Glutathione (GSH) is a tripeptide which plays a major role in the detoxification of electrophilic drugs and metabolites and active oxygen formed during drug metabolism, via reactions catalysed by GSH S-transferases, transpeptidases, transhydrogenases, and peroxidases. Preliminary evidence from this laboratory has demonstrated that GSH depletion results in the profound enhancement of the toxicity of the aminoglycoside antibiotics, cisplatin, and loop diuretics, which are limited in their clinical usefulness by their oto- and nephrotoxicity. This supports the contention that synergistic oto- and nephrotoxic agents share common metabolic pathways which involve GSH in one of its many roles as a protectant agent against xenobiotic toxicity. Perturbation of the GSH system potentiates the toxicities of the compounds which share these protective pathways. Manipulation of endogenous GSH levels may ameliorate the toxicity of these agents, which although chemically dissimilar, interact strongly to potentiate each others' toxicity by a mechanism which may be common to both the kidney and the cochlea. Loop diuretics are known to be potent inhibitors of GSH S- transferases, by binding irreversibly to these enzymes. Aminoglycosides and cisplatin can deplete GSH levels, particularly in the kidney, which has a limited capacity for GSH synthesis. Inhibition or inactivation of this important detoxification mechanism may be the central factor in the potentiation of the toxicities of these and other compounds with oto- and nephrotoxic potential. Although this hypothesis has been central to toxicology research in other systems, this involvement has never been fully evaluated in the auditory system. Ototoxic mechanisms will be studied with auditory brainstem response measurements, and light and electron microscopy. GSH levels will be directly measured, as will the activities of enzymes which synthesize or utilize GSH, in cochlea, kidney, liver and brain. Drug metabolites and conjugates will then be identified at these sites, to better define the mechanism(s) of toxicity, and the location of the generation of reactive, toxic metabolites.

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Toxicology Subcommittee 2 (TOX)
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Dartmouth College
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