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- Title
Aminoglycoside-induced alterations of phosphoinositide metabolism.
- Authors
Marche, Pierre; Olier, Béatrice; Girard, Arlette; Fillastre, Jean-Paul; Morin, Jean-Paul
- Abstract
There exists a strong interaction between aminoglycosides and phosphoinositides, and these membrane lipids are even considered as the drug receptors. To shed some light on the role of such an interaction in the drug nephrotoxicity, we have investigated the influence of aminoglycosides on phosphoinositide metabolism in kidney proximal tubules where these compounds accumulate. Experiments were carried out by measuring 32-P labelling of phosphatidylinositol 4-phosphate (PI-P) and of phosphatidylinositol 4,5-bisphosphate (PI-P2) after incubation of homogenates of isolated proximal tubules with [γ-32P] ATP. The treatment of rabbits with neomycin. gentamicin and amikacin (50, 50 and 300 mg/kg/day. respectively for seven days) promoted a decrease in 32-P-PI-P2 and an increase in 32P-PI-P, when compared lo the respective values observed in tubules from untreated rabbits. Under these conditions, the extent of modifications in lipid labelling was similar with the three drugs tested. In in vitro experiments, the exogenous addition of the above aminoglycosides to the incubation medium containing tubule homogenates from untreated rabbits also produced, in a dose dependent manner, a decrease in 32P-Pl-P2 and an increase in 32P-PI-P. In the in vitro experiments, however, amikacin and gentamicin appeared lo be less potent than neomycin. The results indicated moreover that phosphoinositide metabolism was more sensitive to the in vivo (vs. in vitro) action of the drugs. Phosphoinositides are involved in Ca2+ transport and/or mobilization processes, and aminoglycosides are known lo interfere with the Ca2+ binding to membranes. From our results, one may therefore envisage that aminoglycoside-induced impairment of phosphoinositide metabolism can result in a modification of Ca2+ handling by the tubular cells and this may be of relevance for the development of the drug toxicity.
- Subjects
AMINOGLYCOSIDES; PHOSPHOINOSITIDES; METABOLISM; AMINO compounds; GLYCOSIDES; PHOSPHOLIPIDS
- Publication
Kidney International, 1987, Vol 31, Issue 1, p59
- ISSN
0085-2538
- Publication type
Article
- DOI
10.1038/ki.1987.9