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)

Increased risk of environmentally induced cancer is associated with various types of exposures and host factors, including differences in carcinogen metabolism. Since many carcinogenic compounds require metabolic activation to enable them to react with cellular macromolecules, individual features of carcinogen metabolism may play an essential role in the development of environmental cancer. In this context, cigarette smoking has often been the main type of carcinogenic exposure examined in human studies. Increasing attention has recently been paid to the dose level at which individual susceptibility may be observed. Present studies on increased risk of smoking-related lung cancer associated with phenotypic or genotypic variation of the genes encoding for CYP1A1 or CYP2D6 enzymes are summarized. Similarly, higher risks of lung or bladder cancer seen at various levels of smoking in association with polymorphism of the glutathione S-transferase gene GSTM1 or NAT1 and NAT2 genes involved in N-acetylation are reviewed. Finally, the influence of CYP2E1, GSTM1, or the combined at-risk genotype on the risk of hepatocellular carcinoma in smokers is briefly discussed.
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PMID:Interaction between dose and susceptibility to environmental cancer: a short review. 925 56

The human respiratory epithelium is in direct contact with chemical carcinogens and toxins in inhaled air. Therefore, the activities of xenobiotic-metabolising enzymes in this epithelium could modulate respiratory toxicity and carcinogenesis. We determined the expression of several xenobiotic-metabolising enzymes, including phase I and phase II enzymes, in human bronchial mucosa and peripheral lung tissues. Reverse transcription-polymerase chain reaction (RT-PCR) analysis of phase I enzymes showed CYP1A1 and CYP2C (CYP2C8 and CYP2C18) mRNA expression in all of the 14 bronchial mucosa specimens. CYP2A6 and CYP2B6 mRNAs were found in 85% of the samples, whereas 50 and 90% of the tissues displayed CYP2E1 and CYP3A5 expression, respectively. However, CYP1A2, CYP2D6 and CYP3A4 mRNAs were not detected in all samples analysed. Normal human bronchial epithelial cells (NHBE cells) cultured in serum-free conditions showed reduced P450 expression in comparison with the bronchial mucosal samples. Similar to the bronchial mucosa, the peripheral lung tissues expressed CYP1A1, CYP2A6, CYP2B6, CYP2C (CYP2C8 and CYP2C18), CYP2E1 and CYP3A5 mRNAs, but did not show detectable levels of CYP2D6. Additional P450s, such as CYP1A2 and CYP3A4, were detected. The expression of CYP1A1, CYP1A2, CYP2B6, CYP2E1 and CYP3A4/5 in peripheral lung tissues was confirmed at the protein level, whereas CYP2A6 protein was undetectable. The use of specific primers for the detection of the phase II isoenzymes belonging to the glutathione S-transferase mu (GST mu) and N-acetyl transferase (NAT) families showed that GSTM1 was expressed in 40% of the bronchial mucosa and 25% of the peripheral lung tissues, whereas GSTM3 and NAT1 mRNAs were found in all bronchial and lung samples. Finally, NAT2 expression was detected in all peripheral lung tissues, but was not detected in the bronchus. In conclusion, these results describing the diversity of the xenobiotic-metabolising enzymes expressed in the bronchus and lung tissues indicate that the human respiratory system could significantly and specifically contribute to the activation and metabolism of several environmental procarcinogens.
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PMID:Characterisation of xenobiotic-metabolising enzyme expression in human bronchial mucosa and peripheral lung tissues. 979 7

It has become clear that several polymorphisms of human drug-metabolizing enzymes influence an individual's susceptibility for chemical carcinogenesis. This review gives an overview on relevant polymorphisms of four families of drug-metabolizing enzymes. Rapid acetylators (with respect to N-acetyltransferase NAT2) were shown to have an increased risk of colon cancer, but a decreased risk of bladder cancer. In addition an association between a NAT1 variant allele (NAT*10, due to mutations in the polyadenylation site causing approximately two fold higher activity) and colorectal cancer among NAT2 rapid acetylators was observed, suggesting a possible interaction between NAT1 and NAT2. Glutathione S-transferases M1 and T1 (GSTM1 and GSTT1) are polymorphic due to large deletions in the structural gene. Meta-analysis of 12 case-control studies demonstrated a significant association between the homozygous deletion of GSTM1 (GSTM1-0) and lung cancer (odds ratio: 1.41; 95% CI: 1.23-1.61). Combination of GSTM1-0 with two allelic variants of cytochrome P4501A1 (CYP1A1), CYP1A1 m2/m2 and CYP1A1 Val/Val further increases the risk for lung cancer. Indirect mechanisms by which deletion of GSTM1 increases risk for lung cancer may include GSTM1-0 associated decreased expression of GST M3 and increased activity of CYP1A1 and 1A2. Combination of GST M1-0 and NAT2 slow acetylation was associated with markedly increased risk for lung cancer (odds ratio: 7.8; 95% CI: 1.4-78.7). In addition GSTM1-0 is clearly associated with bladder cancer and possibly also with colorectal, hepatocellular, gastric, esophageal (interaction with CYP1A1), head and neck as well as cutaneous cancer. In individuals with the GSTT1-0 genotype more chromosomal aberrations and sister chromatid exchanges (SCEs) were observed after exposure to 1,3-butadiene or various haloalkanes or haloalkenes. Evidence for an association between GSTT1-0 and myelodysplastic syndrome and acute lymphoblastic leukemia has been presented. A polymorphic site of GSTP1 (valine to isoleucine at codon 104) decreases activity to several carcinogenic diol epoxides and was associated with testicular, bladder and lung cancer. Microsomal expoxide hydrolase (mEH) is polymorphic due to amino acid variation at residues 113 and 139. Polymorphic variants of mEH were associated with hepatocellular cancer (His-113 allele), ovarian cancer (Tyr-113 allele) and chronic obstructive pulmonary disease (His-113 allele). Three human sulfotransferases (STs) are regulated by genetic polymorphisms (hDHEAST, hM-PST, TS PST). Since a large number of environmental mutagens are activated by STs an association with human cancer risk might be expected.
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PMID:Polymorphisms of N-acetyltransferases, glutathione S-transferases, microsomal epoxide hydrolase and sulfotransferases: influence on cancer susceptibility. 1002 93

2-Amino-alpha-carboline (A alpha C) is a mutagenic and carcinogenic heterocyclic amine present in foods cooked at high temperature and in cigarette smoke. The mutagenic activity of A alpha C is dependent upon metabolic activation to N-hydroxy-A alpha C (N-OH-A alpha C); however, the metabolism of N-OH-A alpha C has not been studied. We have synthesized 2-nitro-alpha-carboline and N-OH-A alpha C and have examined in vitro bioactivation of N-OH-A alpha C by human and rodent liver cytosolic sulfotransferase(s) and acetyltransferase(s) and by recombinant human N-acetyltransferases, NAT1 and NAT2. The sulfotransferase-dependent bioactivation of N-OH-A alpha C by human liver cytosol exhibited large inter-individual variation (0.5-75, n = 14) and was significantly higher than bioactivation of N-hydroxy-2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (N-OH-PhIP). Correlation and inhibition studies suggested that the isoform of sulfotransferase primarily responsible for bioactivation of N-OH-A alpha C in human liver cytosol is SULT1A1. O-Acetyltransferase-dependent bioactivation of N-OH-A alpha C by human liver cytosol also exhibited large inter-individual variation (16-192, n = 18). In contrast to other N-hydroxy heterocyclic amines, which are primarily substrates only for NAT2, both NAT1 and NAT2 catalyzed bioactivation of N-OH-A alpha C. The rate of bioactivation of N-OH-A alpha C by both NAT1 and NAT2 was significantly higher than that for N-OH-PhIP. In rat and mouse liver cytosols, the level of sulfotransferase-dependent bioactivation of N-OH-A alpha C was similar to the level in the high sulfotransferase activity human liver cytosol. The level of O-acetyltransferase-dependent bioactivation of N-OH-A alpha C in rat liver cytosol was also comparable with that in the high acetyltransferase activity human liver cytosol. However, the level of O-acetyltransferase-dependent bioactivation of N-OH-A alpha C in mouse liver cytosol was comparable with that in the low acetyltransferase activity human liver cytosol. In contrast to N-OH-PhIP, bioactivation of N-OH-A alpha C was not inhibited by glutathione S-transferase activity; however, DNA binding of N-acetoxy-A alpha C was inhibited 20% in the presence of GSH. These results suggest that bioactivation of N-OH-A alpha C may be a significant source of DNA damage in human tissues after dietary exposure to AalphaC and that the relative contribution of each pathway to bioactivation or detoxification of N-OH-A alpha C differs significantly from other N-hydroxy heterocyclic or aromatic amines.
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PMID:In vitro bioactivation of N-hydroxy-2-amino-alpha-carboline. 1087 13

Inter-individual variability in carcinogen metabolism has been attributed in part to the polymorphic expression of several phase I and II detoxification enzymes. The role of these genetic polymorphisms in cancer susceptibility has been most extensively evaluated for isozymes of cytochrome P450 (CYP1A1, CYP2D6, and CYP2E1), N-acetyltransferase (NAT1 and NAT2), glutathione S-transferase (GSTM1, GSTT1, and GSTP1), microsomal epoxide hydrolase, and NAD(P)H:quinone oxidoreductase. Our understanding of the genetic basis of cancer risk has been enhanced most recently by establishment of genotype-phenotype correlations in humans and identification of numerous diverse factors, both genetic and environmental, that can modify risk.
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PMID:Genetic polymorphism and cancer risk. 1112 50

Everyone has a unique combination of polymorphic traits that modify susceptibility and response to drugs, chemicals and carcinogenic exposures. The metabolism of exogenous and endogenous chemical toxins may be modified by inherited and induced variation in CYP (P450), acetyltransferase (NAT) and glutathione S-transferase (GST) genes. We observe that specific 'at risk' genotypes for GSTM1 and NAT1/2 increase risk for bladder cancer among smokers. Genotypic and phenotypic variation in DNA repair may affect risk of somatic mutation and cancer. Variants of base excision and nucleotide excision repair genes (XRCC1 and XPD) appear to modify exposure-induced damage from cigarette smoke and radiation. We are currently engaged in discovering genetic variation in environmental response genes and determining if this variation has any effect on gene function or if it is associated with disease risk. These and other results are discussed in the context of evaluating inherited or acquired susceptibility risk factors for environmentally caused disease.
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PMID:Genetic variability in susceptibility and response to toxicants. 1132 85

Human prostate epithelial cells from a 17- and 42-year-old donor and designated as HuPrEC(17) and HuPrEC(42), were used to metabolize 2-aminodipyrido[1,2-a:3',2-d]imidazole (Glu-P-2), 2-amino-3,8-dimethylimidazo[4.5-f]quinoxaline (MeIQx), and 2-amino-1-methyl-6-phenylimidazo[4,5-b] pyridine (PhIP). The ability of the HuPrEC to metabolize these chemicals was measured as the mutagenicity of the test chemicals in V79 cells. Arylamine N-acetyltransferase (NAT1 and NAT2) genotype and activity, cytochrome P4501A2 (CYP1A2) activity and genotype, and glutathione S-transferase (GSTM1, GSTP1 and GSTT1) genotype were measured. HUPrEC(17) expressed a slow form of NAT1 (*4/*3) and an intermediate form of NAT2 (*4/*6) while HuPrEC(42) expressed the rapid form of NAT1 (*10/*10) and an intermediate form of NAT2 (*4/*5). Both had comparable NAT1 activity (2.9 and 3.6 nmol substrate acetylated/mg protein/min) but neither had detectable NAT2 activity. Cells from both donors metabolized the pro-mutagens, although there were some significant differences in the extent of mutagenicity produced. HuPrEC(42) more efficiently converted the three heterocyclic amines to mutagens than the HuPrEC(17), the ratios being Glu-P-2 (2.3:1), MeIQx (1.6:1), and PhIP (7.3:1). These data show that human prostate epithelial cells can metabolize important dietary chemicals to mutagenic species.
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PMID:Human prostate epithelial cells metabolize chemicals of dietary origin to mutagens. 1174 41

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

Allele frequencies are rather constant among different ethnic groups in many genetic polymorphisms, but some polymorphisms vary in the allele frequency depending on the time when the germ-line base exchanges occurred in the history of humans and on the adaptability of the phenotypes to given environment. This review documented the allele frequencies of polymorphisms pertaining to cancer risk for Japanese, Koreans, and Chinese. Twenty-five polymorphisms of 21 genes whose allele frequencies were available for at least two out of the three ethnic groups were selected. They were ALDH2 Glu487Lys, COMT Val158Met, CYP1A1 MspI and Val/Ile, CYP1B1 Leu432Val, CYP2E1 RsaI, CYP17 T-34C, ER C975G, GSTM1, GSTT1, GSTP1 Ile105Val, IL-1B C-511T, IL-1RN 86-bp VNTR (variable number of tandem repeats), MTHFR C677T and A1298C, NAT1, NAT2, NQO1 Pro187Ser, OGG1 Ser326Cys, p21 Ser31Arg, p53 Arg72Pro, TNF-A G-308A and G-238A, and XRCC1 Arg194Trp and Arg399Gln. The allele frequencies were found for 24 in Japanese, 16 in Koreans, and 24 in Chinese. All of the polymorphisms had similar allele frequencies for these ethnic groups, except the following polymorphisms; ALDH2 Glu487Lys whose Lys allele was more common for Japanese and Taiwanese, COMT Val158Met whose Met allele was more common for Japanese, and NAT2 rapid/slow whose slow alleles were more common for Chinese. When compared with the allele frequencies among Caucasians, the following minor alleles were more frequent among Japanese/Koreans/Chinese; ALDH2 478Lys, CYP1A1 m1 and m2, CYP2E1 c2, ER 975G, GSTT1 null, NAT1 *10, NQO1 187Ser, OGG1 326Cys, p21 31Arg, and XRCC1 194Trp, and less frequent in COMT 158Met, GST-P1 105Val, IL-1RN non-4R, MTHFR 1298C, and TNF-A -308A. The differences in genetic background may affect the impact on the lifestyle factors and/or genotypes examined in epidemiological studies. However, the influences of the variations in the allele frequency seemed to be limited among Japanese, Koreans, and Chinese. The substantial differences in the allele frequency from Caucasians could modify the influences of lifestyle factors and polymorphism genotypes, resulting in the inconsistent results of epidemiologic studies.
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PMID:Allele Frequencies of 25 Polymorphisms Pertaining to Cancer Risk for Japanese, Koreans and Chinese. 1271 76

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


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