Glutathione S-transferase Gene Polymorphisms Research Articles

Glutathione S-transferase gene polymorphisms and risk of nasal or colorectal polyposis.

We observed inconsistent conclusions regarding the genetic role of glutathione S-transferase gene polymorphisms, including glutathione S-transferase M1 (GSTM1), glutathione S-transferase T1 (GSTT1) present/null, and glutathione S-transferase pi (GSTP1) Ile105Val polymorphisms, in the susceptibility to nasal or colorectal polyposis (NP or CP). Thus, we aimed to perform a meta-analysis to comprehensively evaluate this association by applying Stata/SE software. After the heterogeneity assumption, Mantel–Haenszel statistics were used to obtain the odds ratio (OR), 95% confidence interval (95% CI) and P-value of the association test (PA). We obtained a total of 235 articles by searching online databases. After screening, ten eligible case–control studies were finally enrolled in our meta-analysis. For the meta-analysis of the GSTT1 gene under present versus null, we observed a decreased risk of NP [OR = 0.65; PA=0.018], but not CP. In addition, we did not detect any evident association between the GSTM1 present/null polymorphism and NP or CP risk. For the meta-analysis of the GSTP1 Ile105Val polymorphism, compared with controls, an increased risk of NP cases was detected under the models of Val versus Ile (OR = 1.36; PA=0.027), Ile/Val versus Ile/Ile (OR = 1.70; PA=0.011) and Ile/Val+Val/Val versus Ile/Ile (OR = 1.65; PA=0.010). In conclusion, the null genotype of the GSTT1 polymorphism may be linked to an increased susceptibility to NP, whereas the Ile/Val genotype of the GSTP1 Ile105Val polymorphism may be associated with a decreased risk of NP.

Association of GST gene polymorphism and noise-induced hearing loss: GST gene polymorphism and NIHL.

BackgroundIt has been proposed that Noise-induced hearing loss is a complex disease that is combination of environmental and genetic factors. There are inconsistent results concerning the association between variation in glutathione S-transferase (GST) genetic polymorphisms (GSTT1 rs1049055 and GSTM1 rs10712361) and susceptibility to Noise-induced hearing loss.ObjectiveThis study was designed to assess the association between GST gene polymorphism and Noise-induced hearing loss among noise-exposed workers. Methods: In a case-control study, male workers from tile and ceramic factories were selected randomly. Subjects were classified into two groups according to the result of audiometry: 73 subjects showed Noise-induced hearing loss which was considered in the case group and 87 subjects without hearing loss was enrolled in the control group. The GSTT1 and GSTM1 polymorphism of both groups were assessed by multiplex polymerase chain reaction.ResultsNull GSTT1 and GSTM1 genotypes were more frequent in case group but no significant statistical difference was seen in case and control groups. No significant link between GSTT1 and GSTM1 genotypes was found.ConclusionThis study suggests that the genetic variability of GSTT1 and GSTM1 has no effect on susceptibility to noise induced hearing loss.

Genetic variants of glutathione S-transferase and the risk of acute myeloid leukemia in a Saudi population.

ObjectiveThis study aims to investigate the genetic association of acute myeloid leukemia and glutathione S-transferase (GST) gene polymorphisms in a Saudi population.Method100 AML cases and 100 healthy controls were recruited from the Riyadh regional hospital. In the GST gene, GSTM1 and GSTT1 variants were genotyped by multiplex PCR, and GSTP1 variants were genotyped by PCR-RFLP analysis. Statistical analysis between AML cases and controls included anthropometric measurements and evaluation of the genotypic and allelic frequencies.ResultThe null genotypes of GSTM1 and GSTT1 showed no association with AML [OR 0.56 (0.26–1.19); p = 0.31 and OR 0.65 (0.37–1.16); p = 0.14]. Similarly, the GSTP1 genotype and allele frequencies did not indicate any association with AML [GG + AG vs. AA: OR 0.75 (0.43–1.31) and p = 0.32; GG vs. AA: OR 1.73 (0.55–5.44) and p = 0.34; G vs. A: OR 0.95 (0.61–1.46) and p = 0.82]. Further, a haplotype analysis between AML cases and controls did not show any positive association (p < 0.05).ConclusionIn conclusion, there was no statistical association of the genotypes and alleles in GSTM1, GSTT1, and GSTP1 with AML. Our results confirm the negative association of the investigated genetic markers with susceptibility to AML. Further association studies would be required in different ethnic populations to facilitate a meta-analysis in the future. Our findings suggest that the GST gene has no role in the pathogenesis of AML in patients from Saudi Arabia.

Glutathione S-transferase gene polymorphisms (GSTT1 and GSTM1) and risk of cancers; a case-control study in southeast of Iran

Glutathione S-Transferases (GSTs)11Glutathione S-Transferases. are enzymes catalyzing reactive oxygen species which are believed to participate in the carcinogenesis of different cancers. We aimed to assess the distribution and the potential impact of GSTT1 and GSTM1 polymorphisms on the risk of several types of cancers in an Iranian population. In this case–control study, 213 cancer patients along with 213 healthy volunteers were included. GSTM1 and GSTT1 polymorphisms were genotyped using multiplex-PCR. In all the subjects, GSTT1 (+)/GSTM1 (−) genotype (43.9%) was of the highest frequency following by GSTT1 (+)/GSTM1 (+) (35.9%). No significant differences were observed in the distributions of GSTM1 and GSTT1 gene polymorphisms between cases (45.5% and 9.4%, respectively) and controls (42.3% and 9.9% respectively). The GSTM1 gene polymorphism was not associated with the overall risk of cancer (OR = 0.85), nor with the individual risk of breast (OR = 1.04), thyroid (0.63), lymphatic (1.05) or bone (0.97) neoplasms. Accordingly, there were no significant associations between GSTT1 polymorphism with neither overall cancer risk (1), nor with the risk of breast (OR = 1.36), thyroid (0.93), lymphatic (0.84) and bone (1.64) tumors. Although statistically insignificant, GSTT1(−)/GSTM1(−) genotype represented the highest risk for lymphoma (OR = 1.89, 95% CI: 0.75–4.81, P = 0.13). Our results indicated no significant association between GSTM1 and GSTT1 polymorphisms and risk of cancers in southeast population of Iran.

Early prediction of liver carcinogenicity due to occupational exposure to pesticides

Several studies linked between pesticides exposure and development of liver cancer, through several mechanisms inform of genotoxicity, cytotoxicity, tumor promotion, immunotoxicity and hormonal actions. This study aimed to estimate novel biomarkers for early prediction of liver malignancy due to occupational exposure to pesticides in two groups of workers with different socioeconomic standard (highly educated urban researchers and low educated rural pesticides sprayers). This study included 50 urban researchers and 50 rural pesticides sprayers occupationally exposed to pesticides. They were compared with 50 non-exposed urban researchers and 50 non-exposed rural subjects. Several tumor biomarkers were estimated; P53 protein, Alfa fetoprotein (AFP), and Alpha-L-fucosidase (AFU). Additionally, telomerase enzyme activity, Relative telomere length (RTL), and DNA damage using comet assay were measured. Furthermore, the glutathione-S-Transferase (GST) gene polymorphisms were identified for both exposed groups. Statistical analysis revealed elevated level of tumor biomarkers among exposed subjects relative to control groups in spite of being within the normal range. Increase in the DNA damage was detected, with shortening of telomere length and decrease in telomerase enzyme activity in pesticides-exposed subjects compared to their controls. Most of these changes were related to the levels of butyrylcholinesterase. Subjects with GSTT1 genotype were suggested to be more susceptible to hepatic carcinogenicity. Telomere relative length and comets assay together with GST genes polymorphisms could be used as early predictors for liver cancer susceptibility among pesticides exposed workers.

Association of Glutathione S-transferase gene polymorphism with bladder Cancer susceptibility

BackgroundWe conducted a meta-analysis to evaluate the relationship between the glutathione S-transferase μ1 (GSTM1)– and glutathione S-transferase θ1 (GSTT1)– null genotypes and susceptibility to bladder cancer.MethodsWe identified association reports from the databases of PubMed, Embase, the Cochrane Library and the China Biological Medicine Database (CBM disc) on July 1, 2017 and synthesized eligible investigations. Results were expressed using odds ratios (ORs) for dichotomous data, and we also calculated 95% confidence intervals (CIs).ResultsIn this meta-analysis, we found that the GSTM1-null genotype was associated with bladder cancer risk in the overall population, and individually in whites, Africans and Asians (overall population: OR = 1.40, 95% CI: 1.31–1.48, P<0.00001; whites: OR = 1.39, 95% CI: 1.26–1.54, P<0.00001; Africans: OR = 1.54, 95% CI: 1.16–2.05, P = 0.003; Asians: OR = 1.45, 95% CI: 1.33–1.59, P<0.00001). The GSTT1-null genotype was associated with bladder cancer risk in the overall population, but not in whites, in Africans or Asians (overall population: OR = 1.11, 95% CI: 1.01–1.22, P = 0.03; whites: OR = 1.16, 95% CI: 0.99–1.36, P = 0.07; Africans: OR = 1.07, 95% CI: 0.65–1.76, P = 0.79; Asians: OR = 1.05, 95% CI: 0.91–1.22, P = 0.51). Interestingly, a dual-null GSTM1–GSTT1 genotype was associated with bladder cancer risk in the overall population and in Asians (overall population: OR = 1.48, 95% CI: 1.15–1.92, P = 0.002; Asians: OR = 1.62, 95% CI: 1.15–2.28, P = 0.006). In conclusion, the GSTM1-null, GSTT1-null and dual-null GSTM1–GSTT1 genotypes might be associated with the onset of bladder cancer, but additional genetic-epidemiological studies should be conducted to explore this association further.

Lifetime Risk Factors for Post Bronchodilator Lung Function Decline: A Population-Based Study from 1st to 6th Decade

Background: Interactions between early life and adult insults on lung function decline are not well understood, with most studies investigating pre-bronchodilator (BD) FEV1 decline. We investigated relationships between adult risk factors and post-BD lung function decline and their potential effect modification by specific early life and genetic factors. Methods: Multivariable regression was used to examine associations between adult exposures (asthma, smoking, occupational exposure, traffic pollution, atopy and obesity) and decline in post-BD spirometry between ages 45 to 53 years in the Tasmanian Longitudinal Health Study (n=857). Effect modification of these relationships by childhood respiratory risk factors including low childhood lung function, and glutathione S-transferase (GST) gene polymorphisms was investigated. Findings: Accelerated FEV1 decline was associated with baseline asthma of early onset (excess rate: -7·0; -12·5, -1·6 mL/year) and smoking (-13·8; -18·7, -9·0 mL/year). In addition, it was associated with occupational exposure to vapours/gases/dusts/fumes (-11·8: -19·0, -4·2 mL/year) only in carriers of the GSTM1 null allele (p-interaction=0·04). Findings for changes in exposure status support those for baseline exposures. Accelerated FEV1/FVC decline was associated with these factors and living <200m from main roads. Associations of occupational exposures and personal smoking with FEV1 decline were accentuated for those with lower childhood lung function (p-interaction= 0·04 and 0·06, respectively). Maternal smoking accentuated the effect of personal smoking on FEV1 decline (p-interaction=0·08). Interpretation: While establishing adult risk factors that affect post-BD lung function decline, this study provides new evidence for accentuation of individual susceptibility to adult risk factors by low childhood lung function, GSTM1 genotype and maternal smoking. These findings suggest that susceptibility to adult risk factors may be programmed in early life. Strategies should target high-risk groups to minimize synergy between potential risk factors on accelerated lung function decline. Funding Statement: This study was supported by the National Health and Medical Research Council (NHMRC) of Australia under NHMRC project grant scheme (299901, 1021275) and NHMRC European collaborative grant scheme (1101313) as part of ALEC (Ageing Lungs in European Cohorts funded by the European Union’s Horizon 2020 research and innovation programme under grant agreement No 633212); The University of Melbourne; Clifford Craig Medical Research Trust of Tasmania; the Victorian, Queensland & Tasmanian Asthma Foundations; The Royal Hobart Hospital; Helen MacPherson Smith Trust; and GlaxoSmithKline. Declaration of Interests: Authors have no conflicts of interest Ethics Approval Statement: The study was approved by the Human Ethics Review Committees of all relevant institutions. Written informed consent was obtained from all participants.

Glutathione S-Transferase Gene Polymorphisms are Associated with an Improved Treatment Response to Cisplatin-Based Chemotherapy in Patients with Non-Small Cell Lung Cancer (NSCLC): A Meta-Analysis.

BackgroundPrevious studies have shown an association with glutathione S-transferase (GST) gene polymorphisms in patients with non-small cell lung cancer (NSCLC) and treatment response. This study aimed to undertake a literature review and meta-analysis of GST gene polymorphisms, including GSTT1, GSTM1, and GSTP1 IIe105Val, and the treatment response to cisplatin-based chemotherapy in patients with NSCLC.Material/MethodsA literature search was undertaken of the main medical publication databases for publications, up to March 2017, on the association between GSTT1, GSTM1, and GSTP1 IIe105Val polymorphisms and the clinical outcome in patients with NSCLC treated with cisplatin-based chemotherapy. A random fixed-effects model was used to calculate the pooled odds ratio (OR) and 95% confidence interval (CI) to evaluate the associations, considering multiple genetic models. A subgroup analysis according to ethnicity was performed.ResultsTwenty-three published studies were identified that showed that both the null GSTM1 and the GG genotype of GSTP1 IIe105Val were associated with improved treatment response to cisplatin-based chemotherapy (GSTT1 present/null: OR=1.328; 95% CI, 1.074–1.643) (GSTP1 GG + AG vs. AA: OR=0.596; 95% CI, 0.468–0.759). In subgroup analysis, the GSTP1 polymorphism was significantly associated with treatment response in East-Asian patients, but not in Caucasian patients.ConclusionsMeta-analysis showed that the GG genotype of GSTP1 IIe105Val and the null GSTM1 genotype were associated with an improved treatment response to cisplatin-based chemotherapy in patients with NSCLC, especially in East-Asian patients.

The diagnostic potential of glutathione S-transferase (GST) polymorphisms in patients with colorectal cancer.

Colorectal cancer (CRC) is one of the most common cancers in the world. Despite improvements in screening for early diagnosis, CRC is one of the leading causes of cancer deaths. The aim of the study was to determine a potential association between the frequency of GSTM1 and GSTT1 null genotypes and the risk of CRC in the Polish population. Moreover, we analyzed the clinical parameters with the glutathione S-transferase (GST) gene polymorphisms in patients with CRC. The study was conducted on 512 Caucasians, including 279 patients (105 women and 174 men) with CRC. DNA from peripheral blood was extracted and the multiplex polymerase chain reaction (PCR) technique was used for glutathione S-transferase theta (GSTT1) and mu (GSTM1) gene deletion genotyping. We found no statistically significant differences in the frequency of the GST gene polymorphisms in patients with CRC and controls. The prevalence of the GSTM1*0 variant in the test subjects was higher than in controls (45.9% vs 42.9%; p > 0.05). The frequency of the GSTT1*0 variant was also higher in patients with CRC compared to the control population (21.1% vs 18.9%; p > 0.05). In addition, the effect of the GSTM1 and GSTT1 polymorphisms on the incidence of CRC was also analyzed. There was a slight, but not statistically significant, increase of the risk of colon cancer for the GSTM1*0 and GSTT1*0 variants. Moreover, we examined the GST genotype due to the cancer TNM classification and the location of the primary tumor. Statistically significant differences in the distribution of the GSTT1*0 and GSTT1*1 genotypes in both the stage and the location of the primary tumor were observed. It is suggested that the GSTT1 polymorphism may have an impact on the severity of the tumor and its location.

Genetic susceptibility of glutathione S-transferase genes (GSTM1/T1 and P1) to coronary artery disease in Asian Indians.

Genetic polymorphisms in glutathione S-transferase (GST) genes may modulate the risk of cardiovascular diseases. The objective of present study was to investigate the potential association between the polymorphisms of GSTM1/T1 and P1 genes and their influence on diverse clinical parameters and oxidative stress biomarkers in coronary artery disease (CAD) patients in Asian Indians. The present study includes 562 angiographically confirmed CAD patients and 564 healthy control subjects from the north Indian population. Anthropometric and clinical measurements were performed for all the participants. The oxidative stress biomarkers including malondialdehyde and total antioxidant capacity were also measured. The genotyping of the GSTM1/T1 and P1 genes was performed using the multiplex-PCR and PCR-RFLP methods. The CAD patients exhibit significantly high values of waist circumference, waist-to-hip ratio, body fat (%), glucose, triglycerides, and very low-density lipoprotein, and reduced high-density lipoprotein levels compared to control subjects (P<0.001). Malondialdehyde levels were significantly enhanced, and the total antioxidant capacity was reduced in CAD patients compared to controls (P<0.001). However, no significant difference in body mass index and total cholesterol levels were observed in CAD patients and control subjects. The frequencies of the GSTM1 and GSTM1/T1 null genotypes in the CAD patients were significantly higher than the control subjects. In contrast, the GSTT1(-) genotype frequencies were significantly lower in CAD patients than the controls. Logistic regression analysis of the data revealed the null genotype of GSTM1 and the GG genotype of the GSTP1 (313A/G) gene were associated with an approximately twofold enhanced risk of developing CAD, whereas GSTT1(-) plays a defensive role against CAD development in north Indians. Upon stratification of data according to the genotypes of the GSTM1/T1 and P1 genes, we did not find significant a difference among the various metabolic traits in CAD patients and controls. Our results suggest that oxidative damage induced by lipid peroxidation with reduced antioxidant capacity and genetic variants in GST genes (GSTM1/T1 and P1) may modify the risk of CAD development in Asian Indian population.

A systematic review and meta-analyses of the relationship between glutathione S-transferase gene polymorphisms and renal cell carcinoma susceptibility

BackgroundAssociation of GSTM1- and GSTT1-null genotypes, GSTP1 A/G gene polymorphism with renal cell carcinoma (RCC) susceptibility was detected, and the relationship between the GSTM1/GSTT1-null genotype and clinical TNM stages of RCC was assessed, using meta-analysis method.MethodsAssociation investigations according to eligibility criteria were searched and identified from the databases of Cochrane Library, PubMed, and Embase from establishment time of databases to July 1, 2017, and eligible reports were analyzed by meta-analysis. 95% confidence intervals (CI) were also detected, and odds ratios (OR) was used to express the results for dichotomous data.ResultsThis meta-analysis indicated that there was no an association between GSTM1-null genotype, GSTT1-null genotype, GSTP1 A/G gene polymorphism and RCC risk in the overall population of Caucasians or Asians. The dual GSTM1–GSTT1-null genotype was also not associated with RCC in the overall population of Caucasians. Interestingly, there was an association between the dual GSTM1-GSTT1-null genotype and the susceptibility of RCC in Asians. Relationship of the GSTM1-null genotype with clinical TNM stage of RCC was not observed in the overall population of Asians or Caucasians. In this meta-analysis, no association between the GSTT1-null genotype and clinical TNM stage of RCC was observed in Caucasians or Asians. Interestingly, GSTT1-null genotype was detected to be associated with the clinical TNM stages in patients with RCC in the overall population.ConclusionThe dual GSTM1-GSTT1-null genotype is detected to be associated with the onset of RCC in Asians, and there is an association between the GSTT1-null genotype and the clinical TNM stages in patients with RCC in the overall population.

GSTM1, GSTT1, and GSTP1 polymorphisms and colorectal cancer risk in Polish nonsmokers.

Glutathione S-transferase (GST) enzymes are responsible for cellular detoxification of many carcinogens and are important anticancer elements. This study assessed potential relationships between GSTM1, GSTT1, and GSTP1 polymorphisms and colorectal cancer (CRC) risk in Polish nonsmokers. We also analyzed the influence of GST gene polymorphisms on CRC clinical and histopathological features. Our study included 197 CRC patients and 104 healthy controls. GSTM1, GSTT1, and GSTP1 polymorphisms were evaluated using qPCR. Polymorphism frequencies observed in our control group corresponded to those in other European populations. The GSTM1 null and GSTT1 null genotypes were observed with similar frequencies in both CRC patients and controls (GSTM1 null: 46.7% vs. 45.2%; GSTT1 null: 15.7% vs. 20.2%). GSTP1 Ile/Ile, Ile/Val, and Val/Val genotype frequencies were respectively 42.1%, 48.2%, and 9.6% in patients and 48.1%, 42.3%, and 9.6% in controls. GSTT1 polymorphism correlated with higher tumor grade in CRC patients, and the GSTM1 null/null genotype was associated with more frequent metastasis to lymph nodes (pN classification). Our results suggest that GST gene polymorphisms may influence CRC tumor grade and stage.

Effect of the GSTM1 gene deletion on glycemic variability, sympatho-vagal balance and arterial stiffness in patients with metabolic syndrome, but without diabetes

AimsAn increased rate of cerebrovascular complications in patients with metabolic syndrome (MetS) has been reported. Previous studies demonstrated an association between glycemic variability (GV) and cerebrovascular reactivity (CRV) in MetS, thus suggesting a putative role of GV on cerebrovascular events. Although the pathophysiological mechanism linking GV to damage is still to be elucidated, evidence suggests oxidative stress plays a crucial role. Since functional variants in glutathione S-transferases (GST) genes modulate the cellular detoxification processes, the aim of this study was to elucidate the involvement of GSTs in MetS and investigating the correlation with GV, arterial stiffness, and sympatho-vagal (SV) balance. MethodsA hundred metabolic syndrome patients without diabetes underwent GST gene polymorphism analysis and a sub-sample 36 patients were randomly selected to investigate the correlation between GST gene polymorphisms and GV, and sympatho-vagal (SV) balance and arterial stiffness. ResultsGSTM1 showed a significant association with several GV, arterial stiffness, and SV balance indexes. In particular, the GSTM1 deletion positively correlates with lower values of these indexes when compared to the presence of the gene. ConclusionsTherefore, we suggested a global influence of GSTM1 deletion on the GV, arterial stiffness, and SV balance pathways in MetS patients, probably also interacting with AMP-activated protein kinase (AMPK) regulation.Our novel findings indicate GSTM1 could be a risk locus in MetS development and shed light novel scenarios on the role of glucose fluctuations in neurological impairments.

GENETIC SUSCEPTIBILITY AND HEALTH EFFECTS OF OCCUPATIONAL EXPOSURE TO NITROAROMATIC COMPOUNDS IN AMMUNITION INDUSTRY (B)

Introduction: In factory workers, exposure to nitroaromatic compounds has been linked to many adverse health effects. Aim of work: To study the role of polymorphisms of Glutathione S-transferase ( GST) gene as an effect modifier in relation to nitroaromatic induced health hazards. Materials and methods: The study was conducted on 40 workers as an exposed group comprising all workers engaged in ammunition production in a military factory in Helwan area, and a control group of 40 workers. All participants were subjected to an occupational and medical history questionnaire with full clinical examination, slit lamp examination, ECG scanning and laboratory investigations that included: liver and kidney functions, complete blood picture and serum 8-OHdG. Genetic study of GST gene polymorphism was done for the whole population. Multiplex PCR was performed for determination of GSTM1 and GSTT1 genes polymorphisms in the isolated DNAs, while PCR –Restriction Fragment Length Polymorphism (PCR- RFLP) was performed for GSTP1 gene polymorphisms. Results: Regarding frequency distribution of GST genes, in the exposed workers, intact gene of GST (M, T) and the wild GST (P) genes were more prevalent (57.5%, 65% and 62.5% respectively). However, in the control group, the intact gene of GST (M) and the wild GST (P) genes were more prevalent (95% and 77.5% respectively). In the exposed group regarding GST genes polymorphism, null GSTM gene group were predisposed to flushing, lower levels of Hematocrit value and Hb levels and blood urea. GSTP mutation group showed highly significant elevation of ALT and AST levels compared with intact gene group, while significant higher prevalence of ischemic heart diseases and level of Introduction Nitroaromatic compounds have been reported as toxic, mutagenic and carcinogenic. They are used in multiple applications as pharmaceuticals, antimicrobial agents, food additives, pesticides, explosives, dyes and raw materials in several industrial processes (Oliveira et al., 2010).TNT is one of the most recalcitrant and toxic of all the military explosives used (Padda et al., 2003). It is used in military shells, bombs, and grenades, in industrial uses, and in underwater blasting (Oliveira et al., 2010). TNT has accumulated in areas of manufacturing, storage, and decommissioning over recent decades. Various government agencies, such as the EPA have listed TNT as a priority pollutant and have recommended that it should be removed from contaminated sites to prevent environmental and health problems (Van Aken, 2009).Despite the strong causal associations between certain occupational exposures and related health hazards, still there are differences in disease incidence between workers that cannot be accounted for by differences in exposures or work practices. Genetic polymorphisms account for some of these differences, thus should be included as relevant variables in study design and analysis (NIOSH, 2004).Glutathione S-transferase (GST) enzymes comprise a family of phase II detoxifying metabolic enzymes best known for their ability to catalyze the conjugation of the reduced form of glutathione (GSH) to xenobiotic substrates (Atkinson and Babbitt, 2009), thus preventing their interaction with crucial cellular proteins and nucleic acids (Hayes et al., 2005 and Josephy, 2010). It is an important detoxifying mechanism ensuring more soluble substrates and allowing them toALT in GSTT null gene carriers on the other hand a significant higher mean level of creatinine and lower mean level of AST, was noted among exposed workers with GSTT nun null gene carriers. Conclusion: Genetic polymorphism in members of the GST gene family may be considered as an effect modifier and as genetic susceptibility for some nitroaromatic compounds health hazards. Recommendations: Further studies are recommended on a larger scale to study the net effect of multiple contributing genes.

Investigation of Gluthatione S-Transferase Variants in a Healthy Population in Goiânia-Go

Genetic polymorphisms in glutathione S-transferases (GSTs) genes might influence the detoxification activities of the enzymes predisposing individuals to a lot of disiases. Owing to the presence of these genetic variants, inter-individual and ethnic differences in GSTs detoxification capacity have been observed in various populations. Therefore, the present study was performed to determine the prevalence GSTM1*0/*0, GSTT1*0/*0 and GSTP1 Ile105Val polymorphisms in 100 healthy individuals from Goiânia - GO. GSTM1 and GSTT1 polymorphisms were analyzed by a Multiplex-PCR approach, whereas GSTP1 polymorphisms were examined by PCR-RFLP. The frequencies of GSTM1 and GSTT1 *0/*0 genotypes are 49% and 31%, respectively. The frequencies of GSTP1 Ile/Ile, Ile/Val and Val/Val genotypes were 40%, 53% and 7%, respectively. The wild-type (Ile) and variant (Val) allele frequencies were 66.5% and 33.5%, respectively. The combined genotypes distribution of GSTM1, GSTT1 and GSTP1 polymorphisms showed 12 possible genotypes present in our population; seven of them have a frequency greater than 5%. The effect of combined genotypes of these GSTs polymorphisms is still unknown. These findings in healthy population, give us such more information for the future epidemiological and clinical studies. Using to examine the effect of these combinations in drugs metabolism and cancer predisposition, further largest group would be needed, since their frequencies are quite low. To our of GSTs polymorphisms, this is the first study indicating the frequencies of genetic polymorphisms of GST superfamily in a health population in a Goiania population.

Polymorphism of glutathione S-transferase M1 and T1 genes and susceptibility to psoriasis disease: A study from North India.

Increased oxidative stress and resulting inflammation has been emphasized as a factor in the pathogenesis of many diseases including psoriasis. Glutathione S-transferases (GSTs) protect against oxidative stress, inflammation, and genotoxicity. Polymorphisms in the GST genes may lead to an imbalance in pro- and antioxidant systems resulting in the increased production of reactive oxygen species that could influence the pathogenesis of psoriasis. The aim of this study was to investigate the association between GSTs (GSTM1 and GSTT1) gene polymorphism in patients with chronic plaque psoriasis as a factor in the susceptibility and development of psoriasis. We assessed 128 patients with psoriasis and 250 age- and sex-matched healthy controls. Genomic DNA was extracted from peripheral blood by the phenol chloroform method. The null GSTT1 and GSTM1 genotypes were identified by multiplex polymerase chain reaction (PCR) method. The null genotype of GSTM1 and GSTT1 was seen in 45.3% and 40.6% in psoriasis patients whereas in the controls it was 34.4% and 20.0%, respectively. A significant association was seen between the null alleles of the GSTT1 (OR = 2.74) and GSTM1 (OR = 1.58) alone or in combination with tobacco use (P < 0.001) and psoriasis risk. The presence of both null genotypes of GSTM1 and GSTT1 further increased the risk of psoriasis (OR = 3.52) when compared with the positive genotypes of GSTM1 and GSTT1. A major limitation of this study was the small sample size. A large epidemiological study is necessary to confirm these findings. The null genotype of GSTT1 is a strong predisposing factor for psoriasis in North India.

Glutathione S-Transferase Gene Polymorphisms and the Development of New-Onset Diabetes After Liver Transplant.

The association between the glutathione S-transferase polymorphisms and the development of new-onset diabetes mellitus after liver transplant was studied. Peripheral blood samples were collected from 106 liver transplant patients divided into 2 groups: 52 with new-onset diabetes mellitus and 54 without new-onset diabetes mellitus; 169 healthy individuals with no clinical evidence of diabetes mellitus were selected as a control group. The multiplex polymerase chain reaction technique was used for genotyping GSTM1 and GSTT1 genes, using the cytochrome P450, family 1, subfamily A, polypeptide 1 (CYP1A1) gene as an internal control. The genotype of GSTP1 was determined using the restriction fragment length polymorphism-polymerase chain reaction technique. The frequency of both GSTM1 null and GSTT1 null genotypes was not significantly different in liver transplant patients with new-onset diabetes mellitus compared with the control group (P = .11 for GSTM1; P = .71 for GSTT1). Also, there was no statistically significant association between the frequency of the GSTP1 genotypes in the liver transplant patients with new-onset diabetes mellitus compared with controls. Neither GSTM1 nor GSTT1 null genotypes were associated with the risk of developing new-onset diabetes mellitus (P = .22 for GSTM1; P = .56 for GSTT1). However, the frequency of the heterozygous mutation (AG) in the A313G GSTP1 polymorphism in patients with new-onset diabetes mellitus was significantly higher than in patients without new-onset diabetes mellitus (55.8% vs 7.4%; P = .00). Thus, the risk of developing new-onset diabetes mellitus was significantly higher in patients presenting with heterozygous GSTP1 genotypes (odds ratio = 15.76; 95% confidence interval = 4.53-60.28; P = .00). The GSTP1 AG genotype was associated with an increased susceptibility to the development of new-onset diabetes mellitus after liver transplant.

Effect of Glutathione S-transferase mu 1 (GSTM1) gene polymorphism on chronic myeloid leukemia risk and Imatinib treatment response

Glutathione S-transferases (GSTs) gene polymorphisms were demonstrated to be associated with inter-individual variability of Imatinib mesylate (IM) response for chronic myeloid leukemia (CML) patients in a few studies; however, the results have been inconclusive. The aim of this study was to assess the role of such GSTs gene polymorphisms (GSTT1 and GSTM1) in relation to IM treatment outcome in 96 Syrian CML in chronic phase (CP) patients. Screening of GSTM1 and GSTT1 genotypes (null or present of these genes) was determined by multiplex polymerase chain reaction. Our results revealed that a GSTM1 null genotype frequency was significantly higher in CML patients than control (reference group) (OR=2.12, 95% CI: 1.24–3.7; p=0.007) while the GSTT1 null had no significant effect on CML development (OR=1.54, 95% CI: 0.83–2.9; p=0.19). Dual GSTM1 and GSTT1 null were associated with the risk of CML development (OR=3.6, 95% CI: 1.37–9.3; p=0.01). The GSTM1 null significantly increased the risk of minimal cytogenetic response (p=0.001). The similar trend was observed in patients with GSTT1 present/GSTM1 null genotypes (p=0.009). The highest number of patients with minimal cytogenetic response was in the group treated with 400mg of IM, while 600 and 800mg of IM significantly decreased this frequency. Our results highlight the significance of GSTM1 null alone, or in combination with the GSTT1 gene null, significantly increased the likelihood of IM failure in the CML patients studied. Especially patients with minimal cytogenetic response and GSTM1 null suffered from IM treatment failure in case of low dosage IM.

Glutathione S Transferases: Biochemistry, Polymorphism and Role in Colorectal Carcinogenesis

Glutathione S-transferases (GSTs) are enzymes detoxifying a wide range of hazardous substances both of endogenous or exogenous origin, such as reactive oxygen species (ROS) or xenobiotics and environmental carcinogens; thereby imparting protection to DNA against oxidative damage. GST gene polymorphisms on the other hand, exert an effect on the functioning of enzymes encoded by these genes at both gene expression level and the activity of the protein. In this way it may influence the possibility of detoxification of carcinogens, and consequently, the level of DNA damage; thus it may have an effect on the risk of development of cancer. In this review we aim to understand the function of GSTs in the xenobiotic metabolism and their role in modulation of colorectal cancer (CRC).

Association Study of Glutathione S-transferases Gene Polymorphisms (GSTM1 and GSTT1) with Ulcerative Colitis and Crohn's Disease in the South of Iran.

Background:Inflammatory bowel diseases (IBDs), including ulcerative colitis (UC) and Crohn's disease (CD), are chronic inflammatory disorders of the gastrointestinal tract. A combination of environmental factors and interactions with a genetic predisposition are suggested to play an important role in the etiology and pathogenesis of the IBD. Glutathione S-transferases (GSTs) are multifunctional enzymes involved in the cellular oxidative stress handling. Possible associations between GSTs gene polymorphisms and susceptibility to UC and CD have been reported in different population. The relationship between GSTM1 and GSTT1 deletion polymorphisms and susceptibility to UC and CD were investigated in the Iranian population.Materials and Methods:The study was performed in 106 IBD patients and 243 age- and sex-matched healthy Iranian controls consulting the IBD registry center of the Motahari Clinic, Shiraz University of Medical Sciences, Shiraz, Iran, between 2011 and 2013. GSTM1 and GSTT1 genotyping were performed using multiplex polymerase chain reaction and differences in the distribution of gene polymorphisms were analyzed statistically between the studied groups.Results:Statistically significant higher frequency of GSTM1 null genotype was observed in IBD patients (P = 0.01) and in the subgroup of patients with UC (P = 0.04) compared to healthy controls, whereas this was not true for CD patients. No significant association was found between GSTT1 gene polymorphism and UC or CD.Conclusions:Absence of GSTT1 functional gene does not play an important role in the pathophysiology and development of IBD, UC, and CD in Iranian population whereas GSTM1 null genotype could be considered as a possible genetic predisposing factor for more susceptibility to IBD and UC.