancer; PCR: multiplex polymerase chain reaction;
OS: oxidative stress; MDA: malondialdehyde; NO: nitric oxide; T-AOC: total
antioxidant capacity.
Competing interests
The authors declare that they have no competing interests.
Authors’contributions
KT designed the research; HZ, XW, YX, MC, ZL and XW performed the
research; and HZ analyzed the data and drafted the manuscript. All authors
read and approved the final version of the manuscript.
Acknowledgements
We are grateful to all subjects who participated in this study. This project
was supported by the Application Fundamentals Foundation of Yunnan
Province, China (Grant No. 2010ZC198) and National Natural Science Fund of
China (Grant No. 81300541).
Author details
1
Affiliated Yan’an Hospital of Kunming Medical University, No. 245 Renmin
East Road, Kunming 650051, China.
2
Affiliated Hospital of Guiyang Medical
College, No. 9 Beijing Road, Guiyang 550004, China.
Received: 29 January 2014 Accepted: 17 November 2014
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doi:10.1186/s40001-014-0067-3
Cite this article as: Zhang et al.:Genetic polymorphisms of
glutathione S-transferase M1 and T1, and evaluation of oxidative
stress in patients with non-small cell lung cancer. European Journal
of Medical Research 2014 19:67.
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Zhang et al. European Journal of Medical Research 2014, 19:67 Page 6 of 6
http://www.eurjmedres.com/content/19/1/67