Glutathione (GSH) is important in protection of cells against electrophilic drug injury and against reactive oxygen species. Both steady-state concentrations and turnover of GSH are important determinants of susceptibility of the hepatocyte to injury. Chronic ethanol administration is known to enhance susceptibility to electrophilic drug injury. We have examined the effects of chronic ethanol feeding on GSH turnover and the hepatic activities of GSH peroxidase and enzymes of the γ-glutamyl cycle in the rat. Turnover of GSH was measuremed in individual animals by measuring the decrease in specific activity of GSH in bile over time after i.v. administration of [35S]cysteine. Rats fed ethanol had significantly increased rates of GSH turnover, 0.287 ± 0.050 hr-1 vs 0.131 ± 0.041 hr-1 (P < 0.001), as well as steady-state GSH levels, 6.59 ± 1.55 vs 4.30 ± 1.28 μmoles/g liver (P < 0.01). The activities of gamma-glutamyltransferase (GGT) and GSH-synthesizing enzymes were corresponding increased significantly. By contrast, GSH peroxidase activity was decreased in ethanol-fed rats, 194 ± 20.8 vs 311 ± 89.9 nmoles NADPH oxidized/min/mg protein (P < 0.001). Biliary output and concentrations of GSH and GSSG were similar in both groups. The increase in turnover of GSH was not due to an increase in oxidation of GSH. There was, however, an association between GSH turnover and the activity of hepatic GGT in ethanol-fed but not in control rats.
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