| Amiodarone (AM) is a potent antidysrhythmic agent that causes life-threatening pulmonary fibrosis. Susceptibilities of different hamster lung cell types to AM-induced cytotoxicity were compared. AM (100 and 200 μM)-induced cytotoxicity was significantly greater in hamster alveolar macrophages than in alveolar type II (PT) cells or non-ciliated bronchiolar epithelial (Clara) cells. However, Clara cells were most susceptible to 50 μM AM-induced cytotoxicity.; Disruption of cellular energy homeostasis as an initiating mechanism of AM-induced cell death was investigated. In all enriched, hamster lung cell preparations, AM (100 μM) and N-desethylamiodarone (DEA, 50 μM) disrupted mitochondrial membrane potential and decreased intracellular ATP levels prior to cell death. Glucose, niacin, or cyclosporin A did not decrease AM-induced cytotoxicity. In isolated lung mitochondria, DEA was more potent at disrupting function and accumulated to a greater extent than AM. Therefore, AM- and DEA-induced disruption of mitochondrial function may initiate cell death.; Free radical formation and subsequent lipid peroxidation may initiate AM-induced cytotoxicity. Vitamin E (300 μM) decreased 100 μM AM-induced cytotoxicity in hamster macrophages but not in any other enriched lung cell fraction or in any fraction incubated with 50 μM DEA. AM and DEA did not cause lipid peroxidation in any fraction. Thus, lipid peroxidation does not initiate AM- and DEA-induced cytotoxicity.; AM-induced cytotoxicity in isolated human PT cells and alveolar macrophages was similar to that observed in rodent models. However, PT cells were more susceptible than macrophages to AM-induced cell death. Vitamin E slightly protected against AM-induced cytotoxicity. An HPLC peak that co-elutes with DEA was observed in some PT cells, as well as in human lung microsomes exposed to AM.; Overall, AM and DEA initiate cell death in hamster alveolar macrophages, PT cells and Clara cells by disrupting mitochondrial function and not by inducing lipid peroxidation. Human lung cells can be used to study AM-induced cytotoxicity and biotransformation of AM to DEA may occur in human lung. |
