Variable efficacy of radical scavengers and iron chelators to attenuate gentamicin ototoxicity in guinea pig in vivo.
Recent studies from our laboratory have suggested that the ototoxic side effects of gentamicin are caused by a metabolized or 'activated' from the drug. Furthermore, we have postulated that the activation proceeds via the formation of an iron-gentamicin complex and that this complex produces free radicals. The present study assessed the protection effects of free radical scavengers and iron chelators on gentamicin-induced ototoxicity in guinea pigs in vivo. Gentamicin (120 mg/kg per day for 19 days) caused progressive threshold shifts reaching 50-65 dB at 18 kHz. Co-therapy with different radical scavengers yielded results ranging from no protection (with allopurinol, dimethyl sulfoxide, benzoate, lazaroid U74389G) to a moderate attenuation of hearing loss (with mannitol, 4-methylthiobenzoate, WR-2721). This finding agrees well with previous reports of inconsistent effects of scavengers on aminoglycoside-induced ototoxicity although it should be cautioned that only a single dose and route of application was tested. Two iron chelators, deferoxamine and 2,3-dihydroxybenzoate, significantly reduced the gentamicin-induced threshold shifts to about 10 dB or less. Iron chelators markedly decreased total serum iron levels while gentamicin treatment alone had no influence. There were no differences in serum gentamicin levels among all treated groups. This study confirms that iron plays a critical role in gentamicin ototoxicity and suggests that iron chelators, which are well-established drugs in clinical therapy, may be promising therapeutic agents to reduce aminoglycoside ototoxicity.
Song
B B
BB
Kresge Hearing Research Institute, University of Michigan, Ann Arbor 48109-0506, USA.
Schacht
J
J
D000284:Administration, Oral; D000493:Allopurinol / Q000008:administration & dosage / Q000494:pharmacology; D004999:Amifostine / Q000008:administration & dosage / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity*; D000963:Antimetabolites / Q000008:administration & dosage / Q000494:pharmacology; D000975:Antioxidants / Q000008:administration & dosage / Q000494:pharmacology*; D001309:Auditory Threshold / Q000187:drug effects* / Q000502:physiology; D001565:Benzoates / Q000008:administration & dosage / Q000494:pharmacology; D003676:Deferoxamine / Q000008:administration & dosage / Q000494:pharmacology; D004121:Dimethyl Sulfoxide / Q000008:administration & dosage / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000008:administration & dosage / Q000494:pharmacology*; D005839:Gentamicins / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity*; D006168:Guinea Pigs; D062385:Hydroxybenzoates / Q000008:administration & dosage / Q000494:pharmacology; D007274:Injections, Intraperitoneal; D007279:Injections, Subcutaneous; D007501:Iron / Q000097:blood; D007502:Iron Chelating Agents / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D008353:Mannitol / Q000008:administration & dosage / Q000494:pharmacology; D011281:Pregnatrienes / Q000008:administration & dosage / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D000963:Antimetabolites; D000975:Antioxidants; D001565:Benzoates; D016166:Free Radical Scavengers; D005839:Gentamicins; D062385:Hydroxybenzoates; D007502:Iron Chelating Agents; D011281:Pregnatrienes; C074965:U 74389F; D008353:Mannitol; D000493:Allopurinol; C009135:2,3-dihydroxybenzoic acid; D007501:Iron; D003676:Deferoxamine; D004999:Amifostine; D004121:Dimethyl Sulfoxide