Hepatic glutathione metabolism in mice acutely treated with lead acetate

Hepatic glutathione content decreased in a dose-dependent manner after the administration of lead acetate (5-100 mg/kg, i.p.). Hepatic cysteine content, a substantial rate limiting factor in glutathione synthesis, also decreased transiently but significantly, whereas total cysteine (cysteine plus cystine) content remained unchanged. The pretreatment of mice with L-methionine (250 mg/kg, i.p.) partially prevented the decrease in glutathione content in lead-treated mice at least partly through the elevation of hepatic cysteine content; in contrast, L-cysteine administration (250 mg/kg, i.p.) depleted hepatic glutathione contrary to a quick increase in hepatic cysteine content. The activity of gamma-glutamylcysteine synthetase (GCS), a rate limiting enzyme in glutathione synthesis, was not altered by either the administration of lead or sulfur amino acids. On the other hand, lead facilitated the disappearance of glutathione from the livers of mice treated with buthionine sulfoximine, a specific inhibitor of GCS. These lines of evidence suggest that for the decrease in glutathione content elicited by lead-loading, the increased efflux of glutathione into extra-hepatic spaces is a more crucial event than the fluctuation of intrahepatic cysteine concentration.