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

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Abstract
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 was 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 γ–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.