title: Net efflux of cysteine, glutathione and related metabolites from rat hippocampal slices during oxygen/glucose deprivation: dependence on gamma-glutamyl transpeptidase.
abstract: Extracellular metabolism of the protective substance glutathione (gamma-glutamyl-cysteinyl-glycine) may generate cysteine, glycine, several gamma-glutamyl-containing dipeptides and possibly free glutamate, all of which could participate in neurotoxicity. In the present study, we have examined how blockage of gamma-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, gamma-glutamyl-glutamate, gamma-glutamyl-glutamine, glutathione, gamma-glutamyl-cysteine and glutamate increased as a result of anoxia/aglycemia. These increases in net efflux of cysteine, cysteine sulfinate, gamma-glutamyl-glutamate and gamma-glutamyl-glutamine were reduced or blocked by acivicin, an inhibitor of gamma-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 gamma-glutamyl-cysteine was similar to that of glutathione although less pronounced. Addition of beta-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 gamma-glutamyl transpeptidase may be involved in the regulation of the extracellular concentrations of cysteine, several gamma-glutamyl-containing dipeptides and glutathione but not glutamate during ischemia.
authors.affiliation: Institute of Anatomy and Cell Biology, University of Göteborg, Sweden.
authors.forename: X
authors.initials: X
authors.lastname: Li
authors.forename: C
authors.initials: C
authors.lastname: Wallin
authors.forename: S G
authors.initials: SG
authors.lastname: Weber
authors.forename: M
authors.initials: M
authors.lastname: Sandberg
mesh_terms: D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects / Q000502:physiology; D015687:Cell Hypoxia / Q000502:physiology; D003545:Cysteine / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005110:Extracellular Space / Q000378:metabolism; D005260:Female; D005947:Glucose / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism*; D006624:Hippocampus / Q000201:enzymology*; D007555:Isoxazoles / Q000494:pharmacology; D008297:Male; D009924:Organ Culture Techniques; D010100:Oxygen / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D005723:gamma-Glutamyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism*