Glutathione depletion and resynthesis in laboratory animals

The availability of tissue glutathione (GSH) appears to depend upon a balance between tissue concentrations, the rate of reactive metabolite formation and the re-synthesis of GSH. To test this hypothesis, diethyl maleate (DEM, 5.8 mmol/kg bw) was administered intraperitoneally to male and female mice, hamsters, rats and guinea pigs. The regeneration of hepatic and renal GSH was examined at 0.5, 1, 2, 4, 8 and 24 hr post-treatment. DEM caused a rapid and marked depletion of tissue GSH but re-synthesis began to occur by 4 hr post-treatment in all species with the exception of the guinea pig. By 24 hr after treatment, the mouse, hamster and rat had tissue levels of GSH in excess of usual values but, in the guinea pig, recovery of hepatic GSH was still significantly reduced. Considering the reported species differences in S-alkenetransferases which detoxify DEM, the present results revealed that the conjugation of DEM proceeded rapidly in all four species but that the toxicity elicited in the guinea pig may have arisen from the unavailability of GSH during the slow re-synthesis stage following maximal depletion of this agent.