Role of Oxidative Stress in Amiodarone-induced Toxicity

Abstract

Background: The clinical usefulness of amiodarone for the treatment of cardiac arrhythmias is limited by multiorgan toxicity, especially pulmonary and hepatic. There are conflicting reports in the literature regarding the role of free radicals in the initiation of amiodarone- induced toxicity. We evaluated the possible oxidative stress in a chronic model that is known to manifest pulmonary toxicity. Methods and Results: A group of 20 Fischer-344 rats were injected with 60 mg/kg/day of amiodarone for 21 days. A control group of 20 animals received only saline injections. The alveolar macrophages obtained by lung lavage were incubated with hydroethidine and opsonized green fluorescent zymosan particles to measure oxidative and phagocytic activities by flow cytometry. Malondialdehyde levels were measured to assess the extent of lipid per oxidation in lung, liver, spleen, kidney, and heart. Total phospholipid levels in all the col lected tissues and distribution of phospholipid classes in the lung and the liver were mea sured. The levels of amiodarone and its metabolite desethylamiodarone in serum and all collected tissues were measured by high-performance liquid chromatography. The phago cytic activity of the macrophages from treated animals was decreased by 18-22% ( P < .03) compared to controls; however, the oxidative activities of control and treated groups were not significantly different. The tissue malondialdehyde levels were not significantly different except in the spleen where they increased after amiodarone treatment (18.2 ± 1.1 vs 23.7 ± 2.8 μM/g tissue, P < .0001). Malondyaldehyde levels were not significantly different when normalized to lipid phosphorous content. Lung, liver, and spleen showed significantly higher phospholipid levels in the treated group. The tissue amiodarone and desethylamiodarone lev els in the treated group were highest in spleen followed by lung, liver, kidney, and heart. Conclusions: The results show that amiodarone-induced pulmonary and hepatic toxicity is not directly mediated by oxidative stress; however, increased lipid peroxidation in the spleen, although secondary to phospholipidosis, may be physiologically significant.