Direct mitochondrial dysfunction precedes reactive oxygen species production in amiodarone-induced toxicity in human peripheral lung epithelial HPL1A cells.
Amiodarone (AM), a drug used in the treatment of cardiac dysrrhythmias, can produce severe pulmonary adverse effects, including fibrosis. Although the pathogenesis of AM-induced pulmonary toxicity (AIPT) is not clearly understood, several hypotheses have been advanced, including increased inflammatory mediator release, mitochondrial dysfunction, and free-radical formation. The hypothesis that AM induces formation of reactive oxygen species (ROS) was tested in an in vitro model relevant for AIPT. Human peripheral lung epithelial HPL1A cells, as surrogates for target cells in AIPT, were susceptible to the toxicity of AM and N-desethylamiodarone (DEA), a major AM metabolite. Longer incubations (> or =6 h) of HPL1A cells with 100 microM AM significantly increased ROS formation. In contrast, shorter incubations (2 h) of HPL1A cells with AM resulted in mitochondrial dysfunction and cytoplasmic cytochrome c translocation. Preexposure of HPL1A cells to ubiquinone and alpha-tocopherol was more effective than that with Trolox C or 5,5-dimethylpyrolidine N-oxide (DMPO) at preventing AM cytotoxicity. These data suggest that mitochondrial dysfunction, rather than ROS overproduction, represents an early event in AM-induced toxicity in peripheral lung epithelial cells that may be relevant for triggering AIPT, and antioxidants that target mitochondria may potentially have beneficial effects in AIPT.
Nicolescu
Adrian C
AC
Department of Pharmacology and Toxicology, Queen's University, Kingston, ON, Canada K7L 3N6. adrian.nicolescu@ualberta.ca
Ji
Yanbin
Y
Comeau
Jeannette L
JL
Hill
Bruce C
BC
Takahashi
Takashi
T
Brien
James F
JF
Racz
William J
WJ
Massey
Thomas E
TE
D000638:Amiodarone / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000633:toxicity*; D000889:Anti-Arrhythmia Agents / Q000037:antagonists & inhibitors / Q000633:toxicity*; D002460:Cell Line; D002839:Chromans / Q000008:administration & dosage; D003497:Cyclic N-Oxides / Q000008:administration & dosage; D045304:Cytochromes c / Q000378:metabolism; D003593:Cytoplasm / Q000201:enzymology; D004847:Epithelial Cells / Q000187:drug effects / Q000648:ultrastructure; D006801:Humans; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014451:Ubiquinone / Q000008:administration & dosage; D024502:alpha-Tocopherol / Q000008:administration & dosage
D000889:Anti-Arrhythmia Agents; D002839:Chromans; D003497:Cyclic N-Oxides; D017382:Reactive Oxygen Species; D014451:Ubiquinone; C017245:5,5-dimethyl-1-pyrroline-1-oxide; D045304:Cytochromes c; D024502:alpha-Tocopherol; C036116:desethylamiodarone; D000638:Amiodarone; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid