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

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.

Partial prevention of glutathione depletion in rats following acute intoxication with diethylmaleate.

To assess the ability of L-2-oxothiazolidine-4-carboxylate (OTC) to stimulate the biosynthesis of glutathione (GSH) in non-fasted male rats, the time-courses of GSH and cysteine contents were studied in liver, kidney, heart and brain, following a single intraperitoneal injection of OTC (5 mmol/kg), with or without co-administration of the GSH depletor diethylmaleate (3 mmol/kg). In the absence of diethylmaleate, OTC did not change the GSH or cysteine content of heart and kidney. The liver was the only organ where systemic administration of OTC resulted in a fast and quasi-linear increase in GSH as a function of time, with no appreciable lag-time. A maximal, i.e. 2.1-fold increase in liver GSH was induced by OTC at the times corresponding to the low GSH values of the diurnal cycle observed in control rats. A smaller, i.e. 1.4-fold increase in brain GSH was observed after 6 hours. A marked increase in cysteine always preceded that of GSH in liver and brain. In the liver, the OTC-mediated stimulation of GSH biosynthesis was optimal when cysteine delivery was achieved at the onset of the cysteine decrease that was observed in the diurnal cycle of control rats. These results support the view that cysteine is a limiting factor in the biosynthesis of GSH. Following an acute dose of diethylmaleate (3 mmol/kg), OTC afforded a general and significant protection of rat tissues against GSH depletion.(ABSTRACT TRUNCATED AT 250 WORDS)