Aminoglycoside-induced hearing loss: a molecular hypothesis.

A multi-step hypothesis of aminoglycoside ototoxicity is presented which is consistent with the data elaborated by our laboratory and others. The first step in the reaction sequence is an electrostatic interaction of the aminoglycoside with negatively charged components of the outer plasma membrane. The resulting displacement of calcium accounts for the acute effects of the drug action and is reversible and antagonized by cations. The drug is then transported into the cell by an energy-dependent process. The next and most crucial step is the binding of the drug to phosphatidylinositol bisphosphate, a physiologically important phospholipid. The formation of the drug-lipid complex prevents the hydrolysis of phosphatidylinositol bisphosphate and disturbs membrane integrity and structure resulting in nonspecific permeability changes of the membrane. Once inside the cell, the aminoglycosides may interfere with further intracellular reactions. This interference may be based on competition with divalent cations or polyamines or on binding to negatively charged compounds.