Amiodarone induced lipidosis similar to Niemann-Pick C disease. Biochemical and morphological study

Abstract

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.