Glutathione conjugation and conversion to mercapturic acids can occur as an intrahepatic process

Abstract

By catalyzing the reaction of electrophilic compounds with the sulfhydryl group of glutathione, the glutathione S‐transferases play physiologically important roles in the detoxication of potential alkylating agents. The glutathione S‐conjugates thus formed are transported out of cells for further metabolism by γ‐glutamyltransferase and dipeptidases, ectoproteins that catalyze the sequential removal of the glutamyl and glycyl moieties, respectively. These ectoproteins are not found in all cells, but are localized predominantly to the apical surface of epithelial tissues. The resulting cysteine S‐conjugates can be reabsorbed by specific cell types, and acetylated on the amino group of the cysteinyl residue by intracellular N‐acetyl‐transferases, to form the corresponding mercapturic acids (N‐acetylcysteine S‐conjugates). Mercapturic acids are then released into the circulation and delivered to the kidney for excretion in urine, or they may undergo further metabolism. Mercapturic acid biosynthesis is generally considered to be an interorgan process, with the liver serving as the major site of glutathione conjugation, and the kidney as the primary site for conversion of glutathione conjugates to cysteine conjugates. Cysteine conjugates formed in the kidney appear to be transported back to the liver for acetylation. This interorgan model of mercapturic acid synthesis is based largely on the interorgan distribution of the enzymes involved in their formation, and in particular of the enzyme γ‐glutamyltransferase. Rats have relatively low hepatic and high renal activities of γ‐glutamyltransferase, the only protein known to initiate the breakdown of glutathione S‐conjugates. The low γ‐glutamyltransferase activity in rat liver limits the hepatic degradation of glutathione S‐conjugates, particularly after large doses of xenobiotic. In contrast, hepatic γ‐glutamyltransferase is significantly higher in species such as rabbit, guinea pig, and dog, and as a consequence, nearly all of the glutathione and glutathione S‐conjugates released by liver cells of these species is degraded within the liver. Recent studies demonstrate that glutathione S‐conjugates synthesized within hepatocytes are secreted preferentially across the canalicular membrane into bile, and are broken down within biliary spaces to form cysteine S‐conjugates. The latter are then reabsorbed by the liver, N‐acetylated to form mercapturic acids, and reexcreted into bile, completing an intra‐hepatic pathway for mercapturic acid biosynthesis. The contribution of this intrahepatic pathway to overall mercapturate formation is dependent on dose of the electrophile, route of exposure, and the physicochemical properties of the glutathione S‐conjugate formed, as well as the tissue distribution and activity of γ‐glutamyltransferase. Intrahepatic mercapturic acid formation via the γ‐glutamyl cycle may provide an efficient mechanism of detoxification for a variety of electrophiles.