SULFHYDRYL COMPOUNDS AND ANTIOXIDANTS INHIBIT CYTOTOXICITY TO OUTER HAIR-CELLS OF A GENTAMICIN METABOLITE IN-VITRO

Aminoglycoside antibiotics such as gentamicin have long been known to destroy cochlear and vestibular hair cells in vivo. In the cochlea out er hair cells are preferentially affected. In contrast, gentamicin wil l not damage outer hair cells in vitro unless it has been enzymaticall y converted to a cytotoxic metabolite. Several potential inhibitors of this enzymatic reaction were tested in an in vitro assay against oute r hair cells isolated from the guinea pig cochlea. Viability of hair c ells (viable cells as per cent of total number of cells observed) aver aged about 70% under control conditions. Addition of metabolized genta micin significantly reduced viability to less than 50% in one hour. Su lfhydryl compounds (glutathione, dithioerythritol) and antioxidants (v itamin C, phenylene diamine, trolox) prevented the cytotoxic actions o f the gentamicin metabolite. Inhibitors of amine oxidases and compound s reportedly protective against renal and acute lethal toxicity of ami noglycosides (poly-L-aspartate and pyridoxal phosphate, respectively) were ineffective as protectants. The results reinforce the hypothesis that gentamicin is enzymatically converted to a cytotoxin and imply th e participation of sulfhydryl-sensitive groups or free radicals in thi s reaction. Alternatively or additionally, sulfhydryl compounds or ant ioxidants may participate in detoxification reactions.