Honegger U E, Scuntaro I, Wiesmann U N
Department of Pharmacology, University of Bern, Switzerland.
Biochem Pharmacol. 1995 Jun 16;49(12):1741-5. doi: 10.1016/0006-2952(95)00100-e.
Chronic administration of amiodarone (AMIO), widely used by clinicians for the treatment of therapy-resistant cardiac arrhythmias, is frequently associated with serious side-effects. AMIO and its main metabolite desethylamiodarone (DEA) are known to induce phospholipidosis in vivo and in cultured cells presumably by inhibition of lysosomal phospholipid degradation. D-alpha-Tocopherol = vitamin E (alpha-TOC) was able to reduce AMIO and DEA toxicity in cell cultures. Results from the present study showed that alpha-TOC reduced phospholipidosis in cultured human skin fibroblasts chronically exposed to micromolar concentrations of AMIO and DEA and inhibited cumulative uptake of the drugs in a dose-dependent manner. A linear correlation was observed between cellular AMIO levels and phospholipid accumulation suggesting a stoichiometric relationship. alpha-TOC was also effective in clearing previously accumulated phospholipids after discontinuation of the drug treatment. The results can best be explained by an interference of alpha-TOC (a) with drug-phospholipid complex formation responsible for both phospholipid storage and drug accumulation, and (b) with pre-existing drug-phospholipid complexes, accelerating their dissociation and rendering phospholipids to substrates for lysosomal phospholipases. The finding raises hope that side-effects of AMIO and DEA can be prevented or made reversible by the administration of alpha-TOC. It must, however, be proven that the antiarrhythmic drug will still be effective.
胺碘酮（AMIO）被临床医生广泛用于治疗难治性心律失常，长期使用常伴有严重副作用。已知AMIO及其主要代谢产物去乙基胺碘酮（DEA）在体内和培养细胞中可诱导磷脂沉积，推测是通过抑制溶酶体磷脂降解实现的。D-α-生育酚 = 维生素E（α-TOC）能够降低细胞培养中AMIO和DEA的毒性。本研究结果表明，α-TOC可减轻长期暴露于微摩尔浓度AMIO和DEA的培养人皮肤成纤维细胞中的磷脂沉积，并以剂量依赖方式抑制药物的累积摄取。细胞内AMIO水平与磷脂积累之间呈线性相关，提示存在化学计量关系。在药物治疗中断后，α-TOC对清除先前积累的磷脂也有效。这些结果最好的解释是α-TOC（a）干扰负责磷脂储存和药物积累的药物 - 磷脂复合物形成，以及（b）干扰预先存在的药物 - 磷脂复合物，加速其解离并使磷脂成为溶酶体磷脂酶的底物。这一发现带来了希望，即通过给予α-TOC可以预防或逆转AMIO和DEA的副作用。然而，必须证明这种抗心律失常药物仍然有效。
