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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)

Genetic traits that confer increased susceptibility to DNA and chromosomal damage from reactive epoxide and peroxides could be important individual risk factors in the development of human cancers. To provide an index of individual sensitivity to expoxides, we previously studied sister chromatid exchange (SCE) induction in peripheral blood lymphocytes and identified a trait involving sensitivity to chromosomal damage by monoepoxybutene and diepoxybutane (DEB), both potential carcinogenic metabolites of 1,3-butadiene. Individuals sensitive to DEB induction of SCEs also had an increased number of background or "spontaneous" SCEs. The present investigation was conducted to test whether a newly described deletion polymorphism in the glutathione S-transferase class theta (GSTT1) was significantly associated with the previously described inherited chromosomal sensitivity to DEB. The background and DEB-induced SCE frequencies in peripheral blood lymphocytes from 78 healthy volunteers were determined with the use of fluorescence plus Giemsa staining. The presence or absence of the homozygous deletion of the GSTT1 gene was determined for each participant using PCR methods. In the present study, we report a close correlation of the DEB sensitivity trait with the novel polymorphism in GSTT1. The GSTT1 polymorphism was also highly associated with the background frequencies of SCE. These studies raise the possibility that DBE is a substrate for GST-theta. Individuals who carry a homozygous deletion of the GSTT1 gene may be at increased risk for genotoxic damage from environmental or occupational 1,3-butadiene exposures. The association of the GSTT1 deletion polymorphism with increases in background SCEs indicates that substrates for this isozyme are encountered commonly in the environment or are endogenous in nature.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Gene deletion of glutathione S-transferase theta: correlation with induced genetic damage and potential role in endogenous mutagenesis. 760

The M1 member of the Mu subclass of glutathione S-transferase (GSTM1) is only expressed in about 50% of individuals. In contrast, GSTT1, a member of the theta class which has been recently shown to be polymorphic, is expressed in 85% of Australian individuals. Previous studies have shown a significant excess of homozygous null GSTM1 genotypes among individuals with colorectal cancer, particularly those with proximal tumours. This suggests that GSTM1 plays a role in susceptibility to this neoplasm. In this study of 132 individuals with colorectal cancer and 200 controls, no significant excess of GSTM1 homozygous null genotypes was found among colorectal cancer patients with either a proximal or distal tumour. This suggests that the association between GSTM1 homozygous null genotypes and colorectal cancer is of smaller effect than has been reported previously using larger sample sizes. We have also examined the frequency of homozygous null GSTT1 genotypes in patients with colorectal cancer. Although the frequency was not significantly different in cases compared to control individuals, GSTT1 null homozygotes were significantly more common in patients who were diagnosed before the age of 70 years than in those who were diagnosed at an older age. This suggests that the GSTT1 genotype, and perhaps also the GSTM1 genotype for which a similar, but non-significant effect was seen, might influence the age of onset of colorectal cancer.
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PMID:Glutathione S-transferase M1 and T1 polymorphisms: susceptibility to colon cancer and age of onset. 761 2

Experimental data indicate that active oxygen species may be casually involved in the development of asbestos-related disease. Thus, it was hypothesized that individual differences in glutathione transferase activity, which may affect the ability to inactivate molecules formed in relation to oxidative stress, could influence the biological response to asbestos exposure. We could, however, not demonstrate an increased risk for radiographic changes or reduced lung function among asbestos cement workers deficient for glutathione transferase theta (GSTT1), glutathione transferase mu (GSTM1), or having a combined deficiency of enzyme activity.
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PMID:Radiographic changes and lung function in relation to activity of the glutathione transferases theta and mu among asbestos cement workers. 761 63

We describe a case-control study to identify associations between polymorphism at the cytochrome P-450 (CYP2D6) and glutathione S-transferase (GSTT1 and GSTM1) loci and susceptibility to astrocytoma and meningioma. Accordingly, genotype frequencies in 112 astrocytoma and 50 meningioma patients were compared with frequencies in 577 controls. GSTM1 genotype frequencies in these groups were not different. Logistic regression analysis showed GSTT1 null and CYP2D6 poor metabolizer were risk factors in astrocytoma (odds ratio = 2.67 P = 0.0005 and odds ratio = 4.17 P = 0.0043, respectively) and meningioma (odds ratio = 4.52, P = 0.0001 and odds ratio = 4.90, P = 0.0132, respectively) when corrected for the other variables. No interactive effects between genotypes were identified. The data suggest polymorphism at loci encoding carcinogen-metabolizing enzymes influences susceptibility to astrocytoma and meningioma, possibly by determining effectiveness in the detoxification of environmental carcinogens.
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PMID:Susceptibility to astrocytoma and meningioma: influence of allelism at glutathione S-transferase (GSTT1 and GSTM1) and cytochrome P-450 (CYP2D6) loci. 767 Dec 27

The individual genotoxic response of cultured human lymphocytes to diepoxybutane (DEB), an epoxide metabolite of 1,3-butadiene, shows a bimodal distribution. Blood donors can be classified as either DEB-sensitive or DEB-resistant on the basis of the frequency of sister chromatid exchanges (SCEs) induced by DEB in whole-blood lymphocyte cultures. The genetic basis of this phenomenon has thusfar been unknown. To investigate if differences in the ability of individuals to detoxify DEB could explain the bimodal response, sister chromatid exchanges (SCEs) induced by a 48-h treatment with DEB (2 and 5 microM) were analyzed in whole-blood lymphocyte cultures of 20 human donors with known genotypes of two polymorphic glutathione S-transferases (GSTs), GSTT1 and GSTM1. Both polymorphisms include a homozygous null genotype lacking the respective GST gene and isozyme. The mean frequency of SCEs/cell was 1.6 times higher among GSTT1 null donors (n = 8) than GSTT1 positive donors (n = 12) at both 2 microM DEB (mean 67.3 versus 40.9) and 5 microM DEB (mean 123.2 versus 77.5), with no overlapping in DEB-induced individual SCE frequencies between the two genotypes. Thus, all DEB-sensitive individuals were of the GSTT1 null genotype, while all DEB-resistant persons had a detectable GSTT1 gene. A significant (P < 0.05) negative correlation (r = -0.65 at 5 microM, r = -0.56 at 2 microM) was obtained in the GSTT1 positive donors between DEB-induced individual SCE frequency and RBC GSTT1 activity, measured by formaldehyde formation from dichloromethane; the GSTT1 null individuals showed no GSTT1 activity. At 5 microM DEB, the lymphocyte cultures of the GSTT1 null donors also had a significantly decreased replication index, indicating an impact of GSTT1 genotype on the cytotoxicity of DEB. No influence on DEB-induced SCEs or cytotoxic effects was observed for GSTM1 genotype. It is concluded that sensitivity to in vitro SCE induction by DEB is explained by the lack of GSTT1.
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PMID:Role of GSTT1 and GSTM1 genotypes in determining individual sensitivity to sister chromatid exchange induction by diepoxybutane in cultured human lymphocytes. 778 40

Until recently the Theta-class glutathione S-transferases (GSTs) were largely overlooked due to their low activity with the model substrate 1-chloro-2,4-dinitrobenzene (CDNB) and their failure to bind to immobilized glutathione affinity matrices. Little is known about the number of genes in this class. Recently, Pemble et al. (Biochem J. 300: 271-276, 1994) reported the cDNA cloning of a human Theta-class GST, termed GSTT1. In this study, we describe the molecular cloning of a cDNA encoding a second human Theta-class GST (GSTT2) from a lambda gt11 human liver 5'-stretch cDNA library. The encoded protein contains 244 amino acids and has 78.3% sequence identity with the rat subunit 12 and only 55.0% identity with human GSTT1. GSTT2 has been mapped to chromosome 22 by somatic cell hybrid analysis. The precise position of the gene was localized to subband 22q11.2 by in situ hybridization. The absence of other regions of hybridization suggests that there are no closely related sequences (e.g., reverse transcribed pseudogenes) scattered throughout the genome and that if there are closely related genes, they must be clustered near GSTT2. Southern blot analysis of human DNA digested with BamHI shows that the size of the GSTT2 gene is relatively small, as the coding sequence falls within a 3.6-kb BamHI fragment.
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PMID:Molecular cloning of a cDNA and chromosomal localization of a human theta-class glutathione S-transferase gene (GSTT2) to chromosome 22. 778 71

The factors that determine progression of cervical intra-epithelial neoplasia (CIN) to squamous cell carcinoma (SCC) are unknown. Cigarette smoking is a risk factor, suggesting polymorphism at loci that encode carcinogen-metabolizing enzymes such as glutathione S-transferase (GSTT1, GSTM1) and cytochrome P450 (CYP2D6) may determine susceptibility to these cancers. We have studied the frequency of the null genotype at the theta class GSTT1 locus in women with low-grade CIN, high-grade CIN and SCC. The control group comprised women with normal cervical pathology suffering menorrhagia. We found the frequency of GSTT1 null in the control and case groups was not significantly different, though frequency distributions of combinations of the genotype with smoking in mutually exclusive groups in the high-grade CIN group and the other case groups were significantly different. Interactive effects of GSTT1 null with the GSTM1 null and CYP2D6 EM genotypes, and cigarette smoking were also studied by comparing the multinomial frequency distributions of these factors over mutually exclusive categories. These showed no significant differences between the controls and SCC or low-grade CIN. Frequency distributions in high-grade CIN, however, were significantly different to the controls, and both SCC and low-grade CIN; frequency distributions of GSTT1 null with smoking and CYP2D6 EM, individually and in combination, were significantly different. However, inspection of our data does not indicate that GSTT1 null is a major factor mediating risk. Thus, comparison of chi 2 values for the differences between frequency distributions in high-grade CIN and other groups shows that values for combinations of GSTT1 null with other factors are lower than those for equivalent combinations with smoking and CYP2D6 EM. Interestingly, the combination GSTT1 null/GSTM1 null did not appear to influence susceptibility to CIN or SCC.
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PMID:Theta class glutathione S-transferase GSTT1 genotypes and susceptibility to cervical neoplasia: interactions with GSTM1, CYP2D6 and smoking. 800 Dec 44

In humans, glutathione-dependent conjugation of halomethanes is polymorphic, with 60% of the population classed as conjugators and 40% as non-conjugators. We report the characterization of the genetic polymorphism causing the phenotypic difference. We have isolated a cDNA that encodes a human class Theta GST (GSTT1) and which shares 82% sequence identity with rat class Theta GST5-5. From PCR and Southern blot analyses, it is shown that the GSTT1 gene is absent from 38% of the population. The presence or absence of the GSTT1 gene is coincident with the conjugator (GSST1+) and non-conjugator (GSTT1-) phenotypes respectively. The GSTT1+ phenotype can catalyse the glutathione conjugation of dichloromethane, a metabolic pathway which has been shown to be mutagenic in Salmonella typhimurium mutagenicity tester strains and is believed to be responsible for carcinogenicity of dichloromethane in the mouse. In humans, the enzyme is found in the erythrocyte and this may act as a detoxification sink. Characterization of the GSTT1 polymorphism will thus enable a more accurate assessment of human health risk from synthetic halomethanes and other industrial chemicals.
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PMID:Human glutathione S-transferase theta (GSTT1): cDNA cloning and the characterization of a genetic polymorphism. 819 45

The magnitude of health risks to workers associated with current and past exposures to butadiene has been the subject of considerable recent debate. Butadiene is metabolized in-vivo and in-vitro to the genotoxic intermediates 3,4-epoxybutene and diepoxybutane. Studies in animals and in-vitro systems have clearly demonstrated that 1,3-butadiene is a genotoxin and a potent inducer of sister-chromatid exchanges (SCEs). Data on the genotoxicity of butadiene in humans is, however, limited. Epidemiologic data indicate that butadiene is a probable human carcinogen. Recent work has further demonstrated that cultured lymphocytes from the approximately 20% of the Caucasian population that lack the glutathione S-transferase class theta gene (GSTT1) are relatively sensitive to the induction of cytogenetic damage by butadiene metabolites. In order to test whether butadiene exposure was associated with increases in SCE frequencies in peripheral blood lymphocytes and whether any increase observed could be affected by the DEB sensitivity-GSTT1 deletion, we studied 40 workers employed in the production of butadiene. In these workers baseline frequencies of SCEs, diepoxybutane-induced SCE frequencies and GSTT1 deletion status were assessed. Questionnaires were administered to each worker and exposure to 1,3-butadiene was determined using three separate approaches. Industrial hygiene personal sampling was used to measure breathing zone butadiene exposure and urine was collected to use in measurement of the urinary butadiene metabolite 1,2-dihydroxy-4-(N-acetylcysteinyl-S-)-butane (M1). Exposure to butadiene was generally below 2 ppm. The urinary metabolite M1 was found in all workers, but it did not correlate significantly with exposure. Six of 40 of the workers were GST theta-deleted DEB sensitive. No measure of acute or chronic exposure to butadiene was associated with an increase in SCE frequency. However, smoking and DEB sensitivity-GSTT1 null status were each significantly associated with elevations in baseline SCE frequency.
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PMID:Sister-chromatid exchanges, glutathione S-transferase theta deletion and cytogenetic sensitivity to diepoxybutane in lymphocytes from butadiene monomer production workers. 852 42

Polymorphism of glutathione S-transferase theta (GSTT1) modulates the toxicity of halogenated alkanes and epoxides in humans. The enzymatic activity of glutathione S-transferase theta and its corresponding gene is lacking in about 30% of the central European population. It has now been demonstrated that the background rate for sister chromatid exchange (SCE) is affected by this particular polymorphism. Smoking as a known inducer of SCE was taken into account. A group of GSTT1-positive subjects exhibited lower SCE rates than GSTT1-negative individuals (7.55 +/- 0.77 versus 8.74 +/- 1.24 SCE/mitosis, respectively, p < 0.005). Non-smoking GSTT1-positive individuals showed the lowest SCE rate (7.26 +/- 0.71 SCE/mitosis), significantly lower than the rates of smoking GSTT1-positive and non-smoking GSTT1-negative subjects (8.14 +/- 0.55 SCE/mitosis and 8.12 +/- 0.88 SCE/mitosis, respectively, p < 0.025 in both cases). Smoking GSTT1-negative subjects exhibited the highest SCE rates (9.28 +/- 1.3 SCE/mitosis). It is hypothesized that GSTT1 is protective against background genotoxic damage. Since ethylene oxide is a proven substrate of GSTT1, the detoxification of this epoxide arising from endogenous ethylene may modulate SCE background rates.
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PMID:Glutathione-S-transferase (GST) theta polymorphism influences background SCE rate. 852 47


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