Hepato-renal cooperation in biotransformation, membrane transport, and elimination of cysteine S-conjugates of xenobiotics.

Biosynthesis of N-acetylcysteine S-conjugates of xenobiotics, mercapturic acids, occurs via inter-organ metabolism of the corresponding glutathione derivatives (Inoue, M., Okajima, K., & Morino, Y. (1982) Hepatology 2, 311-316). To elucidate the mechanism of mercapturate biosynthesis and its urinary elimination, hepato-renal cooperation in the enzymic processing and membrane transport of cysteine derivatives was studied in isolated hepatocytes, perfused liver and renal cortical tubules. Isolated hepatocytes rapidly accumulated S-benzylcysteine by a carrier-mediated mechanism and metabolized it to the N-acetylcysteine conjugate. Experiments in perfused rat liver revealed that, upon infusion of S-benzylcysteine, N-acetyl-S-benzylcysteine appeared in the effluent perfusate and hepatic excretion of this mercapturate was inhibited by simultaneous infusion of probenecid, an inhibitor of the organic anion transport system. Isolated renal cortical tubules actively accumulated N-acetyl-S-benzylcysteine by a dinitrophenol-sensitive, carrier-mediated mechanism which was competitively inhibited by probenecid and hippuric acid. These and other results indicate that a cysteine S-conjugate in plasma is rapidly taken up by the liver and converted to the N-acetyl derivative which is translocated into plasma via a probenecid-sensitive transport system in hepatic sinusoidal membranes. The mercapturic acid excreted in plasma is transferred to the kidney and finally excreted into urine by a probenecid sensitive transtubular transport system for organic anions in renal cortical tubules. Hepato-renal cooperation in metabolic conjugation and membrane transport of these intermediates appears to constitute an important process in mercapturate biosynthesis and urinary excretion of the final metabolites.