Cytogenetic biomarkers, urinary metabolites and metabolic gene polymorphisms in workers exposed to styrene

The present study comprised a biomonitoring study in 95 workers occupationally exposed to styrene and 98 unexposed controls, employing an integrated approach involving biomarkers of exposure, effect, and susceptibility. Airborne styrene was evaluated at workplace, and urinary styrene metabolites, mandelic acid (MA), phenylglyoxylic acid (PGA), vinylphenols (VPTs) and phenylhydroxyethylmercapturic acids (PHEMAs), were measured as biomarkers of internal dose. Cytogenetic alterations were evaluated by analysing the frequency of chromosomal aberrations (CAs) and micronucleated binucleated cells (MNBN) in peripheral blood lymphocytes. The micronucleus assay was coupled with centromeric fluorescence in situ hybridization to distinguish micronuclei (MN) arising from chromosomal breakage (C- MN) from those harboring whole chromosomes (C+ MN). The possible influence of genetic polymorphisms of xenobiotic-metabolizing enzymes involved in styrene biotransformation (EPHX1, GSTT1, GSTM1, GSTP1) and NAT2 on the cytogenetic endpoints was investigated. The exposed workers showed a significantly higher frequency of MNBN (13.8+/-0.5% versus 9.2+/-0.4%; P<0.001) compared to control subjects. The effect appeared to concern both C- and C+ MN. A positive correlation was seen between the frequency of C+ MN and urinary level of MA+PGA (P<0.05) and VPTs (P<0.001). Chromosome-type CAs positively correlated with airborne styrene level and VPTs (P<0.05), whereas chromatid-type CAs correlated with PHEMAs (P<0.05). Workers bearing GSTM1 null genotype showed lowered levels of PHEMAs (P<0.001). The GSTT1 null genotype was associated with increased MNBN frequencies in the exposed workers (P<0.05) and the fast activity EPHX genotype with a moderate decrease in both MNBN and CAs in the controls. Our results suggest that occupational exposure to styrene has genotoxic effects that are potentiated by the GSTT1 gene deletion. These observations may have relevance considering the risk of lymphatic and haematopoietic malignancies tentatively associated with styrene exposure.     

Effect of genetic polymorphism of GSTM1 and GSTT1 genotypes on cytogenetic biomarkers among coaltar workers

Chromosomal aberrations (CAs) in peripheral blood lymphocytes and micronuclei (MN) in exfoliated buccal cells have been used for decades as cytogenetic biomarkers to investigate genotoxicity among occupationally or environmentally exposed population. In our study, we investigated the association of increased cytogenetic damage with genetic polymorphism in glutathione-S transferase genotypes among occupationally exposed 115 coaltar workers and 105 unexposed controls. We found higher mean value of chromosome aberrations (chromatid type-2.01 ± 1.76; chromosomal type-2.22 ± 1.73) and buccal micronuclei (BMN-7.10 ± 1.56) in exposed subjects when compared to referents (chromatid type-0.82 ± .51; chromosomal type-0.87 ± .54; BMN-5.09 ± 2.88). We observed that individuals having null genotype of GSTM1 and GSTT1 have significantly higher frequency of CAs and MN. Despite of small sample size, our findings suggest a significant association between polymorphism of glutathione-S transferase genotypes and cytogenetic biomarkers which are considered as early effects of genotoxic carcinogens.     

Association between cancer risk and drug-metabolizing enzyme gene (CYP2A6, CYP2A13, CYP4B1, SULT1A1, GSTM1, and GSTT1) polymorphisms in cases of lung cancer in Japan

Genetic polymorphisms of enzymes involved in the metabolism of carcinogens are suggested to modify an individual's susceptibility to lung cancer. The purpose of this study was to investigate the relationship between lung cancer cases in Japan and variant alleles of cytochrome P450 (CYP) 2A6 (CYP2A6*4), CYP2A13 (CYP2A13*1-*10), CYP4B1 (CYP4B1*1-*7), sulfotransferase 1A1 (SULT1A1*2), glutathione S-transferase M1 (GSTM1 null), and glutathione S-transferase T1 (GSTT1 null). We investigated the distribution of these polymorphisms in 192 lung cancer patients and in 203 age- and sex-matched cancer-free controls. The polymorphisms were analyzed using various techniques including allele-specific PCR, hybridization probe assay, multiplex PCR, denaturing high-performance liquid chromatography (DHPLC), and direct sequencing. We also investigated allele and genotype frequencies and their association with lung cancer risk, demographic factors, and smoking status. The prevalence of the CYP2A6*4/*4 genotype in lung cancer cases was 3.6%, compared with 9.4% in the controls (adjusted OR = 0.36, 95% CI = 0.15-0.88, P = 0.025). In contrast, there was no association between the known CYP2A13, CYP4B1, SULT1A1, GSTM1, and GSTT1 polymorphisms and lung cancer. These data indicate that CYP2A6 deletions may be associated with lung cancer in the Japanese population studied.     

GSTM1和GSTT1基因多态性与抗结核药物性肝损害的关系

目的 探讨汉族人群谷胱甘肽S转移酶M1(GSTMl)和T1(GSTT1)基因多态性与抗结核药物性肝损害(ATDLI)易感性的关系.方法 回顾性分析抗结核治疗后发生肝损害的结核病患者228例(病例组)及未发生肝损害的结核病患者300例(对照组),应用多重PCR技术检测其GSTM1和GSTT1基因多态性.结果 病例组与对照组GSTM1基因缺失型频率分别为58.3％和50.7％,差异无统计学意义(OR=1.363,95％CI=0.963～1.929); GSTT1基因缺失型频率分别为45.2％和49.3％,差异也无统计学意义.联合分析也未发现两种基因在抗结核药物性肝损害发生中具有协同作用.结论 汉族人群GSTM1和GSTT1基因多态性与抗结核药物性肝损害的发生无关.     

Are individuals with glutathione S-transferase GSTT1 null genotype more susceptible to in vitro oxidative damage?

Recent epidemiological studies proposed that glutathione S-transferase (GST) T1 null genotype was correlated with an increased susceptibility to diseases associated with oxidative stress, including cancer. A comparative study using erythrocytes from individuals with GSTT1 null genotype was carried out to determine how resistance to oxidative stress is affected by lack of this gene, and whether the GST status of a person is an important factor in risk toward oxidant chemicals. Malondialdehyde and carbonyl levels and fluorescence and chemiluminescence formation were used as biomarkers of oxidative stress in erythrocytes exposed in vitro to cumene hydroperoxide (CumOOH), an oxidizing agent. When peroxidation-dependent changes in these parameters were compared between GSTT1 null genotype and controls, who are both GSTM1 and GSTT1 positive, no significant differences were found between the two genotypes, although the erythrocytes of the GSTT1 null group had lower GSTT1 activity toward CumOOH. Our results indicate that erythrocytes from individuals with GSTT1 null genotype are not abnormally susceptible to CumOOH-induced oxidant challenge.     

ARE INDIVIDUALS WITH GLUTATHIONE S-TRANSFERASE GSTT1 NULL GENOTYPE MORE SUSCEPTIBLE TO IN VITRO OXIDATIVE DAMAGE?

Recent epidemiological studies proposed that glutathione S-transferase (GST) T1 null genotype was correlated with an increased susceptibility to diseases associated with oxidative stress, including cancer. A comparative study using erythrocytes from individuals with GSTT1 null genotype was carried out to determine how resistance to oxidative stress is affected by lack of this gene, and whether the GST status of a person is an important factor in risk toward oxidant chemicals. Malondialdehyde and carbonyl levels and fluorescence and chemilum inescence formation were used as biomarkers of oxidative stress in erythrocytes exposed in vitro to cumene hydroperoxide (CumOOH), an oxidizing agent. When peroxidation-dependent changes in these parameters were compared between GSTT1 null genotype and controls, who are both GSTM1 and GSTT1 positive, no significant differences were found between the two genotypes, although the erythrocytes of the GSTT1 null group had lower GSTT1 activity toward Cum OOH. Our results indicate that erythrocytes from individuals with GSTT1 null genotype are not abnorm ally susceptible to CumOOH-induced oxidant challenge.     

Glutathione S-transferases mu 1, theta 1, pi 1, alpha 1 and mu 3 genetic polymorphisms and the risk of colorectal and gastric cancers in humans

INTRODUCTION: Glutathione S-transferases (GSTs) are considered to be cancer susceptibility genes as they play a role in the detoxification of carcinogenic species. This study aimed to elucidate the influence of several GST polymorphisms on colorectal and gastric cancer risk. PATIENTS AND METHODS: GST mu1 (GSTM1), theta1 (GSTT1), pi1 (GSTP1), alpha1 (GSTA1) and mu3 (GSTM3) genotypes were determined in 144 colorectal cancer patients, 98 gastric cancer patients and 329 healthy control individuals. RESULTS: Colorectal cancer: the risk is greater for carriers of the GSTM1 null genotype (odds ratio [OR] = 1.91, 95% confidence interval [CI] = 1.25-2.91), for carriers of the GSTT1 null genotype (OR = 3.62, 95% CI = 2.34-5.62), and for simultaneous carriers of both GSTM1 and GSTT1 null genotypes (OR = 4.98, 95% CI = 2.77-9.00). Carriers of the GSTP1 104 Val/Val genotype are at a lower risk (OR = 0.31, 95% CI = 0.09-0.88). Among carriers of the GSTP1 Ile/Ile genotype, smoking increases the risk compared with nonsmoking (OR = 2.35, 95% CI = 1.11-4.99). Gastric cancer: the risk is greater for carriers of the GSTT1 null genotype (OR = 2.58, 95% CI = 1.53-4.36) and for simultaneous carriers of both GSTM1 and GSTT1 null genotypes (OR = 3.32, 95% CI = 1.62-6.77). Carriers of the GSTP1 104 Val/Val genotype are at a lower risk (OR = 0.20, 95% CI = 0.02-0.86). DISCUSSION: The GSTT1 null genotype, particularly if it is associated with the GSTM1 null genotype, greatly increases the risk for colorectal and gastric cancers. The GSTP1 104 Val/Val genotype may protect from both malignant tumors. CONCLUSION: This study indicates that GST polymorphisms, in particular the GSTM1/GSTT1 double-null haplotype, can be considered low-penetrance genes for gastrointestinal cancer.     

NAT2 slow acetylation and GSTM1 null genotypes may increase postmenopausal breast cancer risk in long-term smoking women

N-acetyltransferase (NAT) 1 and 2 and glutathione S-transferase (GST) M1 and T1 are phase II enzymes that are important for activation and detoxification of carcinogenic heterocyclic and aromatic amines, as present in cigarette smoke. We studied whether genetic polymorphisms in these genes modifies the relationship between smoking and breast cancer. A nested case-control study was conducted among participants in a Dutch prospective cohort. Breast cancer cases (n=229) and controls (n=264) were frequency-matched on age, menopausal status and residence. Compared to never smoking, smoking 20 cigarettes or more per day increased breast cancer risk statistically significant only in postmenopausal women [odds ratio (OR)=2.17; 95% confidence interval (CI) 1.04-4.51]. Neither NAT1 slow genotype, or GSTT1 null genotype, alone or in combination with smoking, affected breast cancer risk. However, compared to individuals with rapid NAT2 genotype, women with the very slow acetylator genotype (NAT2*5), who smoked for 20 years showed an increased breast cancer risk (OR=2.29; 95% CI 1.06-4.95). Similarly, the presence of GSTM1 null genotype combined with high levels of cigarette smoking (OR=3.00; 95% CI 1.46-6.15) or long duration (OR=2.53; 95% CI 1.24-5.16), increased rates of breast cancer. The combined effect of GSTM1 null genotype and smoking high doses was most pronounced in postmenopausal women (OR=6.78; 95% CI 2.31-19.89). In conclusion, our results provide support for the view that women who smoke and who have a genetically determined reduced inactivation of carcinogens (GSTM1 null genotype or slow NAT2 genotype (especially very slow NAT2 genotype)) are at increased risk of breast cancer.     

Polymorphisms of glutathione S-transferases M1 and T1 do not account for interindividual differences for smoking behavior

To identify whether the polymorphisms of glutathione S-transferase M1 (GSTM1) and GSTT1 genes predict a high-tended risk of using tobacco, the GSTM1 and GSTT1 genotypes of 369 Iranian males (254 nonsmokers and 115 smokers) and 314 Iranian females (245 nonsmokers and 69 smokers) were determined. The frequencies of GSTM1 (males: OR=0.98, 95% CI=0.62-1.57, P=.974; females: OR=1.34, 95% CI=0.75-2.39, P=.358) and GSTT1 (males: OR=1.25, 95% CI=0.76-2.04, P=.412; females: OR=0.84, 95% CI=0.46-1.51, P=.626) null genotypes were similar in nonsmokers and smokers. The risk of being a smoker was to be equally frequent in each combination of the genotypes. The present results revealed that there was no difference between smokers and nonsmokers for these two genetic polymorphisms.     

Glutathione S-transferase genotypes and stomach cancer in a population-based case-control study in Warsaw, Poland.

Glutathione S-transferases are important in the detoxification of a wide range of human carcinogens. Previous studies have shown inconsistent associations between the GSTT1 and GSTM1 null genotypes and stomach cancer risk. We investigated the relationship between these and related genotypes and stomach cancer risk in a population-based case-control study in Warsaw, Poland, where stomach cancer incidence and mortality rates are among the highest in Europe. DNA from blood samples was available for 304 stomach cancer patients and 427 control subjects. We observed a 1.48-fold increased risk for stomach cancer (95% confidence interval 0.97-2.25) in patients with the GSTT1 null genotype but no evidence of increased risk associated with the GSTM1, GSTM3 or GSTP1 genotypes. Furthermore, the stomach cancer risk associated with the GSTT1 null genotype varied by age at diagnosis, with odds ratios of 3.85, 1.91, 1.78 and 0.59 for those diagnosed at ages less than 50, 50-59, 60-69 and 70 years or older, respectively (P trend = 0.01). This was due to a shift in the GSTT1 genotype distribution across age groups among stomach cancer patients only. These results suggest that the GSTT1 null genotype may be associated with increased risk of stomach cancer.     

Genetic polymorphisms of human cytosol glutathione S-transferases and prostate cancer

Glutathione S-transferases (GSTs) are involved in the metabolism of a wide range of carcinogenic chemicals. In humans, cytosol GSTs are divided into eight classes: alpha (GSTA), mu (GSTM), pi (GSTP), theta (GSTT), tau (GSTZ), sigma (GSTS), omicron (GSTO) and kappa (GSTK). The allelic polymorphism of these enzymes is associated with variations in enzyme activity; hence, it may affect the concentration of activated carcinogenic chemicals in the body. In addition to the metabolism of chemical carcinogens, GSTs metabolize steroid hormones, compounds in the diet and other agents potentially involved in prostate carcinogenesis. Three genetic polymorphisms of GSTs, GSTM1*0 (null), GSTT1*0 (null) and GSTP1 A313G, have been well documented. No consistent associations between GSTM1, GSTT1 or GSTP1 genotypes and prostate cancer have been observed. Recent meta-analysis reports show that these polymorphisms of GSTM1, GSTT1 and GSTP1 are unlikely to be major determinants of susceptibility to prostate cancer.     

Genetic polymorphisms involved in toxicant-metabolizing enzymes and the risk of chronic benzene poisoning in Chinese occupationally exposed populations

Benzene is a recognized haematotoxin and leukaemogen, but its mechanism of action and the role of genetic susceptibility are still unclear. Cytochrome P450 2E1 (CYP2E1) and myeloperoxidase (MPO) are involved in benzene activation; and NAD (P)H:quinine oxidoreductase 1 (NQO1), glutathione S-transferase theta 1 (GSTT1) and glutathione S-transferase mu 1 (GSTM1) participate in benzene detoxification. The common, well-studied single-nucleotide polymorphisms (SNPs) were analysed in these genes drawn from the toxicant-metabolizing pathways. A total of 100 workers with chronic benzene poisoning (CBP) and 90 controls were enrolled in China. There was a 2.82-fold (95% CI = 1.42-5.58) increased risk of CBP in the subjects with the NQO1 609C > T mutation genotype (T/T) compared with those carrying heterozygous (C/T) and wild-type (C/C). The subjects with the GSTT1 null genotype had a 1.91-fold (95% CI = 1.05-3.45) increased risk of CBP compared with those with GSTT1 non-null genotype. There was no association of CYP2E1 and MPO genotype with CBP. A three genes' interaction showed that there was a 20.41-fold (95% CI = 3.79-111.11) increased risk of CBP in subjects with the NQO1 609C > T T/T genotype and with the GSTT1 null genotype and the GSTM1 null genotype compared with those carrying the NQO1 609C > T C/T and C/C genotype, GSTT1 non-null genotype, and GSTM1 non-null genotype. The study provides evidence of an association of a gene-gene interaction with the risk of CBP.     

Polymorphisms within glutathione S-transferase genes and initial response to glucocorticoids in childhood acute lymphoblastic leukaemia

In children with acute lymphoblastic leukaemia (ALL) treated according to protocols of the Berlin-Frankfurt-Münster (BFM) study group, the initial response to prednisone is the strongest predictor of therapy outcome. Glutathione S-transferases (GSTs) have been implicated in glucocorticoid resistance. In order to assess a potential association of phenotypically relevant GST polymorphisms with prednisone response in childhood ALL, we conducted a case-control study of 45 prednisone poor-responders (cases) and 90 prednisone good-responders (controls) who were frequency matched according to initial white blood cell count. In addition, we analysed the association of GST genotypes with relapse of leukaemia. In univariate analysis, homozygous deletion of GSTT1 (null genotype) conferred a 6.7-fold reduction in risk of prednisone poor-response compared to individuals who were either heterozygous or homozygous for GSTT1 [odds ratio (OR) = 0.15, P = 0.071; multivariate odds ratio = 0.18, P = 0.117]. GSTM1 and GSTP1 genotypes did not show any association with prednisone response. In addition, risk of relapse was predicted strongest by the GSTT1 genotype. In univariate analysis, the GSTT1 null genotype conferred a 5.9-fold reduction in risk of relapse compared to the heterozygous or homozygous presence of GSTT1 (OR = 0.17, P = 0.095; multivariate OR = 0.23; P = 0.173). No associations of the GSTM1 genotype with risk of relapse were observed. GSTP1 codon 105 and codon 114 polymorphisms were predominantely associated with central nervous system relapse. Our results add further support to the hypothesis that genetic polymorphisms within specific GST genes might be of clinical importance in childhood ALL.     

Relationship between glutathione S-transferase M1, P1 and T1 polymorphisms and early onset prostate cancer.

There is evidence suggesting that polymorphic variations in the glutathione S-transferases (GSTs) are associated with cancer susceptibility. Inter-individual differences in cancer susceptibility may be mediated in part through polymorphic variability in the bioactivation and detoxification of carcinogens. The GSTs have been consistently implicated as cancer susceptibility genes in this context. The GST supergene family includes several loci with well characterized polymorphisms. Approximately 50% of the Caucasian population are homozygous for deletions in GSTM1 and approximately 20% are homozygous for deletions in GSTT1, resulting in conjugation deficiency of mutagenic electrophiles to glutathione. The GSTP1 gene has a polymorphism at codon 105 resulting in an Ile to Val substitution which consequently alters the enzymatic activity of the protein and this has been suggested as a putative high-risk genotype in various cancers. We investigated the relationship between GST polymorphisms and young onset prostate cancer in a case-control study. GSTM1, GSTT1 and GSTP1 genotypes were determined for 275 prostate cancer patients and for 280 geographically matched control subjects. We found no significant difference in the frequency of GSTM1 or GSTT1 null genotypes between cases and controls. GSTP1 genotype was, however, significantly associated with prostate cancer risk: the Ile/Ile homozygotes had the lowest risk and there was a trend in increasing the risk with the number of 105 Val alleles: Ile/Val odds ratio (OR)= 1.30 (95% FCI 0.99-1.69), Val/Val OR = 1.80 (95% FCI 1.11-2.91); Ptrend = 0.026. These results suggest that the GSTP1 polymorphism may be a risk factor for developing young onset prostate cancer. We also found that carrying more than one putative high-risk allele in the carcinogen metabolizing GST family was associated with an elevated risk for early onset prostate cancer (OR 2.48, 95% FCI 1.22-5.04, Ptrend = 0.017).     

Genetic susceptibility of term pregnant women to oxidative damage

Genetic polymorphisms involved in the activation and detoxification of exogenous chemicals and in the production and scavenging of reactive oxygen species may modulate the levels of oxidative injury biomarker. We investigated 81 pregnant women in Inchon, Korea. In addition to a questionnaire survey, urinary concentrations of 8-hydroxydeoxyguanosine (8-OH-dG) and malondialdehyde (MDA) were measured as oxidative injury biomarkers. Cytochrome P-450(CYP)1A1, CYP2E1, glutathione S-transferase (GST)M1 and GSTT1 polymorphisms and myeloperoxidase (MPO) and manganese superoxide dismutase (MnSOD) polymorphisms were evaluated to determine the effect of genetic modification on urinary 8-OH-dG and MDA. The concentrations of urinary 8-OH-dG were significantly elevated in the presence of the MnSOD variant genotype (P=0.04) and in the case of GSTM1 null status (P=0.02) by multivariate regression. The concentrations of urinary MDA were not affected significantly by the genetic polymorphisms. This result shows that oxidative stress injury is modified by some heritable polymorphisms, including GSTM1 and MnSOD.     

Low occupational exposure to benzene in a petrochemical plant: modulating effect of genetic polymorphisms and smoking habit on the urinary t,t-MA/SPMA ratio

The identification of reliable biomarkers is critical for the assessment of occupational exposure of benzene: S-phenylmercapturic acid (SPMA) and trans,trans-muconic acid (t,t-MA) are the most currently used. t,t-MA is an open-ring metabolite, but it is also a metabolite of the food preservative sorbic acid, while SPMA is formed by conjugation with glutathione, and several studies suggested that the genetic polymorphism of glutathione S-transferases modulates its production. This study compared the ability of these metabolites to assess the benzene exposure in a big group of petrochemical workers. Furthermore, investigated how genetic polymorphism of glutathione S-transferase theta 1 (GSTT1), glutathione S-transferase mu 1 (GSTM1), glutathione S-transferase pi 1 (GSTP1) and smoking habits, may influence their excretion. Results showed that occupational exposure to benzene was negligible compared to that from smoking and confirmed the modulating effect of the genetic polymorphism of GSTT1 on the urinary excretion of SPMA, but not of t, t-MA, even at very low levels of benzene exposure. The same effect was found for GSTM1, but only for smokers. The t,t-MA/SPMA ratio was not a constant value and resulted to be higher than the corresponding Biological Exposure Index (BEI) ratio, which is currently equal to 20. Higher values of metabolite have been associated with the GSTT1 or GSTM1 null genotype and these are responsible for increase health risk. We suggest that this ratio could be used as a marker of individual susceptibility for subjects with benzene exposure.     

Occupational exposure to styrene: modulation of cytogenetic damage and levels of urinary metabolites of styrene by polymorphisms in genes CYP2E1, EPHX1, GSTM1, GSTT1 and GSTP1

Styrene is widely used in the production of various plastics, synthetic rubber and resins. The aim of this study was to evaluate if individual polymorphisms in xenobiotic metabolizing enzymes, related with the metabolic fate of styrene, could modify individual susceptibility to the possible genotoxic effects of the styrene exposure. Twenty-eight reinforced plastic workers and 28 control subjects were studied. In the selected population the urinary styrene metabolites mandelic (MA) and phenylglyoxylic (PGA) acids were quantified, sister chromatid exchanges (SCE) and micronuclei (MN) were assessed in peripheral lymphocytes and all the subjects were genotyped for GSTM1, GSTT1 (gene deletions), GSTP1 (codon 105 ile==>val), EPHX1 (codons 113 tyr==>his and 139 his==>arg) and CYP2E1 (DraI polymorphism in intron 6). The results obtained showed a significant difference between the levels of SCE, but not in MN levels, in exposed workers as compared with the control group. The GSTP1 and CYP2E1 individual genotypes modulate the baseline levels of SCE that are lower in non-wild type individuals for both polymorphisms. The GSTM1 null individuals with low levels of exposure have significantly higher urinary levels of MA+PGA. The present data seem to suggest that apart from the methodology usually used for monitoring populations occupationally exposed to styrene (urinary metabolites and biomarkers of early biological effects) the analysis of individual genotypes associated with the metabolic fate of styrene should also be carried out in order to evaluate the individual genetic susceptibility of exposed populations.     

Glutathione-S-transferase M1, M3, T1 and P1 polymorphisms and susceptibility to non-small-cell lung cancer subtypes and hamartomas.

Polymorphic glutathione-S-transferase (GST) genes causing variations in enzyme activity may influence individual susceptibility to lung cancer. In this case-control study (consisting of 389 Caucasian lung cancer patients, including 151 adenocarcinomas (ACs) and 172 squamous cell carcinomas (SCCs), and 353 hospital control subjects without malignant disease, genotype frequencies for GSTM1, GSTM3, GSTP1 and GSTT1 were determined by polymerase chain reaction (PCR)/ restriction fragment length polymorphism (RFLP)-based methods. While adjusted odds ratios (ORs) indicated no significantly increased risk for lung cancer overall due to any single GST genotype, the risk alleles for GSTM1, GSTM3 and GSTP1 conferring reduced enzyme activity were present at higher frequency in SCC than in AC patients. This is consistent with a reduced detoxification of carcinogenic polycyclic aromatic hydrocarbons (PAHs) from cigarette smoke that are more important for the development of SCC than for AC. An explorative data analysis also identified statistically significantly increased ORs for the combinations GSTT1 non-null and GSTP1 GG or AG for lung cancer overall (OR 2.23, CI 1.11-4.45), and for SCC (OR 2.69, CI 1.03-6.99). For lung cancer overall, and especially among SCC patients, the GSTT1 null genotype was underrepresented (SCC 11.2% v. control subjects 19%, P = 0.026, OR 0.57, CI 0.30-1.06). Additionally, in 28 patients with hamartomas, the GSTT1 null genotype was also protective (P = 0.013), while GSTP1 variant allele carriers were overrepresented (OR 2.48, CI 1.06-6.51). In conclusion, GST genotypes may act differently, either by detoxifying harmful tobacco carcinogens and/or by eliminating lung cancer chemopreventive agents. The latter role for GSTT1 would explain the observed lower risk of SCC and hamartoma associated with GSTT1 null. Further confirmatory studies are required.     

A comparison of glutathione S-transferase mutant frequencies in healthy Han and Uygur Chinese.

OBJECTIVE: This study was to compare the frequencies of genetic polymorphisms of GSTM1, GSTT1, and GSTP1 in Uygur Chinese with those in Han Chinese. METHODS: GSTM1 and GSTT1 polymorphisms were analyzed by a PCR-Multiplex procedure, whereas GSTP1 polymorphism was analyzed by PCR-RFLP. RESULTS: The frequency of GSTM1 null genotype in Han Chinese (56.1%) was similar to that in Uygur Chinese (53.2%) (P = 0.592), whilst the frequency of GSTT1 null genotype in Han Chinese (50.0%) was significantly (P < 0.05) higher than that of Uygur Chinese (26.6%). GSTP1 had a genotype distribution of 60.7% I/I, 35.2% I/V and 4.1% V/V in Han Chinese, and 51.3% I/I, 40.2% I/V and 8.4% V/V in Uygur Chinese. CONCLUSION: There is marked ethnic difference in the mutant frequencies of GSTT1 and GSTP1, but not GSTM1, between Uygur and Han Chinese.     

Offspring sex ratio is not associated with parental GSTT1 and GSTM1 null genotypes

The present study evaluated the association between offspring sex ratio and parental inherited variations of xenobiotic metabolism by glutathione S-transferase (GST) T1 and GSTM1. Polymorphisms of GSTT1 and GSTM1 were investigated in 235 Iranian Muslims (153 males, 82 females) using polymerase chain reaction-based method. Statistical analysis of 890 offspring in the study families revealed that there was no association between GSTM1 null genotype of either the fathers (OR=1.28; 95% CI=0.88-1.85; P=0.17) or mothers (OR=0.77; 95% CI=0.49-1.19; P=0.22) and offspring sex ratio. There was no association between paternal GSTT1 null genotype and sex ratio in offspring (OR=1.04; 95% CI=0.71-1.54; P=0.84), whereas there was a weak association between maternal GSTT1 null genotype and offspring sex ratio (OR=1.54; 95% CI=1.0-2.38; P=0.05). Combination of parental GSTT1 and GSTM1 genotypes showed no association with offspring sex ratio.