title: Effects of vitamin E on cytotoxicity of amiodarone and N-desethylamiodarone in isolated hamster lung cells.
abstract: 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 microM vitamin E decreased (P<0.05) 100 microM 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 microM 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 II cell and Clara cell enriched fractions incubated with 500 microM carbon tetrachloride (CCl(4)) for 4 h but not in enriched fractions of cells exposed to 100 microM AM or 50 microM 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.
authors.affiliation: Department of Pharmacology and Toxicology, Botterell Hall Room 535, Queen's University, Ont., K7L 3N6, Kingston, Canada.
authors.forename: M W
authors.initials: MW
authors.lastname: Bolt
authors.forename: W J
authors.initials: WJ
authors.lastname: Racz
authors.forename: J F
authors.initials: JF
authors.lastname: Brien
authors.forename: T E
authors.initials: TE
authors.lastname: Massey
mesh_terms: D000638:Amiodarone / Q000031:analogs & derivatives / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000378:metabolism / Q000633:toxicity*; D000975:Antioxidants / Q000494:pharmacology*; D001980:Bronchi / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002251:Carbon Tetrachloride / Q000633:toxicity; D002469:Cell Separation; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D006224:Cricetinae; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016166:Free Radical Scavengers; D015227:Lipid Peroxidation / Q000187:drug effects; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008647:Mesocricetus; D014810:Vitamin E / Q000494:pharmacology*
chemical_list: D000889:Anti-Arrhythmia Agents; D000975:Antioxidants; D016166:Free Radical Scavengers; D014810:Vitamin E; D002251:Carbon Tetrachloride; C036116:desethylamiodarone; D000638:Amiodarone