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.
KeywordsMembrane Fraction Ornithine Decarboxylase Proximal Tubular Cell Aminoglycoside Antibiotic Inositol Trisphosphate
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- 1.J. Schacht, N.D. Weiner and S. Lodhi, Interaction of aminocyclitol antibiotics with polyphosphoinositides in mammalian tissues and artificial membranes, In: Cyclitols and Phosphoinositides, W.W. Wells and F. Eisenberg, ed., Academic Press, New York (1978) .Google Scholar
- 9.S. Peldman, M. Wang and G.J. Kaloyanides, Aminoglycosides induce a phospholipidosis in the renal cortex of the rat: An early manifestation of nephrotoxicity, J. Pharmacol. Exp. Ther. 220:514 (1982).Google Scholar
- 12.C. Josepovitz, L. Ramsammy, B. Lane and G.J. Kaloyanides, Gentamicin inhibits degradation and stimulates synthesis of phosphatidylinositol in primary culture of rabbit proximal tubular cells. Kidney Int. 31:369 (1987) .Google Scholar
- 19.P. Marche, B. Olier, A. Girard, J.-P. Fillastre and J.-P. Morin, Aminoglycoside-induced alterations of phosphoinositide metabolism 31:59 (1987) .Google Scholar
- 21.M. Taub, Growth of primary and established kidney cell cultures in serum-free media, In: Methods for Serum-Free Culture of Epithelial and Fibroblastic Cells, Alan R. Liss, Inc., New York (1984).Google Scholar
- 23.R. Minakuchi, Y. Takai, B. Yu and Y. Nishizuka, Widespread occurrence of calcium-activated, phospholipid dependent protein kinase in mammalian tissues, J. Biochem. 89:165 (1981).Google Scholar
- 27.E. Pastoriza-Munoz, R.E. Colindres, W.E. Lassiter and C. Lechene, Effect of parathyroid hormone on phosphate reabsorption in the rat distal convolntion., Am. J. Physiol. 235:F321 (1978).Google Scholar
- 28.L. Soberon, R.L. Bowman, E. Pastoriza-Munoz and G.J. Kaloyanides, Comparative nephrotoxicities of gentamicin, tobramysinpp gentamicin, netilmicin and tobramysin in the rat, J. Pharmacol. Exp. Thr. 210:324 (1979).Google Scholar