Glutathione and cysteine depletion in rats and mice following acute intoxication with diethylmaleate

Abstract

We examined the dose-dependent glutathione (GSH) depletion in liver, kidney, heart and brain of rats and mice, and cysteine depletion in rat kidney, following i.p. administration of diethylmaleate (DEM). In either rodent, the fall in total GSH concentration in liver and heart reached an upper value of 90 and 80% with 3 and 4 mmol DEM/kg respectively, which did not increase with higher doses. This study suggests that the residual level of GSH corresponds to the mitochondrial pool, in which case DEM might serve as a tool for the measurement of mitochondrial GSH ex vivo. In further experiments, we studied the time course of GSH and cysteine after administration of 3 mmol DEM/kg in rat tissues. Maximal depletion was reached approximately 1 hr after the i.p. injection. Subsequent GSH repletion was fast in liver and kidney, whereas it was slow in heart and brain, with a return to control values by 8-12 and by 48 hr after intoxication, respectively. This study provides new data for cardiac GSH and renal cysteine decrease after intoxication with DEM and should help to optimize GSH depletion models for further pharmacological investigations, especially when the use of inhibitors of glutathione metabolic turnover is undesirable and when side-effects other than GSH depletion must be avoided.