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)

Genetic polymorphisms of the carcinogen-metabolizing enzymes cytochrome P450 (CYP), glutathione S-transferase (GST) M1 and N-acetyltransferase (NAT2) as well as p53 polymorphisms have been studied experimentally as susceptibility markers for hepatocellular carcinoma development in hepatocellular carcinoma cell lines and in mouse hepatocellular carcinomas. In addition, these susceptibility markers have been studied in hepatocellular carcinoma patients, in the context of coexisting alcohol consumption, smoking and/or HBV infection. To date, there is no clear evidence that susceptibility markers have an overall impact on hepatocarcinogenesis, but in subgroups of individuals, such as smokers, susceptibility markers are emerging indicators for hepatocellular carcinoma risk definition.
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PMID:Hepatocellular carcinoma: susceptibility markers. 1122 Jun 63

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

There is growing interest in the potential health benefits of tea, including the anticarcinogenic properties. We report here that white tea, the least processed form of tea, is a potent inhibitor of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-induced colonic aberrant crypts in the rat. Male Fischer 344 rats were treated for 8 wk with white tea (2% wt/vol) or drinking water alone, and on alternating days in experimental Weeks 3 and 4 the animals were given PhIP (150 mg/kg body wt p.o.) or vehicle alone. At the end of the study there were 5.65 +/- 0.81 and 1.31 +/- 0.27 (SD) aberrant crypt foci per colon in groups given PhIP and PhIP + white tea, respectively (n = 12, P < 0.05). No changes were detected in N-acetyltransferase or arylsulfotransferase activities compared with controls, but there was marked induction of ethoxyresorufin O-deethylase, methoxyresorufin O-demethylase, and UDP-glucuronosyltransferase after treatment with white tea. Western blot revealed corresponding increases in cytochrome P-450 1A1 and 1A2 proteins. Enzyme assays and Western blot also revealed induction of glutathione S-transferase by white tea. There was less parent compound and 4'-hydroxy-PhIP but more PhIP-4'-O-glucuronide and PhIP-4'-O-sulfate in the urine from rats given PhIP + white tea than in urine from animals given carcinogen + drinking water. The results indicate that white tea inhibits PhIP-induced aberrant crypt foci by altering the expression of carcinogen-metabolizing enzymes, such that there is increased ring hydroxylation at the 4' position coupled with enhanced phase 2 conjugation.
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PMID:Inhibition by white tea of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine-induced colonic aberrant crypts in the F344 rat. 1209 35

We investigated the polymorphic enzymes cytochrome P450 1A2 (CYP1A2), N-acetyltransferase (NAT2), glutathione S-transferase (GST) M1 (GSTM1), and T1 (GSTT1) in relation to cigarette smoking-associated urinary mutagenicity detected on YG1024 Salmonella typhimurium strain with S9 mix in 97 smokers. In each subject, cigarette smoke intake was checked by analysis of urinary nicotine plus its metabolites. NAT2 and CYP1A2 phenotypes were determined by the molar ratio of urinary caffeine metabolites detected by high-performance liquid chromatography, and GSTT1 and GSTM1 genotypes were determined by PCR. An increase in urinary mutagenicity was significantly related to levels of exposure to cigarette smoke and CYP1A2 N-hydroxylation activity (linear multiple regression analysis t = 4.51 and P < 0.001 and t = 3.09 and P = 0.003; F = 6.31, P < 0.001). Urinary mutagenicity was significantly higher in CYP1A2 extensive metabolizer smokers (n = 49) than in CYP1A2 poor metabolizer ones (n = 48; 2176 +/- 1525 versus 1384 +/- 1206 revertants/mmol creatinine, Mann-Whitney U-test, z = 2.65, P < 0.001). The highest mutagenic activity was seen in subjects CYP1A2 extensive metabolizer/NAT2 slow acetylators (n = 29) with respect to the other phenotype combinations (n = 68; 2392 +/- 1660 versus 1525 +/- 1238 revertants/mmol creatinine, Mann-Whitney U-test, z = 2.37, P = 0.017). NAT2 acetylation activity was slightly but inversely related to urinary mutagenicity, and the association was not significant. No effect of GSTM1 and GSTT1 genotypes in lowering (detoxifying) urinary mutagens was found. The significant enhancement of urinary mutagenicity associated with increased CYP1A2 activity, as already seen for diet-caused urinary mutagenicity, allows for many analogies between the process of mutagen formation derived from cooked meat and that from cigarette smoke condensate. In conclusion, the intensity of tobacco smoke exposure, modulated by CYP1A2 activity, is the major determinant of mutagenic urine among smokers, whereas GSTM1 and GSTT1 genotypes have no influence on this biomarker. This study suggests that CYP1A2 should definitely be determined in future studies involving urinary mutagenicity in cases in which smoking is a factor.
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PMID:Exposure levels and cytochrome P450 1A2 activity, but not N-acetyltransferase, glutathione S-transferase (GST) M1 and T1, influence urinary mutagen excretion in smokers. 1237 99

Genetically determined risk factors may considerably contribute to the development of neoplastic diseases, including neoplasm of urinary organs, e.g. bladder and prostate cancers. It is believed that they may result, among others, from the differences in the metabolism of environmental carcinogens and mechanisms of DNA repair. There is a clear evidence that the kind and rate of metabolism is genetically determined by polymorphic enzyme coding genes participating in the process of xenobiotic transformation. Genetic polymorphism has been confirmed for a number of enzymes involved in the reaction of oxidation or conjugation of exo- and endogenous xenobioties. Gene variability may alter the expression or enzymatic activity of coded enzymes. Therefore, the cancer risk assessment should also be based on individual differences in the ability to activate (phase I) or to detoxify (phase II) possible carcinogens. In the present study, the information on the significance of glutathione 5-transferase (GST) and N-acetyltransferase (NAT) gene families in protection of human health and incidence of various diseases is summarized. The role of hereditary polymorphisms of GST and NAT genes involved in the etiology of neoplasm of urinary organs is controversial. That is why, special attention has to be focused on the recent information on a possible role of GST and NAT polymorphisms in the predisposition to urinary bladder, prostate and urothelial transitional cell carcinoma.
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PMID:Genetic polymorphism of N-acetyltransferase and glutathione S-transferase related to neoplasm of genitourinary system. Minireview. 1238 17

This article describes the development and use of assay models in vitro (genotoxicity assay with genetically engineered cells and human hepatoma (HepG2) cells) and in vivo (genotoxicity and short-term carcinogenicity assays with rodents) for the identification of dietary constituents which protect against the genotoxic and carcinogenic effects of heterocyclic aromatic amines (HAs). The use of genetically engineered cells expressing enzymes responsible for the bioactivation of HAs enables the detection of dietary factors that inhibit the metabolic activation of HAs. Human derived hepatoma (HepG2) cells are sensitive towards HAs and express several enzymes [glutathione S-transferase (GST), N-acetyltransferase (NAT), sulfotransferase (SULT), UDP-glucuronosyltransferase (UDPGT), and cytochrome P450 isozymes] involved in the biotransformation of HAs. Hence these cells may reflect protective effects, which are due to inhibition of activating enzymes and/or induction of detoxifying enzymes. The SCGE assay with rodent cells has the advantage that HA-induced DNA damage can be monitored in a variety of organs which are targets for tumor induction by HAs. ACF and GST-P(+) foci constitute preneoplastic lesions that may develop into tumors. Therefore, agents that prevent the formation of these lesions may be anticarcinogens. The foci yield and the sensitivity of the system could be substantially increased by using a modified diet. The predictive value of the different in vitro and in vivo assays described here for the identification of HA-protective dietary substances relevant for humans is probably better than that of conventional in vitro test methods with enzyme homogenates. Nevertheless, the new test methods are not without shortcomings and these issues are critically discussed in the present article.
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PMID:Development and application of test methods for the detection of dietary constituents which protect against heterocyclic aromatic amines. 1262 16

Determination of protein oligomerization state can be technically challenging. We have combined the methods of expressed protein ligation (EPL) and fluorescence resonance energy transfer (FRET) for the analysis of protein homo-oligomerization states. We have attached fluorescein (donor) and rhodamine (acceptor) chromophores via dipeptide linkages to the C-termini of three recombinant proteins and examined the potential for FRET between mixtures of these semisynthetic proteins. The known protein dimer (glutathione S-transferase) showed evidence of FRET and the known protein monomer (SH2 domain phosphatase-1) did not display FRET. Using this method, the previously uncharacterized circadian rhythm enzyme, serotonin N-acetyltransferase, displayed significant FRET, indicating its likely propensity for dimerization or more complex oligomerization. These results establish the potential of the union of EPL and FRET in the analysis of protein-protein interactions and provide insight into the unusual enzymatic behavior of a key circadian rhythm enzyme.
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PMID:Merging fluorescence resonance energy transfer and expressed protein ligation to analyze protein-protein interactions. 1275 61

N-acetyltransferase (NAT) 1 and 2 and glutathione S-transferase (GST) M1 and T1 are phase II enzymes that are important for activation and detoxification of carcinogenic heterocyclic and aromatic amines, as present in cigarette smoke. We studied whether genetic polymorphisms in these genes modifies the relationship between smoking and breast cancer. A nested case-control study was conducted among participants in a Dutch prospective cohort. Breast cancer cases (n=229) and controls (n=264) were frequency-matched on age, menopausal status and residence. Compared to never smoking, smoking 20 cigarettes or more per day increased breast cancer risk statistically significant only in postmenopausal women [odds ratio (OR)=2.17; 95% confidence interval (CI) 1.04-4.51]. Neither NAT1 slow genotype, or GSTT1 null genotype, alone or in combination with smoking, affected breast cancer risk. However, compared to individuals with rapid NAT2 genotype, women with the very slow acetylator genotype (NAT2*5), who smoked for 20 years showed an increased breast cancer risk (OR=2.29; 95% CI 1.06-4.95). Similarly, the presence of GSTM1 null genotype combined with high levels of cigarette smoking (OR=3.00; 95% CI 1.46-6.15) or long duration (OR=2.53; 95% CI 1.24-5.16), increased rates of breast cancer. The combined effect of GSTM1 null genotype and smoking high doses was most pronounced in postmenopausal women (OR=6.78; 95% CI 2.31-19.89). In conclusion, our results provide support for the view that women who smoke and who have a genetically determined reduced inactivation of carcinogens (GSTM1 null genotype or slow NAT2 genotype (especially very slow NAT2 genotype)) are at increased risk of breast cancer.
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PMID:NAT2 slow acetylation and GSTM1 null genotypes may increase postmenopausal breast cancer risk in long-term smoking women. 1283 15

2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is the most abundant heterocyclic amine derived from food, possibly involved in human carcinogenesis. We evaluated the formation of PhIP-DNA adducts in lymphocytes from 76 incident colorectal cancer patients likely to be exposed to dietary PhIP. To address the role of the metabolic polymorphisms relevant to PhIP-DNA adduct formation, the patients were genotyped for common polymorphisms in the N-acetyltransferase (NAT1 and NAT2), sulfotransferase (SULT1A1) and glutathione S-transferase (GSTM1 and GSTA1) genes. PhIP released from adducted DNA after hydrolysis was quantitated by liquid chromatography-tandem mass spectrometry. Overall, adducts were 3.24 +/- 3.58/10(8) nucleotides (mean +/- SD); they were not related to sex, smoking habits or age, though levels were not significantly higher in smokers, young subjects and high meat consumers. High vegetable intake significantly reduced PhIP-DNA adducts (Mann-Whitney U, p = 0.044). Individuals with the GSTM1 null genotype showed colon cancer onset at earlier age (58.8 +/- 1.8 vs. 63.5 +/- 1.6 years; Mann-Whitney U, p = 0.047). None of the genetic polymorphisms studied significantly affected PhIP-DNA adducts. However, individuals carrying 2 mutated GSTA1 alleles and younger than the median age had higher adduct levels than homozygous wild-type and heterozygous ones (Kruskal-Wallis p = 0.0008). In conclusion, these preliminary data indicate that PhIP-DNA adducts are formed in people likely to be exposed to this carcinogen through the diet, suggesting this biomarker may be useful to detect human exposure and DNA damage. Overall, the genetic polymorphisms considered had limited effect on PhIP-DNA levels, but young people with lower detoxification capacity may form a subgroup particularly susceptible to dietary carcinogen.
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PMID:Genetic polymorphisms and modulation of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-DNA adducts in human lymphocytes. 1460 Oct 45

Bladder cancer is associated with smoking, occupational exposures, and glutathione S-transferase (GST) M1 and N-acetyltransferase (NAT) 2 polymorphisms that may influence carcinogen metabolism, but somatic p53mutations are often CpG dinucleotide G:C-A:T transitions that can occur spontaneously. We conducted a case-control study to determine whether p53mutation characteristics might distinguish cases with environmental versus endogenous causes. p53exons 4-9 were amplified from 146 bladder tumors by PCR, screened by single-strand conformational polymorphism analysis, and sequenced. Thirty-one cases were p53-positive, and 112 were p53-negative (germ line or silent). G:C-A:T transitions were also subclassified as CpG or non-CpG. Cases and 215 clinic controls were interviewed. GSTM1, NAT1, and NAT2 polymorphisms were assayed from peripheral blood. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic and polytomous regression. Case-control ORs for smoking, occupations, and NAT1*10genotype were similar for p53-positive and p53-negative cases. Associations with GSTM1-null and NAT2-slow genotypes were somewhat stronger for p53-positive [OR, 3.3; CI, 1.4-7.8 (GSTM1 null); OR, 1.8; CI, 0.8-4.0 (NAT2 slow)] than p53-negative cases [OR, 1.5; CI:0.9-2.3 (GSTM1 null); OR, 0.9; CI, 0.6-1.4 (NAT2 slow)]. Smoking was strongly associated with CpG G:C-A:T (OR, 15.3; CI:3.6-65) versus other G:C-A:T (OR, 1.8; CI, 0.3-9.8). NAT2 slow genotypes were also associated with CpG G:C-A:T (OR, 6.2; CI:0.7-52), whereas GSTM1 null was associated with non-CpG G:C-A:T (OR, 7.8; CI, 0.9-65). Associations were not substantially different for case subtypes defined by p53mutation status alone. Estimates for p53 subtypes were imprecise but support in vitro evidence that some CpG G:C-A:T transitions may be caused by smoking and other environmental mutagens.
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PMID:p53 mutations in bladder cancer: evidence for exogenous versus endogenous risk factors. 1461 56


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