Metabolism as a determinant of species susceptibility to 2,3,5(triglutathion-S-yl)hydroquinone-mediated nephrotoxicity: The role of N- acetylation and N-deacetylation

2,3,5-(Triglutathion-S-yl)hydroquinone [2,3,5-(triGSyl)HQ] is a potent nephrotoxicant when administered to male rats. We now report that significant species differences exist in susceptibility to 2,3,5-(triGSyl)HQ-mediated nephrotoxicity. Metabolism of glutathione conjugates involves cleavage of the glutamate and glycine moieties by γ-glutamyltranspeptidase (γ-GT) and dipeptidases, respectively, and the nephrotoxicity of 2,3,5-(triGSyl)HQ can be prevented by the inhibition of renal γ-GT. The resulting cysteine conjugate exhibits a balance between N-acetylation, and N-deacetylation of the mercapturate. We have now determined whether differences in the relative activities of the enzymes involved in mercapturic acid biosynthesis in various species contribute to species susceptibility to 2,3,5-(triGSyl)HQ. Renal γ-GT activity toward 2,3,5-(triGSyl)HQ was highest in the rat (Fischer 344 and Sprague-Dawley) and consistent with the sensitivity of this species to 2,3,5-(triGSyl)HQ (20 μmol/kg iv)-mediated nephrotoxicity. The γ-GT- mediated hydrolysis of 2,3,5-(triGSyl)HQ was similar in B6C3F1 and BALB/c mice and guinea pigs. In these species, the γ-GT activity ranged between 30- 45% of the activity measured in rats. Although, the activity of γ-GT was similar in mice and guinea pigs, only guinea pigs were susceptible to 2,3,5- (triGSyl)HQ(200 μmol/kg iv)-induced renal necrosis. The γ-GT-mediated hydrolysis of 2,3,5-(triGSyl)HQ was lowest in the hamster, and this species was not susceptible to the renal toxicity of this conjugate. Thus, factors in addition to γ-GT activity probably contribute to species susceptibility to 2,3,5-(triGSyl)HQ nephrotoxicity. The kinetics of the AT-125-mediated inhibition of γ-GT differed between species, indicative of potential differences in the regulation of γ-GT. Consistent with this view, the ratio between the hydrolysis and transpeptidation of 2,3,5-(triGSyl)HQ varied 10- fold between the species examined, and was highest in the guinea pig (0.48) and lowest in the hamster (0.05). Guinea pigs also exhibited the highest renal cytosolic N-deacetylase activity and the lowest N-acetylase activity. The ratios of N-deacetylation to N-acetylation in guinea pigs, BALB/c mice, BSC3F1 mice, hamsters, Fischer 344 rats, and Sprague-Dawley rats were 4.57, 0.16, 0.14, 0.04, 0.03, and 0.02, respectively. Because quinol-cysteine conjugates seem to undergo oxidation more readily than the corresponding mercapturates, the balance of N-deacetylase and N-acetylase in the guinea pig may contribute to the susceptibility of this species to 2,3,5(triGSyl)HQ nephrotoxicity.