Biochemistry of neomycin ototoxicity

Abstract

The biochemical mechanism of neomycin ototoxicity was investigated in vivo and in vitro. In vivo, the incorporation of [32P]-orthophosphate into the phosphoinositide lipids of inner ear tissues was measured in normal and in neomycin-treated guinea pigs. These lipids are believed to be involved in the control of membrane permeability. There was a decrease of labeling of phosphatidylinositol diphosphate in the organ of Corti and stria vascularis following 3 wk of daily injections of neomycin (100 mg/kg body weight). In homogenates of organ of Corti and stria vascularis the hydrolysis of phosphatidylinositol diphosphate was blocked and the binding of radioactive Ca was inhibited in the presence of neomycin. Further in vitro studies with brain subfractions demonstrated that the effect on phosphoinositide metabolism is exerted by neomycin and related antibiotics that are toxic to the cochlea and the kidney. The hypothesis is discussed that the ototoxic action of neomycin involves an inhibition of polyphosphoinositide turnover by direct binding of the antibiotic to these lipids.