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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM040858-04
Application #
3298753
Study Section
Toxicology Subcommittee 2 (TOX)
Project Start
1988-03-01
Project End
1993-02-28
Budget Start
1991-03-01
Budget End
1992-02-29
Support Year
4
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Dartmouth College
Department
Type
Schools of Medicine
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755
Hoffman, D W; Wiebkin, P; Rybak, L P (1995) Inhibition of glutathione-related enzymes and cytotoxicity of ethacrynic acid and cyclosporine. Biochem Pharmacol 49:411-5
Rybak, L P (1993) Ototoxicity of loop diuretics. Otolaryngol Clin North Am 26:829-44
Henley, C M; Rybak, L P (1993) Developmental ototoxicity. Otolaryngol Clin North Am 26:857-71
Rybak, L P; Weberg, A; Whitworth, C et al. (1992) Effects of organic acids on stria vascularis ultrastructure and function in the chinchilla. Eur Arch Otorhinolaryngol 249:168-71
Rybak, L P (1992) Hearing: the effects of chemicals. Otolaryngol Head Neck Surg 106:677-86
Edkins, R D; Rybak, L P; Hoffman, D W (1992) Comparison of cyclosporine and FK506 effects on glutathione levels in rat cochlea, brain, liver and kidney. Biochem Pharmacol 43:911-3
Rybak, L P; Whitworth, C; Weberg, A et al. (1992) Effects of organic acids on the edema of the stria vascularis induced by furosemide. Hear Res 59:75-84
Rybak, L P; Whitworth, C; Scott, V et al. (1991) Ototoxicity of furosemide during development. Laryngoscope 101:1167-74
Rybak, L P; Whitworth, C; Scott, V (1991) Comparative acute ototoxicity of loop diuretic compounds. Eur Arch Otorhinolaryngol 248:353-7
Shafer, P R; Wilcox, D E; Kruszyna, H et al. (1989) Decomposition and specific exchange of the trans-cyanide ligand on nitroprusside is facilitated by hemoglobin. Toxicol Appl Pharmacol 99:1-10

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