title: Activation of aminoglycoside antibiotics to cytotoxins.
abstract: We have previously postulated an enzymatic transformation of gentamicin (to a metabolite or an 'activated' molecule) as part of its ototoxic action. Here we test with eight aminoglycosides whether the proposed mechanism applies to these antibiotics as a group. Drugs were activated by incubation with a subcellular fraction from liver, and cytotoxicity was tested in a bioassay using isolated outer hair cells from guinea pig. None of the aminoglycosides compromised the viability of the cells when assayed directly, i.e. without a preceding activation. In contrast, all clinically ototoxic aminoglycosides tested were significantly cytotoxic following the incubation. Neamine, considered to be non-ototoxic, did not yield a cytotoxin. A subcellular fraction from cochlear lateral wall tissues also converted gentamicin to a cytotoxin. The results support the hypothesis that activation of aminoglycosides precedes their toxic actions and demonstrate that the capability for activation is not confined to liver.
authors.affiliation: Kresge Hearing Research Institute, University of Michigan, Ann Arbor, USA.
authors.forename: S A
authors.initials: SA
authors.lastname: Crann
authors.forename: J
authors.initials: J
authors.lastname: Schacht
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000633:toxicity*; D001711:Biotransformation; D002470:Cell Survival / Q000187:drug effects; D003051:Cochlea / Q000187:drug effects / Q000502:physiology; D005839:Gentamicins / Q000493:pharmacokinetics / Q000633:toxicity; D006168:Guinea Pigs; D006199:Hair Cells, Auditory, Inner / Q000187:drug effects* / Q000502:physiology; D018072:Hair Cells, Auditory, Outer / Q000187:drug effects* / Q000502:physiology; D008099:Liver / Q000502:physiology; D009428:Netilmicin / Q000493:pharmacokinetics / Q000633:toxicity; D013347:Subcellular Fractions / Q000502:physiology
chemical_list: D000900:Anti-Bacterial Agents; D005839:Gentamicins; D009428:Netilmicin