IMPAIRMENT OF MEMBRANE PHOSPHOINOSITIDE METABOLISM BY AMINOGLYCOSIDE ANTIBIOTICS - STREPTOMYCIN, AMIKACIN, KANAMYCIN, DIBEKACIN, GENTAMICIN AND NEOMYCIN

  • 1 January 1983
    • journal article
    • research article
    • Vol. 227  (2) , 415-420
Abstract
Like many amphiphilic cationic drugs, aminoglycosides are able to produce phospholipidosis, mainly by inhibiting enzymes involved in phospholipid metabolism. Phosphoinositides may function as receptors for aminoglycosides. The influence of these drugs upon phosphoinositide metabolism was studied by measuring the 32P-incorporation into the polyphosphoinositides, using the rat erythrocyte membrane as a model. Depending upon the experimental conditions, neomycin induced a decrease and/or an increase in the 32P-labeling of triphosphoinositides (TPI) and of diphosphoinositides (DPI), respectively. These variations were rapid and depended upon the drug concentration. At 0.3 mM, neomycin reversed the distribution of radioactivities associated with DPI and TPI without modifying the total radioactivity incorporated. This drug concentration altered neither the Mg2+-activated TPI-specific phosphomonoesterase activity nor the Ca2+-activated polyphosphoinositide phosphodiesterase activity. Apparently, the drug inhibits the DPI-kinase activity by interacting with DPI and thereby lowering the substrate availability. Over the range of concentrations studied (up to 1-2 mM), gentamicin, kanamycin and dibekacin behave as neomycin. Their effects could be observed only at drug concentrations higher than those of neomycin. Streptomycin and amikacin did not alter the 32P-labeling of TPI and of DPI. The order of potency of aminoglycosides for the impairment of the phosphoinositide interconversion was neomycin, gentamicin, dibekacin, kanamycin. A possible relationship between the toxicity of aminoglycosides and their capacity to impair the phosphoinositide metabolism is discussed.