Aminoglycoside - Induced Modifications of Membrane Phosphoinositide Metabolism

Several lines of evidence indicate that the first steps in the pathogenesis of anlinoglycoside nephrotoxicity involve the accumulation of the antibiotic in the proximal tubule where it interacts with the plasma membrane of epithelial cells' 2) . In brush border membranes, acidic phospholipids and most particularly phosphoinositides, phosphatidylinositol (PI), phosphatidylinositol-4phosphate (PI-P) and phosphatidylinositol-4,5bisphosphate (PI-P,), have been recently shown to be an integral component of the aminoglycoside binding site'). In addition, the aminoglycosides have been shown to modify the metabolism of phosphoinositides in the kidney cortex`". In a biomembrane model such as the ghost membrane isolated from rat erythrocyte, results from this laboratory') indicated that aminoglycosides impaired the phosphoinositide interconversion since these drugs induced a decrease and an increase in the 32P-labelling of PI-P, and PI-P, respectively likely by inhibiting the PI-P kinase; the existence of a possible relationship between the toxicity of aminoglycosides and their capacity to impair the phosphoinositide metabolism was also suggested. This finding stimulated us to further study the interaction between aminoglycosides and phosphoinositide metabolism within the membrane. For this purpose, using isolated red cell ghosts, experiments were designed to compare the effects of five aminoglycosides in clinical use, namely amikacin, dibekacin, gentamicin, netilmicin and tobramycin on the 12P_ labelling of the polyphosphoinositides PI-P and PI-P2.