2-Bromodiglutathion-S-ylhydroquinone is a more potent nephrotoxicant than 2-bromomonoglutathion-S-ylhydroquinones. In the present study we examined the activity of enzymes involved in mercapturic acid biosynthesis toward both the glutathione conjugates and their cysteine and N-acetylcysteine metabolites and compared the results to the relative nephrotoxicity of these conjugates. Although differences were observed in the kinetics of the γ-glutamyl transpeptidase (γ-GT)-mediated hydrolysis and transpeptidation of the glutathione conjugates, the concentration of this enzyme within the kidney probably precludes it from contributing to their differential toxicity. In contrast, the rate at which the cysteine and corresponding mercapturate conjugates underwent N-deacetylation/N-acetylation Cycling correlated with previously reported differences in toxicity. The relative rates of these two reactions are important because electrochemical data suggest that 2-bromodicystein-S-ylhydroquinone is more readily oxidized to the reactive quinone than its corresponding mercapturic acid. In addition, 2-bromodi(N-acetylcystein-S-yl)hydroquinone, which is the most potent of the mercapturic acid conjugates, exhibited the highest N-deacetylation/N-acetylation ratio. In contrast, 2-bromo-3-(N-acetylcystein-S-yl)hydroquinone, which is essentially not toxic in vivo, was not a substrate for the renal cysteine conjugate N-deacetylase. The data suggest that the rate-determining step for the in vivo toxicity of these conjugates is probably the N-acetylation reaction and the availability of the corresponding acetyl-CoA cofactor.
ASJC Scopus subject areas