Species differences in renal γ-glutamyl transpeptidase activity do not correlate with susceptibility to 2-bromo-(diglutathion-S-yl)-hydroquinone nephrotoxicity

Administration of 2-brono-(diglutathion-S-yl)hydroquinone (2-Br-[diGSyl]HQ)¹ (10-30 μmol/kg; i.v.) to rats causes severe renal proximal tubular necrosis. γ-Glutamyl transpeptidase (γ-GT) catalyses the first step in the metabolism of glutathione (GSH) and its S-conjugates and the toxicity of 2-Br-(diGSyl) HQ can be emeliorated by inhibition of renal γ-GT. Species differences in the specific activity of renal γ-GT have been reported and we now describe the relationship between renal γ-GT and species differences in susceptibility to 2-Br-(diGSyl)HQ nephrotoxicity. Although rats exhibited the highest specific activity of renal γ-GT, and were the most sensitive species toward 2-Br-(diGSyl)HQ-mediated nephrotoxicity, renal γ-GT activity did not correlate with susceptibility in the other species examined. Indeed, the guinea pig, which expressed the lowest activity of renal γ-GT between the species (8% of the rat) was the only other rodent found to be responsive toward 2-Br-(dGSyl)HQ at the highest dose tested (200 μmol/kg; intracardiac). Thus, factors other than γ-GT activity probably play an important role in modulating species susceptibility to 2-Br-(diGSyl)HQ nephrotoxicity. Although the reason(s) for the interspecies variation in response to 2-Br-(diGSyl)HQ are unclear at present, it seems possible that differences in both renal biochemistry, such as differences in the relative activities of cysteine conjugate N-acetyl transferase and deacetylase, and renal physiology, contribute to the observed results.