Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.5.1.18 (glutathione S-transferase)
22,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

One of the side effects of cisplatin therapy in malignant neoplasms is ototoxicity. This effect shows a wide inter-individual range which is more variable than the pharmacokinetic parameters. Oxidative stress has been implicated in cisplatin ototoxicity. The glutathione S-transferase (GST) supergene family encodes isoenzymes that appear to be critical in protection against oxidative stress. Certain GST loci are polymorphic, demonstrating alleles that are null (GSTM1 and GSTT1), encode low-activity variants (GSTP1) or are associated with variable inducibility (GSTM3). The aim of our study was to investigate genetic risk factors involved in the ototoxicity of cisplatin and to determine whether the polymorphisms in five GST genes affect the individual risk of ototoxicity by cisplatin. Two groups of patients were analyzed in this study: group H, 20 patients early and highly sensitive to the ototoxicity of cisplatin; and group N, 19 patients with no hearing impairment under comparable doses of the drug. We found a protective effect for the GSTM3*B allele with a frequency of 0.18 in the group with normal hearing after therapy versus 0.025 in the group with hearing impairment. (chi2=5.37; p=0.02).
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PMID:Glutathione S-transferase genetic polymorphisms and individual sensitivity to the ototoxic effect of cisplatin. 1108 56

Glutathione S-transferase (GST, E.C. 2.5.1.18) comprises a family of isoenzymes that play a key role in the detoxification of such exogenous substrates as xenobiotics, environmental substances, and carcinogenic compounds. At least five mammalian GST gene families have been identified to be polymorphic, and mutations or deletions of these genes contribute to the predisposition for several diseases, including cancer. The gene cluster of GSTM1-GSTM5 has been reported to be localized on chromosome 1p and spans a length of nearly 100 kb. One mutation of the GSTM3 gene generates a recognition site for the transcription factor yin yang 1. As a result of this mutation, the expression of GSTM3 can be influenced. The mutated GSTM3 gene has been reported to be involved in increased susceptibility for the development of cancer, but no information is available concerning its role in bladder cancer. We have identified patients with a heterozygous GSTM3 geno- type who carry a significantly increased risk for the development of bladder cancer. Here we report that the mutation of intron 6 of GSTM3 increases the risk for bladder cancer (odds ratio: 2.31; 95% confidence interval [CI], 1.79-2.82). We developed a procedure to identify heterozygous or homozygous carriers of the GSTM1 alleles. Heterozygous carriers of the GSTM1 null genotype have a significantly elevated risk of developing bladder cancer. We calculated an odds ratio of 3.54 (95% CI, 2.99-4.11) for this genotype. These observations lead to the assumption that the lack of detoxification by glutathione conjugation predispose to bladder cancer when at least one of two alleles is affected. Furthermore, individuals presenting the homozygous wild type of GSTM1 and GSTM3 are significantly protected against bladder cancer.
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PMID:Susceptibility genes: GSTM1 and GSTM3 as genetic risk factors in bladder cancer. 1117 63

In general, the biological activation of nephrocarcinogenic chlorinated hydrocarbons proceeds via conjugation with glutathione. It has mostly been assumed that the main site of initial conjugation is the liver, followed by a mandatory transfer of intermediates to the kidney. It was therefore of interest to study the enzyme activities of subgroups of glutathione transferases (GSTs) in renal cancers and the surrounding normal renal tissues of the same individuals (n = 21). For genotyping the individuals with respect to known polymorphic GST isozymes the following substrates with differential specificity were used: 1-chloro-2,4-dinitrobenzene for overall GST activity (except GST theta); 7-chloro-4-nitrobenzo-2-oxa- 1,3-diazole for GST alpha; 1,2-dichloro-4-nitro-benzene for GST mu; ethacrynic acid and 4-vinylpyridine for GST pi; and methyl chloride for GST theta. In general, the normal tissues were able to metabolize the test substrates. A general decrease in individual GST enzyme activities was apparent in the course of cancerization, and in some (exceptional) cases individual activities, expressed in the normal renal tissue, were lost in the tumour tissue. The GST enzyme activities in tumours were independent of tumour stage, or the age and gender of the patients. There was little influence of known polymorphisms of GSTM1, GSTM3 and GSTP1 upon the activities towards the test substrates, whereas the influence of GSTT1 polymorphism on the activity towads methyl chloride was straightforward. In general, the present findings support the concept that the initial GST-dependent bioactivation step of nephrocarcinogenic chlorinated hydrocarbons may take place in the kidney itself. This should be a consideration in toxicokinetic modelling.
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PMID:Glutathione transferase activities in renal carcinomas and adjacent normal renal tissues: factors influencing renal carcinogenesis induced by xenobiotics. 1121 45

The distribution of polymorphisms in the glutathione S-transferase (GST) family genes has been studied in 355 healthy controls and 206 cancer (59 proximal and 147 distal) patients. All controls were subjected to flexible sigmoidoscopy. Odds ratios (OR) after stratification by age, gender and smoking were slightly higher in the cancer group as a whole for GSTM1-null (*0/*0), GSTT1-null (*0/*0) and GSTM3 *A/*B or *B/*B when compared with the control group, but the differences did not reach statistical significance. GSTP1 variants had no effect. Separate analysis of patients with proximal and distal tumours has shown stronger associations for the distal cancers, the GSTM3*B allele presence being significantly more frequent in these patients [OR = 1.77; 95% confidence interval (CI) = 1.15-2.74]. Taking into account strong linkage between the GSTM1*A and GSTM3*B alleles, a separate analysis of the GSTM1-nulled individuals was undertaken. The combination of GSTM1-null genotype with GSTM3*B allele presence (*A/*B or *B/*B) was significantly overrepresented among patients with proximal and distal tumours taken together (OR = 2.12; 95% CI = 1.24-3.63), and especially in distal cancer patients (OR = 2.75; 95% CI = 1.56-4.84). Male individuals displayed a stronger association between the presence of the GSTM1-null in combination with GSTM3 *A/*B or *B/*B and distal tumours with a higher odds ratio (OR = 3.57; 95% CI = 1.73-7.36). In contrast, the frequency of GSTM1 *B/*0 or *B/*B combined with GSTM3 *A/*A was significantly lower in patients with distal colorectal cancer, especially in males (OR = 0.37; 95% CI = 0.15-0.92). Neither of these combinations was associated with proximal tumours. Our findings suggest that interactions of polymorphic genotypes within the GSTM gene cluster affect individual susceptibility to colorectal carcinogenesis, the GSTM3*B variant presence being a risk factor especially in combination with the GSTM1-null genotype.
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PMID:Glutathione-S-transferase gene polymorphisms in colorectal cancer patients: interaction between GSTM1 and GSTM3 allele variants as a risk-modulating factor. 1140 49

Non-melanoma skin cancer (NMSC) represents a significant cause of morbidity and mortality among renal transplant recipients, with tumors behaving more aggressively than those in nontransplant patients. Not all immunosuppressed patients develop NMSC, however, and in those that do, the rate of accrual and numbers of lesions vary considerably. Though ultraviolet light is critical, it is unlikely that this alone explains the observed phenotypic diversity, suggesting the possible involvement of genetic factors. Furthermore, although twin studies in nontransplant patients with NMSC suggest a low genetic component, several genes associated with susceptibility and outcome in these patients have been identified. Thus, having previously shown that polymorphism in members of the glutathione S-transferase (GST) supergene family is associated with altered NMSC risk in nontransplant patients, we examined allelism in GSTM1, GSTP1, GSTM3, and GSTT1 in 183 renal transplant recipients. GSTM1 null was associated with increased squamous cell carcinoma (SCC) risk (p = 0.042, OR = 3.1). This remained significant after correction for age, gender, and ultraviolet light exposure (p = 0.012, OR = 8.4) and was particularly strong in patients with higher ultraviolet light exposure (e.g., sunbathing score > 3, p = 0.003, OR = 11.5) and in smokers (p = 0.021, OR = 4.8). Analysis of the interaction between GSTM1 null and sunbathing score showed that the two factors were synergistic and individuals with both risk parameters demonstrated a shorter time from transplantation to development of the first SCC (p = 0.012, hazard ratio = 7.1). GSTP1*Ile homozygotes developed larger numbers of SCC (p = 0.002, rate ratio = 7.6), particularly those with lower ultraviolet light exposure and cigarette consumption. GSTM3 and GSTT1 also demonstrated significant associations, though some genotype frequencies were low. These preliminary data suggest that genetic factors mediating protection against oxidative stress are important in NMSC development in immunosuppressed patients and may be useful in identifying high-risk individuals.
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PMID:Polymorphisms in glutathione S-transferases are associated with altered risk of nonmelanoma skin cancer in renal transplant recipients: a preliminary analysis. 1151 1

A vast number of studies are focused on investigating genetic polymorphism in order to estimate genetic contribution to the development of cancer. Possible cancer susceptibility genes have been sought among oncogenes, tumor suppressor genes, DNA repair genes and genes encoding phase I and phase II enzymes. Large individual differences in the biotransformation of xenobiotics have been explained on the basis of genetic polymorphisms in some detoxifying enzymes, regardless of environmental and occupational exposure. Among these enzymes, glutathione S-transferases (GST) constitute a large multigene family of phase II enzymes involved in detoxification of potentially genotoxic chemicals. Five genetic polymorphisms of GST have been well documented. Total or partial deletions and (or) single nucleotide polymorphisms in alleles encoding GSTM1, GSTM3, GSTPI, GSTT1, GSTZ1 are associated with reduction of enzymatic activity toward several substrates of different GST isoenzymes. In addition, molecular epidemiology studies indicate that a single genetic polymorphism of glutathione S-transferase appears to be a moderate lung cancer risk factor. However, the risk is higher when interactions with more GST polymorphisms and other risk factors (e.g. cigarette smoking) occur. Individuals with decreased rate of detoxification, with "high risk" glutathione S-transferase genotypes have a slightly higher level of carcinogen-DNA adducts and more cytogenetic damages.
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PMID:Significance of genetic polymorphisms in glutathione S-transferase multigene family and lung cancer risk. 1154 73

We observed previously that polymorphisms in glutathione S-transferase (GST) genes modified allergic responses to diisocyanate exposure. Here, we extended the study to examine the possible role of N-acetyltransferase (NAT) genotypes in the development of diisocyanate-induced ill effects, both separately and in combination with the previously examined GSTM1, GSTM3, GSTP1 and GSTT1 genotypes. The study population comprised 182 diisocyanate-exposed workers, 109 of whom were diagnosed with diisocyanate-induced asthma and 73 of whom had no symptoms of asthma. The diisocyanates to which the workers had been exposed to were diphenylmethane diisocyanate (MDI), hexamethylene diisocyanate (HDI) and toluene diisocyanate (TDI). The NAT2 genotype did not have any significant effect on the risk of developing asthma, but the putative slow acetylator NAT1 genotypes posed a 2.54-fold risk of diisocyanate-induced asthma (95% confidence interval [CI] 1.32 to 4.91). The effect of the NAT1 genotype was especially marked for workers exposed to TDI, among whom the NAT1 slow acetylator genotypes posed a 7.77-fold risk of asthma (95% CI 1.18 to 51.6). Statistically significant increases in asthma risk were also observed among the whole study population for the concurrent presence of the GSTM1 null genotype and either NAT1 (odds ratio [OR] 4.53, 95% CI 1.76 to 11.6) or NAT2 (OR 3.12, 95% CI 1.11 to 8.78) slow acetylator genotypes, and of NAT1 and NAT2 slow acetylator genotypes (OR 4.20, 95% CI 1.51 to 11.6). The results suggest for the first time that in addition to GSTs, the NATs play an important role in inception of asthmatic reactions related to occupational exposure to diisocyanates.
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PMID:N-Acetyltransferase genotypes as modifiers of diisocyanate exposure-associated asthma risk. 1192 38

This study evaluates the influence of genetic polymorphism at GSTM1, GSTM3 and GSTT1 gene loci on oral cancer risk among Indians habituated to the use of, smokeless tobacco, bidi or cigarette. DNA extracted from white blood cells of 297 cancer patients and 450 healthy controls by the proteinase K phenol-chloroform extraction procedure were analyzed by the polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism (RFLP) analyses. Lifetime tobacco exposure was evaluated as a risk factor in relation to the polymorphism at the GST gene loci using logistic regression analysis. There was no significant difference in the distribution of the GSTM3 and GSTT1 genotypes between oral cancer patients and controls. In contrast, a significant 3-fold increase in risk was seen for patients with the GSTM1 null genotype (age adjusted OR = 3.2, 95% CI 2.4-4.3). The impact of the GSTM1 null genotype on oral cancer risk was also analyzed in separate groups of individuals with different tobacco habits. The odds ratio associated with the GSTM1 null genotype was 3.7 (95% CI 2.0-7.1) in tobacco chewers, 3.7 (5% CI 1.3-7.9) in bidi smokers and 5.7 (95% CI 2.0-16.3) in cigarette smokers. Furthermore, increased lifetime exposure to chewing tobacco appeared to be associated with a 2-fold increase in oral cancer risk in GSTM1 null individuals. The results suggest that the GSTM1 null genotype is a risk factor for development of oral cancer among Indian tobacco habitues.
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PMID:Polymorphism at GSTM1, GSTM3 and GSTT1 gene loci and susceptibility to oral cancer in an Indian population. 1201 53

Two polymorphic sites of the microsomal epoxide hydrolase gene (EPHX1, 113Tyr-->113His, 139His-->139Arg) and four glutathione S-transferase genes (GSTM1, GSTM3, GSTP1, GSTT1) were genotyped in a group of patients with larynx cancer (N=204) and in a group of healthy controls (N=203), all Spanish caucasians. After adjusting for gender, age, and tobacco smoking, none of the polymorphisms alone were found to be associated with larynx cancer risk. The analysis of EPHX1/GST combinations, however, showed a significant over-representation of patients with a combination of 113Tyr/113Tyr EPHX1 and 105Ile/105Ile GSTP1 (adjusted odds ratio (OR): 1.95; 95% confidence interval (CI): 1.02-3.78). The calculation of the predicted epoxide hydrolase (EH) activity also showed an increased risk for the individuals with both predicted high activity EH and 105Ile/105Ile GSTP1 (OR: 2.90; 95% CI: 1.10-7.67). These results on larynx cancer tend to confirm a former study on lung cancer (Cancer Lett. 173 (2001) 155) suggesting the existence of an interaction between variants of EH and GSTpi, both enzymes being involved in the metabolism of aromatic hydrocarbons, that may increase susceptibility to tobacco-related cancers.
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PMID:Microsomal epoxide hydrolase and glutathione S-transferase polymorphisms in relation to laryngeal carcinoma risk. 1235 56

Polymorphism in glutathione S-transferase (GST) genes, causing variations in enzyme activities, may influence susceptibility to oral cancer and leukoplakia in smokers and/or smokeless tobacco users. In this case-control study consisting of 109 leukoplakia and 256 oral cancer patients and 259 controls, genotype frequencies at GSTM1, GSTT1, GSTM3 and GSTP1 loci were determined by polymerase chain reaction-restriction fragment length polymorphism methods and analyzed by multiple logistic regression to determine the risks of the diseases. There were no significant differences in the distributions of GSTM1, GSTM3 and GSTT1 genotypes in patients and controls when all individuals were compared. In contrast, frequencies of ile/ile genotype at codon 105 and variant val-ala haplotype of GSTP1 was significantly higher (OR = 1.5; 95% CI = 1.0-2.0) and lower (OR = 1.4; 95% CI = 1.0-1.9) in oral cancer patients compare to controls, respectively. The impacts of all genotypes on risks of oral cancer and leukoplakia were also analyzed in patients with different tobacco habits and doses. Increased risks of cancer and leukoplakia were observed in tobacco smokers with GSTM3 (A/A) genotype (OR = 2.0, 95% CI = 1.0-4.0; OR = 2.0, 95% CI = 1.0-4.4, respectively). So, GSTM3 (A/A) genotype could become one of the markers to know which of the leukoplakia would be transformed into cancer. Heavy tobacco chewing (> 124 chewing-year) increased the risk of cancer in individuals with GSTT1 homozygous null genotype (OR = 3.0; 95% CI = 1.0-9.8). Furthermore, increased lifetime exposure to tobacco smoking (> 11.5 pack-year) increased the risk of leukoplakia in individuals with GSTM1 homozygous null genotype (OR = 2.4; 95% CI = 1.0-5.7). It may be suggested that polymorphisms in GSTP1, GSTM1, GSTM3 and GSTT1 genes regulate risk of cancer and leukoplakia differentially among different tobacco habituals.
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PMID:Glutathione S-transferase M3 (A/A) genotype as a risk factor for oral cancer and leukoplakia among Indian tobacco smokers. 1473 73


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