Amiodarone-induced injury of human pulmonary artery endothelial cells: protection by alpha-tocopherol.
Amiodarone is a potent antidysrhythmic drug that is associated with severe pulmonary toxicity. The mechanism of amiodarone pulmonary toxicity is poorly understood. To investigate the possible involvement of oxygen-derived metabolites in amiodarone-induced injury, 51Cr-labeled human pulmonary artery endothelial (HPAE) cells were incubated with amiodarone for 18 hr in the presence of various antioxidants and in hypoxic and hyperoxic conditions with cell injury quantified by 51Cr release, expressed as cytotoxic index. Amiodarone (10-50 microM) directly injured HPAE cells in a concentration-dependent manner, but the injury was not modulated by altering ambient oxygen concentrations. Furthermore, amiodarone-induced injury (30 microM) was not reduced by the following antioxidants: catalase, superoxide dismutase, ascorbic acid, dimethyl sulfoxide and ethanol. In contrast, toxicity from 30 microM amiodarone was significantly reduced by alpha-tocopherol (alpha-TOC) at 10, 20 and 40 microM from a cytotoxic index of 41.6 +/- 3.5 to 25.5 +/- 7.9, 10.61 +/- 5.4 and 3.1 +/- 2.8, respectively. As revealed by phase microscopy, alpha-TOC (40 microM) prevented any evidence of toxicity to the amiodarone-treated cells. Amiodarone concentrations in the HPAE cells incubated in the presence and absence of alpha-TOC were not significantly different, indicating that alpha-TOC did not interfere with the uptake of the drug by the cells. Similarly, amiodarone did not interfere with the uptake of alpha-TOC by the HPAE cells. Although the specific mechanism of action remains unclear, alpha-TOC affords nearly complete protection in vitro from the cellular injury induced by amiodarone.
Department of Internal Medicine, Indiana University School of Medicine, Indianapolis.
D L
DL
Kachel
T P
TP
Moyer
W J
WJ
Martin
D000638:Amiodarone / Q000037:antagonists & inhibitors* / Q000633:toxicity; D002478:Cells, Cultured; D004727:Endothelium / Q000187:drug effects*; D006801:Humans; D000860:Hypoxia / Q000139:chemically induced / Q000517:prevention & control; D011651:Pulmonary Artery / Q000187:drug effects* / Q000473:pathology; D014810:Vitamin E / Q000627:therapeutic use*
D014810:Vitamin E; D000638:Amiodarone