Effects of vitamin E on cytotoxicity of amiodarone and N-desethylamiodarone in isolated hamster lung cells

Amiodarone (AM) is a potent and efficacious antidysrhythmic agent that can cause potentially life-threatening pulmonary fibrosis. Vitamin E has been demonstrated to decrease AM-induced pulmonary fibrosis in vivo in hamsters. In the present in vitro study, we investigated the effects of vitamin E on cell death induced by AM and its primary metabolite, N-desethylamiodarone (DEA), in freshly isolated hamster lung cells. Following incubation for 24 or 36 h, 300 muM vitamin E decreased (P 0.05) 100 muM AM-induced cytotoxicity (0.5% trypan blue uptake) in alveolar macrophages by 11.7 +/- 3% or 21.4 +/- 12%, respectively, but did not decrease cytotoxicity in fractions enriched with alveolar type II cells or non-ciliated bronchiolar epithelial (Clara cells) or in isolated unseparated cells (cell digest). Vitamin E had no effect on 50 muM DEA-induced cytotoxicity. Vitamin E did not alter cellular levels of AM or DEA in any cell fraction. Lipid peroxidation (assessed by isoprostane formation) was increased (P < 0.05) in cell digest, alveolar type Il cell and Clara cell enriched fractions incubated with 500 <mu>M carbon tetrachloride (CCl4) for 4 h but not in enriched fractions of cells exposed to 100 LM AM or 50 muM DEA. No AM-induced loss of viability was observed at this time point, but DEA decreased (P < 0.05) Clara cell viability by approximately 25%. These results demonstrate cell type selective protection against AM-induced cytotoxicity by vitamin E, and suggest that lipid peroxidation does not initiate AM- or DEA-induced cytotoxicity in isolated hamster lung cells. <(c)> 2001 Elsevier Science Ireland Ltd. All rights reserved.