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)

Hereditary peculiarities in individual responses to environmental chemicals are a common occurrence in human populations. Genetic variation in glutathione S-transferase, CYP1A2, N-acetyltransferase, and paraoxonase exemplify the relationship of metabolic variation to individual susceptibility to cancer and other toxicants of environmental origin. Heritable receptor protein variants, a subset of proteins of enormous pharmacogenetic potential that have not thus far been extensively explored from the pharmacogenetic standpoint, are also considered. Examples of interest that are considered include receptor variants associated with retinoic acid resistance in acute promyelocytic leukemia, with paradoxical responses to antiandrogens in prostate cancer, and with retinitis pigmentosa. Additional heritable protein variants of pharmacogenetic interest that result in antibiotic-induced deafness, glucocorticoid-remediable aldosteronism and hypertension, the long-QT syndrome, and beryllium-induced lung disease are also discussed. These traits demonstrate how knowledge of the molecular basis and mechanism of the variant response may contribute to its prevention in sensitive persons as well as to improved therapy for genetically conditioned disorders that arise from environmental chemicals.
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PMID:Influence of heredity on human sensitivity to environmental chemicals. 778 56

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

This paper reviews studies published in the international scientific literature evaluating the influence of genetically based metabolic polymorphisms on biological indicators of genotoxic risk in environmental or occupational exposure. Exposures due to life style (i.e. diet or smoking) were not considered. Indicators are subdivided into internal dose indicators (concentration of the substance or its metabolites in biological fluids, urinary mutagenicity, adducts of hemoglobin, plasma proteins and DNA), and early biological effects (chromosome aberrations, sister chromatid exchanges, micronuclei, COMET assay, HPRT mutants). The metabolic genotypes (or phenotypes) examined by various authors are: ALDH2 (aldehyde dehydrogenase), CYP (P450 cytochrome) 1AI, CYP1A2, CYP2E1, CYP2D6, EPHX (epoxidohydrolase), NAT2 (N-acetyl transferase), NQO1 (NAD(P)H: kinone oxidoreductase), PON1 (paraoxonase), GST (glutathione S-transferase) M1, GSTT1 and GSTP1. In more than half the studies (52 out of 96), no influence of genotype was found in the biological indicator. This may be due either to the poor sensitivity of the indicator used, or to low exposure. In studies examining the effect of genotype on the indicator, the biological plausibility of the result was evaluated, i.e., whether the effect is consistent with the type of enzymatic activity expressed. Four studies reported not very reliable results and suggest either the unfavourable influence of genotype GSTM1 with high detoxifying activity, or enzymatic activity poorly involved in the metabolism of the xenobiotics in question (NAT2 in the case of PAH). As regards urinary metabolites of genotoxic agents, eight studies reported the modulating effect of genotype. The urinary excretion of mercapturic acids was greater in subjects with high GST activity. In exposure to PAH, urinary 1-pyrenol and PAH metabolites turn out to be significantly influenced by genotypes CYP1A1 or GSTM1 null; in exposure to aromatic amines, the influence of NAT2 on exposure indicators (levels of acetylated and non-acetylated metabolites) was confirmed. Exposure to benzene led to an increase in t-t-MA in some genotypes, although experimental verification is still necessary. As regards urinary mutagenicity, the effect of genotype GSTM1 null is reported, and of the same genotype combined with NAT2 slow, in non-smoking individuals subjected to high exposure to PAH and in cigarette-smoking/coke-oven workers. Lastly, the determination of urinary metabolites in monitoring exposure to genotoxic substances, provides sufficient evidence that genetically based metabolic polymorphisms must be taken into account in the future. There is still little evidence regarding the importance of genotype on the level of protein adducts in environmental and occupational exposure. A relatively large number of publications (22) dealt with DNA adduct levels in PAH exposure. In 18 studies, the biological indicator clearly increases with respect to values in control subjects. Of these studies, seven reported the influence of GSTM1 null on DNA adducts and, of the five studies which also examined genotype CYP1A1, four reported the influence on DNA adduct level of genotype CYP1A1, alone or in combination with GSTM1 null. It therefore seems as if the unfavourable association for the activating/detoxifying metabolism of PAH is a risk factor for the formation of PAH-DNA adducts. Most publications (25 out of 41; 61%) dealing with metabolic polymorphisms in effect indicators (cytogenetic markers, COMET assay, HPRT mutants) did not report any increase in the indicator due to exposure to the genotoxic agents studied. These indicators of genotoxic damage, including mainly the frequency of HPRT mutants (100%), Mn (90%) and the COMET assay (67%), are not sufficiently sensitive in revealing exposure, confirming that they are not particularly suitable for measuring exposure to genotoxic substances in occupational or environmental exposures. It is therefore difficult to assess the influence of metabolic genotypes by means of this type of biological indicator. The few positive results reported for SCE in occupational studies mentioned the influence of genotype ALDH2, either alone or in combination with genotype CYP2E1 in exposure to CVM, or in combination with GSTM1 null in exposure to epichlorohydrin. For CA the results showed unfavourable combinations of genotypes CYP2E1, GSTM1 and PON1 in exposure to pesticides, and GSTM1 null in combination with NAT2 slow in exposure to urban air. All the remaining studies on the effect of genotype on biological indicators of cytogenetic damage reported negative results.
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PMID:[Biomarkers of gentotoxic risk and metabolic polymorphism]. 1118 84

Both genetic and environmental factors influence coronary heart disease, therefore studies of coronary heart disease risk are often confounded by gene:gene and gene:environment interactions. Such interactions imply that at the molecular level there is synergy between the gene products or with the by-products of the environmental insult, resulting in a greater than additive effect on risk. Genetic risk is thus modifiable in an environment-specific manner. This review focuses on recently reported effects of smoking (environmental factor) on the impact of variation in the genes for glutathione S-transferase, paraoxonase and apolipoprotein E on the risk of coronary heart disease and effects on intermediate lipid traits. We end on a cautionary note for the need for repeat studies to confirm these reported gene:environment effects.
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PMID:Gene:environment interaction in lipid metabolism and effect on coronary heart disease risk. 1189 17

Polymorphisms in genes can lead to differences in the level of susceptibility of individuals to potentially adverse effects of environmental influences, such as chemical exposure, on prenatal development or male or female reproductive function. We have reviewed the literature in this area, with the caveat that papers involving straight gene knock-outs in experimental animals, without a clear human relevance, were largely excluded. This review represents current knowledge in this rapidly moving field, presenting both human epidemiological and animal data, where available. Among the polymorphic genes and environmental interactions discussed with respect to prenatal development are those for P-glycoprotein (multidrug resistance protein) and the avermectins; methylenetetrahydrofolate reductase (MTHFR), an enzyme in folate metabolism, and dietary folic acid; transforming growth factor alpha (TGFalpha) and cigarette smoke; and alcohol dehydrogenase (ADH) and cytochrome P-450 (CYP) 2E1 in association with alcohol consumption. Effects on male reproduction attributable to gene-environment interaction involve infertility seen as a result of either organophosphorous (OP) pesticide interaction with the polymorphic paraoxonase (PON1) gene or antiandrogenic agent interaction with the androgen receptor (AR). MTHFR, folate metabolism, and dietary folic acid are also considered in conjunction with preeclampsia and early pregnancy loss, and the effect of the interaction of glutathione S-transferase (GST) with exposure to benzene or cigarette smoke on pregnancy maintenance is explored. As a conclusion, we offer a discussion of lessons learned and suggested research needs.
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PMID:Gene-environment interactions: a review of effects on reproduction and development. 1560 83

Changes in erythrocyte delta-aminolevulinic acid dehydratase (ALA-D) have been reported after exposure to different pesticides, including organophosphates and paraquat. In this study, we have determined ALA-D in 135 pesticide applicators (sprayers) from an intensive agriculture setting at two periods with different pesticide exposure. Acetylcholinesterase (AChE) was used as a reference biomarker. The effects of the combined polymorphism of enzymes involved in the detoxification of pesticides (paraoxonase (PON1), benzoylcholinesterase (BChE), and glutathione S-transferase (GSTM1 and GSTT1)) on the level of the target erythrocyte enzymes were also studied as biomarkers of individual susceptibility. Sprayers presented significant lower levels of ALA-D and AChE than controls (41.3% and 14.5%, respectively) at the high exposure period. When all biomarkers of individual susceptibility to pesticides were considered at the same time, the GSTT1 null allele determined higher ALA-D and AChE activities at the period of high exposure to pesticides. PON1 R allele in turn determined lower AChE activity at the low exposure period. Null genotype for both GST subclasses (GSTM1 and GSTT1) was found to be the unique independent predictor of pesticide-related symptomatology. Interestingly, sprayers were consistently underrepresented among carriers of "unfavourable" BChE variants. In conclusion, ALA-D appears to be an important biological indicator of pesticide exposure and PON1 and GSTT1 are relevant determinants of susceptibility to chronic pesticide poisoning.
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PMID:Changes in erythrocyte enzymes in humans long-term exposed to pesticides: influence of several markers of individual susceptibility. 1592 24

Epidemiologic studies have failed to establish clearly whether agricultural pesticides contribute to the genesis of non-Hodgkin's lymphoma (NHL). Discordant results may be related to variation in susceptibility factors, including metabolism gene polymorphisms that might influence lymphocyte exposures to active pesticide metabolites. Associations between NHL and polymorphisms that may be relevant to pesticide metabolism have been assessed, including CYP1A1 and glutathione S-transferase variants, but the results are not highly informative because estimates were based on small numbers and convenience samples of cases and controls. Butyrylcholinesterase and paraoxonase (PON1) enzyme variants associated with altered activity and acute organophosphate toxicity are strong candidate susceptibility factors for pesticides and NHL, but others may be identified as knowledge of pesticide metabolism and relevant polymorphisms improves. Studies of metabolic susceptibility must be large and include information on specific exposures and subtypes of NHL for results to further the understanding of the relation between agricultural pesticides and NHL.
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PMID:Metabolic susceptibility to agricultural pesticides and non-Hodgkin's lymphoma. 1619 Jan 46

We used proteomic approach to analyze the protein profile of human follicular fluid (HFF) obtained from 25 normo-ovulatory women undergoing assisted reproduction techniques due to a male infertility factor. In all HFF samples analyzed we found 695 common spots distributed in the 3 to 10 pH range and in the 10-200 kDa range. Only 625 of these spots were also present in the plasma. We used MALDI-TOF-MS analysis to unequivocally assign 183 HFF/plasma matched spots and 27 HFF/plasma unmatched spots. A large number of acute-phase proteins, including transferrin, ceruloplasmin, afamin, hemopexin, haptoglobin and plasma amyloid protein, were identified in HFF in relatively high concentration supporting the hypothesis that mammalian ovulation can be compared to an inflammatory event. We also identified several important antioxidant enzymes; i.e., catalase, superoxide dismutase, glutathione transferase, paraoxonase, heat shock protein 27 and protein disulfide isomerase. This indicates that during maturation the human follicle is well protected against toxic injury due to oxidative stress.
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PMID:Proteome analysis of human follicular fluid. 1706 59

Previously we reported that in sheep dippers exposed to organophosphates the frequency of paraoxonase (PON1) polymorphisms differed between those with or without self-reported ill health. We have now examined whether polymorphisms in other genes involved in xenobiotic metabolism alter disease risk in this population. There were elevated but non-significant risks associated with the CYP2D6 WT genotype (odds ratio (OR) 1.47, 95% CI 0.83-2.60), or a GSTP1*B or *C allele (OR 1.37, 95% CI 0.88-2.01) or being GSTM1*2/GSTT1*2 homozygous (OR 1.61, 95% CI 0.74-3.48). Similar results were generally obtained after the exclusion of subjects to obtain a more homogenous case-referent population: for double null GSTM1 and GSTT1 homozygotes the OR was 2.06 (95% CI 0.85-2.04). In those also likely to have been exposed to diazinon, risks associated with a GSTP1*B or *C allele (OR 1.82, 95% CI 0.92-3.63) or a GSTM1*2/GSTT1*2 homozygous (OR 2.60, 95% CI 0.72-10.42) were elevated but not to a significant extent. Risk associated with PON1 genotype and phenotype varied with CYP2D6 and GSTP1 genotype but not consistently with a priori hypotheses. Further work is necessary to delineate more clearly pathways of organophosphate activation and non-PON1 pathways of detoxification and to confirm whether CYP and GST polymorphisms alter disease risk in populations exposed to organophosphates.
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PMID:GST CYP and PON1 polymorphisms in farmers attributing ill health to organophosphate-containing sheep dip. 1753 68

Male Wistar rats received fat-free diet or diets containing 5, 10 and 30% of fat (sunflower oil + lard, 1:1) for 4 weeks. The direct relationship between dietary fat level and ethoxyresorufin O-dealkylase activity of CYP1A1, methoxyresorufin O-dealkylase activity of CYP1A2, pentoxyresorufin O-dealkylase activity of CYP2B1 and testosterone 6beta-hydroxylase activity of CYP3A was found. Activities of key enzymes of phase II xenobiotic metabolism (total activity of glutathione transferase, activity of UDP-glucuronosyle transferase) and antioxidant enzymes (catalase, glutathione peroxidase, glutathione reductase, paraoxonase-1 and heme oxygenase-1) also increased with higher dietary fat level.
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PMID:[Effects of dietary fat level on the xenobiotic metabolism enzymes activity and antioxidant enzymes in rats]. 2264 61


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