Intrahepatic transport and utilization of biliary glutathione and its metabolites

Abstract

Glutathione transported by hepatocytes into the bile canaliculi is metabolized by the actions of γ-glutamyl transpeptidase and dipeptidase located on the biliary ductular epithelium. This pathway is revealed by the finding of high levels of cyst(e)inylglycine, γ-glutamylglutathione, γ-glutamylcyst(e)ine, glutamate, glycine, and cyst(e)ine in bile, by studies in which intrahepatic metabolism of glutathione was inhibited by administration of a potent inhibitor of γ-glutamyl transpeptidase and by experiments in which glutathione synthesis was inhibited. Canalicular transport of glutathione, as estimated from totals of metabolites found, is much greater than the glutathione found in bile. Glutathione and glutathione metabolites found in bile increase with age, in association with an increase in hepatic glutathione. In younger rats there is apparent uptake of cysteine and glycine moieties that may reflect uptake of cysteinylglycine at the ductular level. This intrahepatic pathway of glutathione transport and metabolism, which resembles that which occurs in the kidney, seems to function as a cellular protective mechanism in the processing of glutathione conjugates and as a recovery system for cysteine moieties.