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 outer hair cells are preferentially affected. In contrast, gentamicin will not damage outer hair cells in vitro unless it has been enzymatically converted to a cytotoxic metabolite. Several potential inhibitors of this enzymatic reaction were tested in an in vitro assay against outer hair cells isolated from the guinea pig cochlea. Viability of hair cells (viable cells as per cent of total number of cells observed) averaged about 70% under control conditions. Addition of metabolized gentamicin significantly reduced viability to less than 50% in one hour. Sulfhydryl compounds (glutathione, dithioerythritol) and antioxidants (vitamin C, phenylene diamine, trolox) prevented the cytotoxic actions of the gentamicin metabolite. Inhibitors of amine oxidases and compounds reportedly protective against renal and acute lethal toxicity of aminoglycosides (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 the participation of sulfhydryl-sensitive groups or free radicals in this reaction. Alternatively or additionally, sulfhydryl compounds or antioxidants may participate in detoxification reactions.
Garetz
S L
SL
Kresge Hearing Research Institute, Department of Otolaryngology, University of Michigan, Ann Arbor 48109-0506.
Rhee
D J
DJ
Schacht
J
J
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D016166:Free Radical Scavengers / Q000494:pharmacology; D005839:Gentamicins / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity*; D005978:Glutathione / Q000378:metabolism; D006168:Guinea Pigs; D018072:Hair Cells, Auditory, Outer / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D066298:In Vitro Techniques; D008658:Inactivation, Metabolic; D013438:Sulfhydryl Compounds / Q000494:pharmacology*
D000975:Antioxidants; D016166:Free Radical Scavengers; D005839:Gentamicins; D013438:Sulfhydryl Compounds; D005978:Glutathione