Metabolic Coordination of Liver and Kidney in Mercapturic Acid Biosynthesis In Vivo

When S-carbamido(14C)methyl glutathione, a model compound of glutathione S-conjugate, was administered i.v. to mice, radioactivity accumulated in the kidney within 1 to 2 min and then decreased gradually during the following 10 to 15 min with concomitant increase in hepatic radioactivity. Most hepatic radioactivity was accounted for by S-carbamidomethyl cysteine and its N-acetyl derivative, a mercapturic acid. The i.v. administration of S-carbamido(14C)methyl cysteine resulted in rapid and predominant accumulation of radioactivity in the liver. In both cases, the radioactive urinary metabolites were fully accounted for by N-acetyl-S-carbamidomethyl cysteine. N-Acetyl-S-carbamido(14C)methyl cysteine administered to mice were accumulated preferentially in the kidney and was excreted into urine very rapidly. These results suggest the following series of events: glutathione S-conjugate accumulated mainly in the kidney and is hydrolyzed into its component amino acids, presumably by gamma-glutamyl transferase and some peptidase(s) on the renal brush border membranes. The cysteine S-conjugate which is formed in the tubular lumen is reabsorbed and transferred to the liver, acetylated to form N-acetylcysteine S-conjugate, and excreted in the urine. Thus, renal hydrolysis of glutathione S-conjugates seems to be coordinated with acetylation in liver and with mercapturic acid biosynthesis in vivo.