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)

We evaluated our data on the occupational exposure to styrene in lamination workers. The battery of parameters included markers of external and internal exposure and biomarkers of biological effects and susceptibility. DNA repair capacities have been determined in both exposed and control groups. Styrene workplace concentration significantly correlated with styrene concentration in blood, exhaled air and urinary mandelic acid. Haemoglobin and O(6)-styrene oxide (SO)-guanine DNA adducts were significantly higher in exposed subjects as compared to controls and correlated with exposure parameters. In styrene-exposed workers 1-SO-adenine DNA adducts were detected (2.6 per 10(9) dNp), while in controls these adducts were below the detection limit. 1-SO-adenine adduct levels were affected by both acute and cumulative exposure (P=0.001, F=86.0 and P=0.017, F=59.0, respectively) and associated with cytochrome P450 2E1 (CYP2E1) polymorphisms (R(2)=0.442). Mutant frequencies (MF) at the hypoxanthine-guanine phosphoribosyltransferase (HPRT) locus appeared to accumulate with exposure over time and were associated with glutathione S-transferase P1 (GSTP1) polymorphism. DNA repair capacity increased with the exposure, except for the group exposed to the highest styrene concentration. In this particular group, increased DNA repair capacity to remove oxidative DNA damage was found.
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PMID:The role of various biomarkers in the evaluation of styrene genotoxicity. 1289 75

Transgenic cell lines were constructed to study dynamic competition between activation versus detoxification of benzo[a]pyrene (B[a]P) and its metabolites. Transfected V79MZ cells expressing human cytochrome P4501A1 (hCYP1A1) alone, or expressing hCYP1A1 in combination with human glutathione S-transferase P1 (hGSTP1), were used to determine how effectively GST protects against macromolecular damage or mutagenicity of B[a]P or its enantiomeric dihydrodiol metabolites (+)-benzo[a]pyrene-7,8-dihydrodiol [(+)B[a]P-7,8-diol] and (-)-benzo[a]pyrene-7,8-dihydrodiol [(-)-B[a]P-7,8-diol]. Mutagenicity of B[a]P at the hprt locus was dose- and time-dependent in cells that expressed hCYP1A1. Mutagenicity was reduced in cells further modified to co-express hGSTP1. Dose-response and time-course studies indicated that mutagenicity was reduced up to 3-fold by hGSTP1 expression, compared with cells expressing hCYP1A1 alone. Mutagenicity induced by the B[a]P 7,8-dihydrodiols was also dose-dependent, and was reduced 2- to 5-fold by hGSTP1. Expression of hGSTP1 reduced B[a]P adducts in total cellular macromolecules by 3.8-fold, which correlated with the reduction in B[a]P mutagenicity and with reduction in the formation of the proximate metabolite B[a]P 7,8-dihydrodiols from B[a]P. However, measurement of total B[a]P metabolites bound to DNA isolated from cells incubated with [3H]-B[a]P revealed only 12, 33 and 24% reduction at 12, 24 and 48 h, respectively, by GSTP1 expression. Nevertheless, (32)P-post-labeling analysis demonstrated nearly total prevention of the known B[a]P-DNA adduct, N2-guanine-benzo[a]pyrene-7,8-diol-9,10-epoxide (BPDE), in cells co-expressing hGSTP1. This adduct, thought to be the most mutagenic of the stable B[a]P adducts, accounts for 15% or less of the total DNA adducts observed. These results indicate that the reduction in hCYP1A1-mediated B[a]P mutagenesis by hGSTP1 is probably largely due to prevention of the N2-guanine-BPDE adduct. However, the significant fraction (30-40%) of this mutagenesis and the majority of the total DNA binding that are not prevented together suggest formation by hCYP1A1 of a subset of mutagenic metabolites of B[a]P that are not effectively detoxified by hGSTP1.
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PMID:Expression of human glutathione S-transferase P1 confers resistance to benzo[a]pyrene or benzo[a]pyrene-7,8-dihydrodiol mutagenesis, macromolecular alkylation and formation of stable N2-Gua-BPDE adducts in stably transfected V79MZ cells co-expressing hCYP1A1. 1688 95

Transgenic cell lines were constructed to study the dynamics of competition between activation versus detoxification of benzo[a]pyrene (B[a]P) or B[a]P-7,8-dihydrodiol metabolites. Stably transfected V79MZ cells expressing human cytochrome P4501A1 (hCYP1A1) alone or in combination with human glutathione-S-transferase M1 (hGSTM1) were used to determine how effectively this GST isozyme protects against cytotoxic, genotoxic, and mutagenic effects of B[a]P or the enantiomeric dihydrodiol metabolites (+)-benzo[a]pyrene-7,8-dihydrodiol ((+)-B[a]P-7,8-diol) and (-)-benzo[a]pyrene-7,8-dihydrodiol ((-)-B[a]P-7,8-diol). Expression of hGSTM1 in the presence of hCYP1A1 conferred significant 8.5-fold protection against B[a]P-induced cytotoxicity, but protection against cytotoxicity of either B[a]P-7,8-diol enantiomer was not significant. Mutagenicity of B[a]P at the hprt locus was dose and time dependent in cells that expressed hCYP1A1. Mutagenicity of B[a]P was reduced by 21-32% and mutagenicity induced by the B[a]P-7,8-diols was reduced 20-58% in cells further modified to coexpress hGSTM1-1 compared to cells expressing hCYP1A1 alone. Expression of hGSTM1-1 reduced adducts in total cellular macromolecules by twofold, in good correlation with the reduction in B[a]P mutagenicity. These results indicate that while hGSTM1-1 effectively protects against hCYP1A1-mediated cytotoxicity of B[a]P, a significant fraction of the mutagenicity that results from activation of B[a]P and its 7,8-dihydrodiol metabolites by hCYP1A1 is derived from B[a]P metabolites that are not detoxified by hGSTM1.
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PMID:Protective efficacy of hGSTM1-1 against B[a]P and (+)- or (-)-B[a]P-7,8-dihydrodiol cytotoxicity, mutagenicity, and macromolecular adducts in V79 cells coexpressing hCYP1A1. 1752 73


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