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)

The brominated trihalomethanes (THMs) are mutagenic and carcinogenic disinfection by-products frequently found in chlorinated drinking water. They can be activated to mutagens by the product of the glutathione S-transferase-Theta (GSTT1++-1) gene in Salmonella RSJ100, which has been transfected with this gene. To evaluate this phenomenon in humans, we have examined the genotoxicity of a brominated THM, bromoform (BF), using the Comet assay in human whole blood cultures exposed in vitro. No differences were found in the comet tail length between cultures from GSTT1-1(+) versus GSTT1-1(-) individuals (1.67 +/- 0.40 and 0.74 +/- 0.54 microm/mM, respectively, P = 0.28). The high variability was due to the relatively weak induction of comets by BF. Combining the data from both genotypic groups, the genotoxic potency of BF was 1.20 +/- 0.34 microm/mM (P = 0.003). GSTT1-1 is expressed in red blood cells but not in the target cells (lymphocytes), and expression within the target cell (as in Salmonella RSJ100) may be necessary for enhanced mutagenesis in GSTT1-1(+) relative to GSTT1-1(-) cultures. To examine this, we exposed Salmonella RSJ100 and a control strain not expressing the gene (TPT100) to the most mutagenic brominated THM detected in Salmonella, dibromochloromethane (DBCM), either in the presence or absence of S9 or red blood cells from GSTT1-1(+) or GSTT1-1(-) individuals. S9 did not activate DBCM in the non-expressing strain TPT100, and it did not affect the ability of the expressing strain RSJ100 to activate DBCM. As with S9, red cells from either genotypic group were unable to activate DBCM in TPT100. However, red cells (whole or lysed) from both genotypic groups completely repressed the ability of the expressing strain RSJ100 to activate DBCM to a mutagen. Such results suggest a model in which exposure to brominated THMs may pose an excess genotoxic risk in GSTT1-1(+) individuals to those organs and tissues that both express this gene and come into direct contact with the brominated THM, such as the colon. In contrast, those organs to which brominated THMs would be transported via the blood might be protected by erythrocytes. Such a proposal is reasonably consistent with the organ specificity of drinking water-associated cancer in humans, which shows slightly elevated risks for cancer of the colon and bladder but not of the liver.
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PMID:Induction of genetic damage in human lymphocytes and mutations in Salmonella by trihalomethanes: role of red blood cells and GSTT1-1 polymorphism. 1047 51

The glutathione S-transferase supergene family is an important part of cellular enzymic defence against endogenous and exogenous chemicals, many of which have a carcinogenic potential. However, while a wide variety of chemicals can act as substrates for different members of the supergene family, the precise function of these enzymes remains unclear. The supergene family comprises several gene families that include polymorphic loci, prompting the hypothesis that allelic variants associated with less effective detoxification of potential carcinogens can confer an increased susceptibility to cancer. For example, the null genotypes at the mu class GSTM1 and theta class GSTT1 loci have attracted particular interest, and recently identified allelic variants at the mu class GSTM3 and pi class GSTP1 loci are also putative susceptibility candidates. However, while associations between GSTM1 and GSTT1 genotypes and risk have been observed in some case-control studies in lung, bladder and colon cancers, other studies have reported contrary findings, and the importance of these polymorphisms in mediating the risk of smoking-related cancers remains generally unproven. We describe the influence of glutathione S-transferase polymorphisms on the risk of several cancers, including basal cell carcinoma of skin. In the latter cancer, associations between tumour numbers, site and accrual have been observed, suggesting a role for GST enzymes in the detoxification of the products of ultraviolet radiation-induced oxidative stress. We review below current knowledge of polymorphism in GST loci, possible in vivo GST substrates, and the difficulties of determining the role of this complex gene family on the basis of available epidemiological data.
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PMID:The glutathione S-transferases: influence of polymorphism on cancer susceptibility. 1049 61

GST, CYP, and CCND1 genotypes have been associated with outcome in several cancers. Accordingly, we have examined, in patients with one squamous cell carcinoma (SCC) of the head and neck, associations between GSTM1, GSTT1, GSTM3, GSTP1, CYP2D6, CYP1A1, CYP2E1, and CCND1 genotypes and the outcome parameters, tumor extension, histological grade, and presence of nodes. We used logistic regression to study, first, each gene individually and, second, in a step-wise model that included all of the genes. Different genes were associated with each outcome parameter. Thus, GSTT1 null was associated with T3/T4 lesions in the oral cavity/pharyngeal (P = 0.029), but not laryngeal, SCC cases. GSTT1 null was also associated with histological differentiation (G3) in the oral cavity/pharyngeal, but not laryngeal, SCC cases, although this association only approached significance (P = 0.069). CCND1 GG was associated with G3 tumors in the oral cavity/pharyngeal (P = 0.011), but not laryngeal, SCC cases. The combination of GSTT1 null/CCND1 GG was also associated with G3 tumors. CYP2D6 PM and HET were associated with lymph node involvement in the laryngeal, but not oral/pharynx, SCC cases. Genes that were individually associated with outcome were also associated with the parameter in the step-wise routine. The GSTT1 null frequency was greater in 39 patients with second primary tumors than in those with one lesion (P = 0.014). The data demonstrate site-dependent associations between GSTT1 null, CCND1 GG, and CYP2D6 PM and tumor extension, differentiation, and nodes.
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PMID:Cyclin D1, glutathione S-transferase, and cytochrome P450 genotypes and outcome in patients with upper aerodigestive tract cancers: assessment of the importance of individual genes using multivariate analysis. 1049 1

Brominated trihalomethanes (THMs) are disinfection by-products present frequently in chlorinated drinking water. Brominated THMs are mutagenic in a variety of systems and are carcinogenic in rodents. The metabolism of brominated THMs is thought to involve a GSH conjugation reaction leading either to formaldehyde or DNA-reactive intermediates via glutathione S-transferase-theta (GSTT1-1), which is polymorphic in humans. In the present study, we have determined the genotoxicity of one of the brominated THMs, bromoform (BF), by measuring its ability to induce sister chromatid exchanges (SCEs) in whole-blood (WB) cultures of human peripheral blood lymphocytes from GSTT1-1+ and GSTT1-1- donors. The results showed no differences in SCEs per cell by BF between GSTT1-1+ and GSTT1-1- individuals when the cells were exposed to 5 x 10(-3) M BF at the beginning of cell culturing (10.8+/-0.85 vs. 10.57+/-0.47, respectively), at the 16th (9.66+/-0.91 vs. 9.57+/-0.07), or the 24th h (8.21+/-0.61 vs. 8.29+/-0.24) of cell growth. Although GSTT1-1 is expressed in the erythrocytes, the lack of expression of the GSTT1-1 gene in the target cells (lymphocytes) may account for this observation.
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PMID:Induction of sister chromatid exchanges in human peripheral blood lymphocytes by bromoform: investigation of the role of GSTT1-1 polymorphism. 1052 10

Preventive strategies require identification of cancer-susceptible individuals resulting from combinations of carcinogen exposure, cancer-predisposing genes, and lack of protective factors. To this aim, related to tobacco smoking and chewing (betel quid), we measured PAH-DNA adducts as exposure and susceptibility markers together with genetic polymorphism in drug-metabolizing enzymes related to CYP1A1, GSTM1, and GSTT1 genes in case-control studies. (+)-anti-Benzo(a)pyrene diol-epoxide (BPDE)-DNA adduct levels were quantitated in white blood cells (WBCs) and lung tissue DNA. CYP1A1 polymorphism and GSTM1 or GSTT1 gene deletion was analyzed in genomic DNA from lung parenchyma, WBCs, or oral biopsies (leukoplakia patients from India) and from oral exfoliated cells (healthy controls). Results from lung cancer patients and PAH-exposed coke oven workers correlated CYP1A1-GSTM1 genotype combinations with BPDE-DNA adduct levels. Smokers with homozygous CYP1A1 variant and GSTM1 null had the highest adduct levels and were, as shown in Japanese smokers, most susceptible to lung cancer. In oral premalignant leukoplakia cases associated with betel quid/tobacco chewing, the prevalence of the GSTM1 null and GSTT1 null genotypes was significantly higher, as compared to healthy controls. The combined GST null genotypes prevailed in 60% of the cases with none detected in controls. Based on this short review we conclude that (i) BPDE-DNA adduct levels resulting from "at risk" genotype combinations may serve as markers to identify most susceptible individuals; (ii) in Indian betel quid/tobacco chewers, the null genotypes of GSTM1 and GSTT1 greatly increased the risk for developing oral leukoplakia.
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PMID:Genetic cancer susceptibility and DNA adducts: studies in smokers, tobacco chewers, and coke oven workers. 1057 54

We examined polymorphisms of glutathione S-transferase (GST) genes in 159 Japanese patients with myelodysplasia and compared the incidence with that in 43 normal individuals to clarify their pathogenetic significance in myelodysplasia. In individuals with the GSTT1 null genotype, the odds ratios for disease risk were elevated to 2.65 (95%CI; 1.27-5.52) in de novo MDS, 4.62 (1.48-14.4) in therapy-related AML, and 2.94 (1.07-8.07) in AML with triliniage dysplasia. Other representative polymorphisms of GSTs had a similar incidence among patients with myelodysplasia, and those of the controls and other hematological disorders. To further investigate the genetic pathway of myelodysplasia, the association between GST genotype and karyotype or configurations of TP53 and NRAS was evaluated, but no relationship was noted. These results suggest that the GSTT1 null genotype may play a role in an increased risk of myelodysplasia unrelated to other mechanisms of myelodysplasia, such as chromosomal alterations or mutation of TP53 or NRAS.
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PMID:Genotype of glutathione S-transferase and other genetic configurations in myelodysplasia. 1057

While 1,3-butadiene is carcinogenic in rodents, cancer causation in humans is less certain. We examined a spectrum of genotoxic outcomes in 41 butadiene polymer production workers and 38 non-exposed controls, in China, to explore the role of butadiene in human carcinogenesis. Because in vitro studies suggest that genetic polymorphisms in glutathione S-transferase enzymes influence genotoxic effects of butadiene, we also related genotoxicity to genetic polymorphisms in GSTT1 and GSTM1. Among butadiene-exposed workers, median air exposure was 2 p.p.m. (6 h time-weighted average), due largely to intermittent high level exposures. Compared with unexposed subjects, butadiene-exposed workers had greater levels of hemoglobin N-(2,3,4-trihydroxybutyl)valine (THBVal) adducts (P < 0.0001) and adduct levels tended to correlate, among butadiene-exposed workers, with air measures (P = 0.03). Butadiene-exposed workers did not differ, however, from unexposed workers with respect to frequency of uninduced or diepoxybutane-induced sister chromatid exchanges, aneuploidy as measured by fluorescence in situ hybridization of chromosomes 1, 7, 8 and 12, glycophorin A variants or lymphocyte hprt somatic mutation. Also among the exposed, greater THBVal levels were not associated with increases in uninduced sister chromatid exchanges, aneuploidy, glycophorin A or hprt mutations. Butadiene-exposed workers had greater lymphocyte (P = 0.002) and platelet counts (P = 0.07) and lymphocytes as a percentage of white blood cells were moderately correlated with greater THBVal levels (Spearman's phi = 0.32, P = 0.07). Among butadiene-exposed workers, neither GSTM1 nor GSTT1 genotype status predicted urinary mercapturic acid butanediol formation, THBVal adducts, uninduced sister chromatid exchanges, aneuploidy or mutations in the glycophorin A or hprt genes. Overall, the study demonstrated exposure to butadiene in these workers, by a variety of short-term and long-term measures, but did not show specific genotoxic effects, at the chromosomal or gene levels, related to that exposure.
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PMID:Genotoxic markers among butadiene polymer workers in China. 1060 34

The frequency of sister chromatid exchanges (SCEs), high SCE frequency cells (HFCs), and genetic polymorphism of genotypes glutathione S-transferase (GST) M1 and T1 were analyzed in peripheral lymphocytes of 35 workers occupationally exposed to chromium (Cr) and 35 matched control group. Results showed that workers exposed to Cr showed 6.07 SCE/cell, as compared to 4.76 SCE/cell for the control group (p<0.01). Smokers showed a statistically significant higher frequency of SCE than non-smokers in both groups. The work duration of Cr workers was an important factor. Workers exposed for more than 5 years showed a significantly higher level of SCEs (p<0.05). Workers exposed to Cr for 5 or more years had higher HFC rates (51.4%) than those exposed for less than 5 years (22.9%), with an odds ratio of 4.5 times than those exposed for less than 5 years. In HFC analysis, Cr workers who smoked showed a higher level of HFC (60%) than the control group (5.7%) and also had a higher odds ratio (60.4) compared with the control group. Among non-smokers, the odds ratio was 9.0. Another objective of this study is to investigate the relationship between SCE and genetic polymorphisms of GST M1 and T1 in Cr workers. The results showed that the incidence of GSTM1 null genotype was 60% in the control group and 77.1% in Cr workers, and percentages of GSTT1 deletion were 42.9% and 62.9% in control and exposed individuals, respectively. There was a slightly increased frequency of SCE among Cr workers with GSTM1 null genotype as opposed to non-null genotype individuals. A similar result was seen among the control group; however, there were no statistically significant differences. In conclusion, the current study found the positive induction of SCE in workers who smoked or/and were exposed to Cr. However, different GST genotypes did not influence the level of cytogenetic damage between groups. Despite slight variation in numbers, they all appear to be not different.
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PMID:Cytogenetic study of workers exposed to chromium compounds. 1064 16

The transformation of ethylene oxide (EO), propylene oxide (PO) and 1-butylene oxide (1-BuO) by human glutathione transferase theta (hGSTT1-1) was studied comparatively using 'conjugator' (GSTT1 + individuals) erythrocyte lysates. The relative sequence of velocity of enzymic transformation was PO > EO >> 1-BuO. The faster transformation of PO compared to EO was corroborated in studies with human and rat GSTT1-1 (hGSTT1-1 and rGSTT1-1, respectively) expressed by Salmonella typhimurium TA1535. This sequence of reactivities of homologous epoxides towards GSTT1-1 contrasts to the sequence observed in homologous alkyl halides (methyl bromide, MBr; ethyl bromide, EtBr; n-propyl bromide, PrBr) where the relative sequence MeBr >> EtBr > PrBr is observed. The higher reactivity towards GSTT1-1 of propylene oxide compared to ethylene oxide is consistent with a higher chemical reactivity. This is corroborated by experimental data of acid-catalysed hydrolysis of a number of aliphatic epoxides, including ethylene oxide and propylene oxide and consistent with semi-empirical molecular orbital modelings.
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PMID:Differential substrate behaviours of ethylene oxide and propylene oxide towards human glutathione transferase theta hGSTT1-1. 1065 Sep 22

Epipodophyllotoxin-associated secondary myeloid leukemia is a devastating complication of acute lymphoblastic leukemia (ALL) therapy. The risk factors for treatment-related myeloid leukemia remain incompletely defined. Genetic deficiencies in glutathione S-transferase (GST) activities have been linked to higher frequencies of a number of human malignancies. Our objective was to determine whether the null genotype for GSTM1, GSTT1, or both, was more frequent in children with ALL who developed treatment-related myeloid malignancies as compared to those who did not. A PCR technique was used to assay for the null genotype for GSTM1 and GSTT1 in 302 children with ALL, 57 of whom also subsequently developed treatment-related acute myeloid leukemia or myelodysplastic syndrome. Among children with ALL who did not develop treatment-related myeloid malignancies, the frequencies of GSTM1 and GSTT1 wild-type, GSTM1 null-GSTT1 wild-type, GSTM1 wild-type-GSTT1 null, and GSTM1 and GSTT1 null genotypes were 40%, 42%, 9% and 9%, respectively. The corresponding frequencies for patients who developed acute myeloid malignancies were 42%, 32%, 11% and 16%, respectively (P = 0.26). A statistically significant increase in the frequency of the GST null genotype was observed in male patients who developed myeloid malignancies as compared to male ALL control patients (P = 0.036), but was not observed in female patients (P = 0.51). Moreover, a logistic regression analysis of possible predictors for myeloid malignancies, controlling for gender and race, did not reveal an association of GSTM1 or GSTT1 null genotypes (P = 0.62 and 0.11, respectively) with treatment-related malignancies. Our data suggest that GSTM1 and GSTT1 null genotypes may not predispose to epipodophyllotoxin-associated myeloid malignancies.
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PMID:Glutathione S-transferase genotypes in children who develop treatment-related acute myeloid malignancies. 1067 38


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