Extracellular metabolism of the protective substance glutathione (γ- glutamyl-cysteinyl-glycine) may generate cysteine, glycine, several γ- glutamyl-containing dipeptides and possibly free glutamate, all of which could participate in neurotoxicity. In the present study, we have examined how blockage of γ-glutamyl transpeptidase, the key enzyme in glutathione degradation, influences the extracellular concentrations of glutathione, cysteine and related metabolites during anoxia/aglycemia of rat hippocampal slices. The net efflux, i.e., the increase in extracellular concentration due to changes in release and/or uptake, of cysteine, cysteine sulfinate, γ- glutamyl-glutamate, γ-glutamyl-glutamine, glutathione, γ-glutamyl-cysteine and glutamate increased as a result of anoxia/aglycemia. These increases in net efflux of cysteine, cysteine sulfinate, γ-glutamyl-glutamate and γ- glutamyl-glutamine were reduced or blocked by acivicin, an inhibitor of γ- glutamyl transpeptidase. In contrast, acivicin caused an increase in both basal and anoxia/aglycemia-induced net efflux of glutathione whereas the basal and anoxia/aglycemia-induced efflux of glutamate was unchanged by acivicin treatment. The effect of acivicin on the efflux of γ-glutamyl- cysteine was similar to that of glutathione although less pronounced. Addition of β-mercaptoethanol to the incubation medium during and after 30 min of anoxia/aglycemia decreased the net efflux of cysteine sulfinate specifically, indicating that the increase in cysteine sulfinate during anoxia/aglycemia may be partly derived from the spontaneous oxidation of cysteine. The results suggest that γ-glutamyl transpeptidase may be involved in the regulation of the extracellular concentrations of cysteine, several γ-glutamyl-containing dipeptides and glutathione but not glutamate during ischemia.
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