Palmeri S, Battisti C, Malandrini A, Federico A
Institute of Neurological Sciences, Medical School, University of Siena, Italy.
Life Sci. 1995;57(21):1963-71. doi: 10.1016/0024-3205(95)02129-7.
Amiodarone is effective in the treatment of supraventricular and ventricular cardiac arrhythmia, however a high incidence of toxic side effects has been observed in various organs and tissues during chronic treatment. Ultrastructural observation of affected tissues reveals myelinoid inclusion bodies. The exact pathogenetic mechanism of these changes is still unknown. In this study we investigated the biochemical effects of this drug on lysosomal hydrolases and the alterations induced in subcellular organelles of fibroblasts cultured for 24 h with different concentrations of amiodarone in the medium. Of the enzyme activities assayed, we only observed a significant reduction in sphingomyelinase. Ultrastructural observation of fibroblasts showed swollen lysosomes and a few onionoid inclusion bodies at lower concentrations of the drug; at higher concentrations the lysosomal system was severely impaired. Cytochemical staining of unesterified cholesterol with filipin showed accumulation of cholesterol. We conclude that chronic amiodarone treatment in experimental conditions induces inhibition in sphingomyelinase activity through interaction with membrane lipids and modification of bilayer structure. Higher concentrations of the drug impair cholesterol transport and induce lipid accumulation. These results may be useful for understanding the pathogenesis of induced lipidosis in patients in chronic treatment with amiodarone.
胺碘酮对室上性和室性心律失常有效，但在长期治疗过程中，已观察到其在各种器官和组织中产生毒副作用的发生率很高。对受影响组织的超微结构观察显示有髓鞘样包涵体。这些变化的确切发病机制仍不清楚。在本研究中，我们调查了该药物对溶酶体水解酶的生化作用，以及在培养基中用不同浓度胺碘酮培养24小时的成纤维细胞亚细胞器中诱导的变化。在所检测的酶活性中，我们仅观察到鞘磷脂酶有显著降低。成纤维细胞的超微结构观察显示，在较低药物浓度下，溶酶体肿胀并有一些葱皮样包涵体；在较高浓度下，溶酶体系统严重受损。用制霉菌素对未酯化胆固醇进行细胞化学染色显示胆固醇积累。我们得出结论，在实验条件下，长期胺碘酮治疗通过与膜脂相互作用和双层结构改变诱导鞘磷脂酶活性抑制。较高浓度的药物损害胆固醇转运并诱导脂质积累。这些结果可能有助于理解胺碘酮长期治疗患者中诱导性脂质沉积症的发病机制。
