Aminoglycosides and cisplatin are known to have serious adverse side effects such as nephrotoxicity and ototoxicity which are often permanent. Although chemically distinct, these drugs injure the same cells within the kidney and inner ear and require prior hepatic metabolism to demonstrate acute ototoxicity. g-glutamyl transpeptidase (GGT) is an enzyme located on the apical surface of renal proximal tubule cells that is thought to be responsible for their selective susceptibility to cisplatin nephrotoxicity. This project is aimed at determining if GGT activity is also involved in aminoglycoside ototoxicity. The proposed experiments will test if OGT is expressed within the inner ear sensory epithelia, if GGT activity is involved in allowing aminoglycosides to enter inner ear hair cells and if inhibiting GGT activity acts to protect against aminoglycoside ototoxicity using anatomical, physiological and pharmacological methods. Additionally, the role of exogenous glutathione and its protective effect against gentamicin ototoxicity is addressed mechanistically as a possible competitive inhibitor of GGT activity. In determining the mechanisms through which aminoglycosides induce sensorineuronal hearing loss, we further our abilities to prevent such injury in people who receive aminoglycoside treatment.
