Net efflux of cysteine, glutathione and related metabolites from rat hippocampal slices during oxygen/glucose deprivation: dependence on gamma-glutamyl transpeptidase

Brain Res. 1999 Jan 2;815(1):81-8. doi: 10.1016/s0006-8993(98)01097-x.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Brain Chemistry / drug effects
  • Brain Chemistry / physiology
  • Cell Hypoxia / physiology
  • Cysteine / metabolism*
  • Enzyme Inhibitors / pharmacology
  • Extracellular Space / metabolism
  • Female
  • Glucose / pharmacology
  • Glutathione / metabolism*
  • Hippocampus / enzymology*
  • Isoxazoles / pharmacology
  • Male
  • Organ Culture Techniques
  • Oxygen / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • gamma-Glutamyltransferase / antagonists & inhibitors
  • gamma-Glutamyltransferase / metabolism*


  • Enzyme Inhibitors
  • Isoxazoles
  • gamma-Glutamyltransferase
  • Glutathione
  • Glucose
  • Cysteine
  • acivicin
  • Oxygen