Schacht J, Weiner N
ORL J Otorhinolaryngol Relat Spec. 1986;48(2):116-23. doi: 10.1159/000275856.
A multi-step hypothesis of aminoglycoside ototoxicity is presented which is consistent with the data elaborated by our laboratory and others. The first step in the reaction sequence is an electrostatic interaction of the aminoglycoside with negatively charged components of the outer plasma membrane. The resulting displacement of calcium accounts for the acute effects of the drug action and is reversible and antagonized by cations. The drug is then transported into the cell by an energy-dependent process. The next and most crucial step is the binding of the drug to phosphatidylinositol bisphosphate, a physiologically important phospholipid. The formation of the drug-lipid complex prevents the hydrolysis of phosphatidylinositol bisphosphate and disturbs membrane integrity and structure resulting in nonspecific permeability changes of the membrane. Once inside the cell, the aminoglycosides may interfere with further intracellular reactions. This interference may be based on competition with divalent cations or polyamines or on binding to negatively charged compounds.
本文提出了一个氨基糖苷类耳毒性的多步骤假说，该假说与我们实验室及其他实验室所阐述的数据一致。反应序列的第一步是氨基糖苷类与外质膜带负电荷成分的静电相互作用。由此导致的钙的置换解释了药物作用的急性效应，且这种效应是可逆的，并可被阳离子拮抗。然后，药物通过一个能量依赖过程被转运进入细胞。接下来也是最关键的一步是药物与磷脂酰肌醇二磷酸（一种生理上重要的磷脂）结合。药物 - 脂质复合物的形成阻止了磷脂酰肌醇二磷酸的水解，并扰乱了膜的完整性和结构，导致膜的非特异性通透性改变。一旦进入细胞内，氨基糖苷类可能会干扰进一步的细胞内反应。这种干扰可能基于与二价阳离子或多胺的竞争，或者基于与带负电荷化合物的结合。
