Differential uptake of isomeric 2-bromohydroquinone-glutathione conjugates into kidney slices

2-Bromo-(diglutathion-Syl)hydroquinone (2-Br-[diGSyl]HQ) is a more potent nephrotoxicant than any of three mono-substituted isomers. The reason for this differential toxicity is unknown. We now report that the rate of uptake of 2-Br-(diGSyl)HQ, 2-Br-3-(GSyl)HQ, 2-Br-5-(GSyl)-HQ and 2-Br-6(GSyl)HQ by kidney slices was 2.4, 1.2, 1.0 and 0.3 nmoles/mg/10 min, respectively. AT-125 (0.5 mM) inhibited γ-glutamyl transpeptidase (GGT) in intact and homogenized kidney slices by 47% and 92%, respectively and decreased the accumulation of the isomeric [³⁵S]-conjugates by 49%, 21%, 25% and 30%, respectively. The data suggest that the accumulation of 2-Br-(GSyl)HQ conjugates into isolated kidney slices may in part be mediated by GGT and that the more extensive renal uptake of the di-substituted conjugate may be partially responsible for its enhanced nephrotoxicity. In addition, 2-Br-(diGSyl)HQ gave rise to the most covalently bound material of the different isomers studied suggesting that both physiological and biochemical factors contribute to the potent and selective nephrotoxicity of this compound.