The mechanisms by which various chemicals cause nephrotoxicity are poorly understood. It has recently been demonstrated that glutathione (GSH) conjugation with xenobiotics can result in the formation of reactive intermediates and the kidney appears particularly susceptible to the toxic effects of these conjugates. GSH dependent metabolic activation within the kidney probably has greater toxicological significance than that mediated by the cytochrome P-450 dependent mono-oxygenases. This is because of the relatively low activity of renal P-450, the high activity of GSH related enzymes and the rapid turnover of GSH within the kidney. However, little is known of the metabolic and pathological mechanisms by which GSH/cysteine conjugates elicit nephrotoxicity nor of those factors which regulate the generation of potentially reactive thiols from GSH/cysteine conjugates. 2-Bromohydroquinone (2-BHQ) gives rise to a mixture of isomeric mono- and disubstituted GSH conjugates, the latter being a potent nephrotoxin. This is the first example of GSH conjugation to an aromatic substrate leading to toxicity. We have also demonstrated that 2-BHQ can be cooxidized in vitro by prostaglandin synthase to (a) covalently bound material and (b) GSH adduct formation in the presence of GSH. This cooxidation process produced a concentration dependent alteration of prostaglandin synthesis. Furthermore, we have demonstrated that selective transport of 2-BHQ-GSH conjugates into kidney may be mediated by Gamma-glutamyl transpeptidase (GGT) and that the more extensive renal uptake of the disubstituted GSH conjugate may be partially responsible for its enhanced nephrotoxicity. High levels of GGT are evident in tumors of a variety of tissues, including hepatocellular carcinoma, malignant squamous carcinoma of the skin, squamous cell carcinoma of the buccal pouch epithelium, adenocarcinomas of the lungs and in some mammary tissues. It is therefore conceivable that the studies detailed in this report on the modulation and mechanism(s) of GSH conjugate mediated toxicity might enable a more rational application of such compounds as potential anticancer agents.
