Aminoglycoside Antibiotics Inhibit the Phosphatidylinositol Cascade in Renal Proximal Tubular Cells: Possible Role in Toxicity
A growing body of evidence supports the conclusion that aminoglycoside antibiotics (AG) interact with phosphoinositides. For example AG have been shown to bind to phosphoinositides in model membranes (1–5) by a mechanism best explained by an electrostatic interaction (3,5). The strong avidity of these drugs for phosphatidylinositol-4,5-bisphosphate (PIP2) (1,5,6) has led to the hypothesis that PIP2 serves as the biological receptor for these agents (6–8). AG have been shown to induce a phosphatidylinositol (PI)-enriched phospholipidosis in rat renal cortex (9,10) and in cells grown in culture (11,12), a phenomenon which may be related to the observation that AG have the capacity to inhibit a PI-specific phospholipase C (13–15). Moreover, neomycin has been shown to block the hydrolysis of PIP2 and the generation of inositol trisphosphate (IP3) in response to agonist stimulation in vitro (16,17) and to depress the synthesis and turnover of (32P]PIP2 in vitro and in vivo (1,18,19) . These observations indicate that AG have the potential to perturb the PI cascade, which serves as the transmembrane signal transducing mechanism for a number of agonists (20). Inhibition of the PI cascade by AG might cause profound derangements in the regulation of a number of intracellular processes and thereby contribute to the toxicity of these agents.
KeywordsToxicity Lipase Hydrocortisone Angiotensin Thrombin
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