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)

Perchloroethene (Per) is a widely used industrial solvent and common environmental contaminant. In rats, long-term inhalation of Per is known to cause a small increase in the incidence of renal tubule cell tumors in males only; renal toxicity is seen in female rats and in both sexes of mice after prolonged Per exposure. The renal toxicity of Per is likely mediated by a glutathione-dependent bioactivation reaction. Glutathione S-transferase mediated formation of S-(1,2,2-trichlorovinyl)glutathione is the first step in a sequence of reactions finally resulting in the formation of reactive intermediates in the kidney. In this study, we compared the enzymatic rates of formation of S-(1,2,2-trichlorovinyl)glutathione in liver and kidney subcellular fractions from rats, mice, and from both sexes of humans (n = 11). In microsomal fractions from the liver and kidney of all three species, enzymatic formation of S-(1,2,2-trichlorovinyl)glutathione from Per could not be observed. S-(1,2,2-Trichlorovinyl)glutathione formation (the structure was confirmed by electrospray mass spectrometry) was observed in liver cytosol from both male and female rats and mice. However, the rates of S-(1,2,2-trichlorovinyl)glutathione formation in liver cytosol from male rats (84.5+/-12 pmol/mg per min) were approximately four times higher than from female rats (19.5+/-8 pmol/mg per min) and from both sexes of mice (27.9+/-6 and 26.0+/-4 pmol/mg per min). Low rates of S-(1,2,2-trichlorovinyl)glutathione formation were also seen in kidney cytosol from mice (12+/-6 pmol/mg per min), but not from rats. In human liver subcellular fractions, enzymatic formation of S-(1,2,2-trichlorovinyl)glutathione could not be detected. The human liver cytosolic fractions, however, exhibited glutathione S-transferase activity (as determined using 1-chloro-2,4-dinitrobenzene and hexachlorobutadiene as marker substrates) in the same order of magnitude as rat and mouse liver cytosol. In contrast to other marker activities for glutathione S-transferases, the ability of all human liver cytosol samples to catalyze the glutathione conjugation of 1,2-dichloro-4-nitrobenzene was three orders of magnitude lower compared to rat and mouse liver cytosol. 1,2-Dichloro-4-nitrobenzene conjugation was also four times higher in liver cytosol from male rats compared to female rats. The results suggest that the ability of the human liver to catalyze the formation of S-(1,2,2-trichlorovinyl)glutathione from Per is at least two orders of magnitude lower than that of rat liver, and that sex-specific differences in the extent of hepatic conjugation of Per with glutathione, which may be relevant for nephrotoxicity, occur in rats.
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PMID:Glutathione conjugation of perchloroethene in subcellular fractions from rodent and human liver and kidney. 987 99

Ethacrynic acid (Ea) is a substrate for glutathione transferase 7-7 (GST-P) in rat. Toxic effects of Ea have been related to its metabolism and GSH depletion, but resistance conferred by GSTP1-1 (the human homologue) has also been reported. Hepatocytes from enzyme altered foci (EAF) express GST-P, and a model for selection of resistant EAF cells has been developed using Ea as a toxic agent. In the present study the effects of Ea in this model have been characterized. Hepatocytes from foci-bearing rats were isolated. Isolated cells were exposed to Ea for 1-4 hr in suspension. They were then allowed to attach to collagen-coated plates in a serum-containing medium. Preferentially GST-P-positive cells attached after Ea treatment, thus increasing the number of positive cells per attached cells (GST-P-%). Extracellular GSH, as well as alpha-tocopherol, did not influence the Ea effect. However, the effect of Ea was counteracted by inhibitors of glutathione transferase activity. Taxol, a microtubule stabilizing agent, also counteracted the effect of Ea on GST-P-%. 1,2-Dichloro-4-nitrobenzene (DCNB, 0.4 mM), which is a substrate for other glutathione transferase isoenzymes than GST-P, also increased the GST-P-%. However, the effect of DCNB was not inhibited by taxol. It was also found that Ea induced a drop in ATP levels, but this effect, as well as cell leakage, came later than the loss of attachment. The data suggest that the critical effect of Ea was cytoskeletal changes, and that GST-P conferred resistance by detoxification of Ea.
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PMID:Resistance against ethacrynic acid in glutathione transferase 7-7 (GST-P)-positive hepatocytes isolated from carcinogen-treated rats: the role of cytoskeletal changes and ATP depletion. 2065 Jan 71