Molecular mechanisms of drug-induced hearing loss

Abstract

Although the ototoxic actions of a variety of drugs have long been documented, the biochemical mechanisms underlying such toxicity largely remain to be established. For example, recent advances have provided us with information about the actions of salicylates (aspirin) and diuretics (furosemide) but we are not yet able to specify the mechanisms by which these drugs damage the cochlea. On the other hand, the considerable amount of biochemical and pharmacological data on the effects of aminoglycosides (streptomycin, neomycin, gentamicin and related compounds) has enabled us to formulate a rational hypothesis of their mechanism of action.We have previously presented evidence for an involvement of polyphosphoinositides in the ototoxic actions of aminoglycosides. Recent electrophysiological and pharmacokinetic studies have shown in addition that aminoglycosides occupy at least two distinct compartments in the course of their actions. Further studies of drug uptake in vitro and of drug toxicity in cochlear perfusions suggested the involvement of an active (energy-requiring) aminoglycoside transport system. These and other data are compatible with the following multi-step model of aminoglycoside toxicity: 1. (1) The initial step in the reaction sequence is an electrostatic interaction of aminoglycosides with the plasma membrane. The resulting displacement of calcium accounts for acute effects but the action is reversible and antagonized by divalent cations.2. (2) An energy-dependent uptake process is required for the expression of toxicity. It can be prevented by select metabolic blockers.3. (3) A crucial step in subsequent intracellular drug actions is the binding of aminoglycosides to phosphatidylinositol bisphosphate inhibiting its hydrolysis and preventing its physiological function. Hydrolysis of phosphatidylinositol bisphosphate is believed to be the key reaction in a fundamental transducing mechanism initiated by a number of physiological stimuli and resulting in a signal cascade to mobilize intracellular calcium stores.4. (4) Other reactions possibly regulated by polyphosphoinositides (such as the synthesis of prostaglandins and the polymerization of actin) are potentially affected by aminoglycoside action.5. (5) Aminoglycosides may interfere with further intracellular reactions which are controlled by calcium or polyamines.