Kanamycin inhibits cochlear-renal ODC in neonatal rats.
Ornithine decarboxylase (ODC), a key enzyme in polyamine biosynthesis, is important in development and regeneration. We hypothesize that aminoglycoside inhibition of ODC mediates developmental hypersensitivity to aminoglycoside ototoxicity. Kanamycin effects on ODC activity (decarboxylation of ornithine) in vitro were determined in the postmitochondrial fraction of cochlear and renal homogenates from 11-day-old rats. Kanamycin inhibited cochlear and renal ODC by an uncompetitive mechanism. For the cochlear enzyme, the inhibitor constant (Ki) for kanamycin was 99 +/- 25 mumol/L; for the renal enzyme, the Ki = 1.5 +/- 0.1 mmol/L. In vivo effects of kanamycin on cochlear, renal, brain ODC activity were determined in rats treated with kanamycin (400 mg/kg/day, intramuscularly) or saline during postnatal days 11 through 20, the hypersensitive period for ototoxicity. Rats were killed on postnatal days 12, 14, 16, and 20 and ODC was assayed. Kanamycin significantly inhibited ODC in the lateral wall-organ of Corti and kidney (ANOVA alpha = 0.05), but had no effect on cochlear nerve and no consistent inhibitory effect in the brain. These results suggest that ODC is a potential target of kanamycin in susceptible tissues and may be a contributing factor in developmental sensitivity to the drug by inhibiting repair and developmental processes mediated by ODC.
Lyos
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Department of Otorhinolaryngology and Communicative Sciences, Baylor College of Medicine, Houston, TX 77030.
Winter
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Henley
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CM
D000818:Animals; D000831:Animals, Newborn; D003051:Cochlea / Q000201:enzymology*; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D007612:Kanamycin / Q000494:pharmacology*; D007668:Kidney / Q000201:enzymology*; D009955:Ornithine Decarboxylase / Q000378:metabolism; D065108:Ornithine Decarboxylase Inhibitors; D051381:Rats; D011919:Rats, Inbred Strains
D065108:Ornithine Decarboxylase Inhibitors; D007612:Kanamycin; D009955:Ornithine Decarboxylase