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)

Epidemiological studies suggested a protective effect of certain phenotypes of polymorphic foreign-compound-metabolizing enzymes in some types of cancer. Poor metabolizers (PM) of debrisoquine 4-hydroxylase (cytochrome P-450IID6, CYP2D6) were found to be underrepresented among patients with lung cancer. Recent advances in molecular genetic characterization of CYP2D6, glutathione S-transferase (GST) class Mu, and arylamine N-acetyltransferase enabled genotypical determination of mutant alleles in lung cancer patients. Restriction fragment length polymorphism (RFLP) with a cDNA gene probe of CYP2D6 was analyzed in 79 lung cancer patients who were phenotyped with debrisoquine. Mutant alleles were detected by allele-specific polymerase chain reaction (PCR). In the same individuals, genotype of GST class Mu was analyzed by PCR and correlated with ex vivo activity of glutathione conjugation towards trans-stilbene oxide. RFLP patterns allowed discrimination between the slow and fast genotype of N-acetyltransferase as well as the heterozygotes. Three phenotypical PMs of debrisoquine (3.8%) were confirmed by PCR and RFLP. No PM could be unambiguously recognized only by RFLP patterns. The PMs were characterized by PCR and RFLP as carriers of the 29B/29B (n = 1), 29A/29B (n = 1), and 29A/44 (n = 1) mutant alleles. Higher debrisoquine hydroxylase activities were found in the homozygous EMs, who possess two active genes, as compared to heterozygous EMs, who have only one active gene. The patients with phenotypically impaired GST Mu activity were confirmed as such by PCR. A complete correspondence between phenotyping of N-acetyltransferase (with caffeine) and genotyping was found. The new genetic techniques proved to be powerful tools for molecular-epidemiological studies aimed at establishing host factors of cancer susceptibility.
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PMID:Mutant genes of cytochrome P-450IID6, glutathione S-transferase class Mu, and arylamine N-acetyltransferase in lung cancer patients. 135 78

The glutathione transferase mu gene (GST1) and the debrisoquine hydroxylase gene (CYP2D6) are known to be polymorphic in the human population and have been associated with increased susceptibility to cancer. Smokers with low lymphocyte GST mu activity are at higher risk for lung cancer, while low debrisoquine hydroxylase activity has been correlated with lower risk for lung and bladder cancer. Phenotypic characterization of these polymorphisms by lymphocyte enzyme activity (GST) and urine metabolite ratios (debrisoquine) is cumbersome for population studies. Recent cloning and sequencing of the mutant alleles of these genes has allowed genotyping via the polymerase chain reaction (PCR). Advantages of PCR approaches are speed, technical simplicity, and minimal sample requirements. This article reviews the PCR-based methods for detection of genetic polymorphisms in human cancer susceptibility genes.
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PMID:Detection of DNA sequence polymorphisms in carcinogen metabolism genes by polymerase chain reaction. 168 53

Polymorphisms in inherited metabolic traits and intake of dietary antioxidants have been reported to be associated with risk for the development of lung cancer in smokers. This increased risk of lung cancer is presumably attributable to the accumulation of DNA damage. We conducted a study to investigate whether genetic metabolic variants and antioxidant consumption affected the sister chromatid exchange (SCE) level in lymphocytes. Study subjects were 78 friends and spouses of cases from a case-control study of lung cancer designed to investigate the association of metabolic polymorphisms with lung cancer. The metabolic traits studied included glutathione S-transferase class mu and variants of P-450 isoenzymes CYP1A1 and CYP2D6. Intake of antioxidants including vitamins A, C, and E and selenium was determined through the administration of a validated, semiquantitative food frequency questionnaire. Detailed information on smoking, family history of cancer, medical history, and environmental and occupational exposures was also obtained in an interviewer-administered questionnaire. Smoking status was found to be significantly associated with SCE frequency. In addition SCE frequency decreased with the period of time since quitting smoking. The presence of one or more glutathione S-transferase class mu alleles was associated with significantly lower SCE. Higher intake of vitamin A and selenium was also inversely associated with SCE level. Thus, the results suggest that glutathione S-transferase class mu and the intake of vitamin A and selenium may modulate the accumulation of chromosomal damage in lymphocytes.
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PMID:Glutathione S-transferase mu genotype, diet, and smoking as determinants of sister chromatid exchange frequency in lymphocytes. 754 11

Up to 90% of all cancers are possibly caused by environmental factors, such as tobacco smoke, diet and occupational exposures. The majority of chemical carcinogens require metabolic activation before they interact with cellular macromolecules and can cause cancer initiation. The xenobiotic-metabolising machinery contains two main types of enzymes: the phase-I cytochromes P-450 (CYP) mediating oxidative metabolism, and phase-II conjugating enzymes. Several phase-I and phase-II genes have recently been cloned and identified in humans. Many of them show polymorphism and have been suggested to contribute to individual cancer susceptibility as genetic modifiers of cancer risk. Altered phenotypes and genotypes in the CYP subfamilies CYP1A1, CYP2D6 and CYP2E1 have been associated with tobacco smoke-induced lung cancer and other cancers. Defective glutathione S-transferase (GST) and N-acetyltransferase (NAT) enzymes have been associated with an increased risk of developing lung and bladder cancer. There are also several studies in each category in which no associations have been found. The risk of developing lung cancer is dramatically (up to 40-fold) elevated in subpopulations having simultaneously high-risk genotypes in CYP1A1 and GSTM1. There are several difficulties in this area of research. First, many of the observed restriction-fragment length polymorphisms (RFLPs) are due to mutations in introns or other silent areas of DNA, raising the possibility that any associations found between RFLPs and cancer occur only by chance. Second, biologically plausible mechanisms linking genotypes and cancer are lacking in most of the observed cases.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Diagnosis of polymorphisms in carcinogen-activating and inactivating enzymes and cancer susceptibility--a review. 760 65

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

Polymorphisms in many xenobiotic metabolizing enzymes occur leading to variation in the level of enzyme expression in vivo. Enzymes showing such polymorphisms include the cytochrome P450 enzymes CYP1A1, CYP1A2, CYP2A6, CYP2D6, and CYP2E1 and the phase two metabolism enzymes glutathione S-transferase MI (GSTMI) and arylamine N-acetyltransferase 2 (NAT2). In the past, these polymorphisms have been studied by phenotyping using in vivo administration of probe drugs. However, the mutations which give rise to several of these polymorphisms have now been identified and genotyping assays for polymorphisms in CYP1A1, CYP2A6, CYP2D6, CYP2E1, GSTMI, and NAT2 have been developed. Specific phenotypes for several of the polymorphic enzymes have been associated with increased susceptibility to malignancy, particularly lung and bladder cancer, and Parkinson's disease. These associations are likely to be due to altered activation or detoxication of chemicals initiating these diseases, including components of tobacco smoke and neurotoxins. The substrate specificity and tissue distribution of polymorphic enzymes implicated in disease causation discussed with particular reference to previously described disease-phenotype associations.
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PMID:Genotyping for polymorphisms in xenobiotic metabolism as a predictor of disease susceptibility. 769 86

The factors that determine progression of cervical intraepithelial neoplasia (CIN) to squamous cell carcinoma (SCC) are unknown. Cigarette smoking is an independent risk factor for cervical neoplasia, suggesting that polymorphism at detoxicating enzyme loci such as cytochrome P450 CYP2D6 and glutathione S-transferase GSTM1 may determine susceptibility to these cancers. We have studied the frequencies of genotypes at these loci in women suffering low-grade CIN, high-grade CIN and SCC. A non-cancer control group was provided by women with normal cervical histology suffering menorrhagia. Comparison of the frequency distributions of the CYP2D6 PM, HET and EM genotypes (G-->A transition at intron 3/exon 4 and base pair deletion in exon 5) revealed no significant differences between the menorrhagia and SCC groups. Frequency distributions in the menorrhagia group, however, were significantly different (P < 0.04) from those in the low- and high-grade CIN groups. Thus, the proportion of EM was significantly larger (P < 0.03) and of HET generally lower. We found that the frequency of GSTM1 null in the menorrhagia and case groups was not significantly different. Interactive effects of enzyme genotypes with cigarette smoking were studied by comparing the multinomial frequency distributions of CYP2D6 EM/GSTM1 null/smoking over mutually exclusive categories. These showed no significant differences between the menorrhagia group and SCC or low-grade CIN groups. The frequency distribution in high-grade CIN, however, was significantly different to that in the menorrhagia group and in both SCC and low-grade CIN groups. This study was identified, for the first time, an inherited characteristic in women with high-grade CIN who appear to be at reduced risk of SCC. Thus, women with CYP2D6 EM who smoke have increased susceptibility to high-grade CIN but are less likely to progress to SCC, possibly because they effectively detoxify an unidentified chemical involved in mediating disease progression.
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PMID:Progression of cervical intraepithelial neoplasia to cervical cancer: interactions of cytochrome P450 CYP2D6 EM and glutathione s-transferase GSTM1 null genotypes and cigarette smoking. 791 23

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

This data in the aggregate suggests that the 3 best studied genetic susceptibility factors (CYP2D6 extensive metabolizers, GST mu null phenotype, and CYP1A1 "mutant" alleles in Asians only) constitute greater risk factors for the more smoking related histologies of lung cancer, but not for adenocarcinoma. The epidemiologic evidence for a these genetic susceptibility factors in tobacco-related cancer is suggestive but not determinant. A consensus estimate of relative risk for extensive metabolizers of debrisoquine is around 2. Variability in study results depend on a number of factors which include: assay misclassification, non-correspondence of phenotype/genotype in certain subjects, disease heterogeneity, exposure variation, ethnic and racial variation. Future studies should emphasize: a high quality approach to data gathering, careful attention to epidemiologic design, and the use of intermediate markers where feasible. Investigators should consider the use of multiple genetic markers since PCR approaches can make this an efficient approach. A meta-analysis may serve to illuminate points of heterogeneity between studies. New discoveries should provide opportunities to explore for analogous associations in other malignancies. It may be speculated that the "specificity" of the association observed for each of the genetic factors tends to support the general causal nature of the hypothesis. The fact that each shares the histologic preference at least suggests that a common mechanism may be operative. The observation that the tobacco-cancer association, though clearly present, is weaker for adenocarcinoma than for the other lung cancer histologies, suggests that the underlying mechanism involves some interaction of the genetic trait with exposure to tobacco smoking, and suggests further attention to this factor to elucidate differences in risk estimates for genetic susceptibility factors among different studies.
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PMID:Molecular epidemiology: a new perspective for the study of toxic exposures in man. A consideration of the influence of genetic susceptibility factors on risk in different lung cancer histologies. 803 47

Polymorphisms have been detected in a variety of xenobiotic-metabolizing enzymes at both the phenotypic and genotypic level. In the case of four enzymes, the cytochrome P450 CYP2D6, glutathione S-transferase mu, N-acetyltransferase 2 and serum cholinesterase, the majority of mutations which give rise to a defective phenotype have now been identified. Another group of enzymes show definite polymorphism at the phenotypic level but the exact genetic mechanisms responsible are not yet clear. These enzymes include the cytochromes P450 CYP1A1, CYP1A2 and a CYP2C form which metabolizes mephenytoin, a flavin-linked monooxygenase (fish-odour syndrome), paraoxonase, UDP-glucuronosyltransferase (Gilbert's syndrome) and thiopurine S-methyltransferase. In the case of a further group of enzymes, there is some evidence for polymorphism at either the phenotypic or genotypic level but this has not been unambiguously demonstrated. Examples of this class include the cytochrome P450 enzymes CYP2A6, CYP2E1, CYP2C9 and CYP3A4, xanthine oxidase, an S-oxidase which metabolizes carbocysteine, epoxide hydrolase, two forms of sulphotransferase and several methyltransferases. The nature of all these polymorphisms and possible polymorphisms is discussed in detail, with particular reference to the effects of this variation on drug metabolism and susceptibility to chemically-induced diseases.
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PMID:Metabolic polymorphisms. 836 90


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