Marche P, Koutouzov S, Girard A
J Pharmacol Exp Ther. 1983 Nov;227(2):415-20.
Like many amphiphilic cationic drugs, aminoglycosides are able to produce phospholipidosis, mainly by inhibiting enzymes involved in phospholipid metabolism. Phosphoinositides have been suggested to function as receptors for aminoglycosides. Therefore, we investigated the influence of these drugs upon phosphoinositide metabolism 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 Mg++-activated TPI-specific phosphomonoesterase activity nor the Ca++-activated polyphosphoinositide phosphodiesterase activity. It appears likely that 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. However, their effects could be observed only at drug concentrations higher than those of neomycin. By contrast, 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.
与许多两亲性阳离子药物一样，氨基糖苷类药物能够引发磷脂质病，主要是通过抑制参与磷脂代谢的酶。有人提出磷酸肌醇可作为氨基糖苷类药物的受体。因此，我们以大鼠红细胞膜为模型，通过测量32P掺入多磷酸肌醇中的量，研究了这些药物对磷酸肌醇代谢的影响。根据实验条件的不同，新霉素分别使三磷酸肌醇（TPI）和二磷酸肌醇（DPI）的32P标记量减少和/或增加。这些变化迅速且取决于药物浓度。在0.3 mM时，新霉素逆转了与DPI和TPI相关的放射性分布，而不改变掺入的总放射性。该药物浓度既不改变Mg++激活的TPI特异性磷酸单酯酶活性，也不改变Ca++激活的多磷酸肌醇磷酸二酯酶活性。似乎该药物通过与DPI相互作用抑制DPI激酶活性，从而降低底物可用性。在所研究的浓度范围内（高达1 - 2 mM），庆大霉素、卡那霉素和地贝卡星的作用与新霉素相似。然而，只有在高于新霉素的药物浓度下才能观察到它们的作用。相比之下，链霉素和阿米卡星没有改变TPI和DPI的32P标记。氨基糖苷类药物损害磷酸肌醇相互转化的效力顺序为新霉素、庆大霉素、地贝卡星、卡那霉素。本文讨论了氨基糖苷类药物的毒性与其损害磷酸肌醇代谢能力之间的可能关系。
