Direct mitochondrial dysfunction precedes reactive oxygen species production in amiodarone-induced toxicity in human peripheral lung epithelial HPL1A cells

Journal Article · Sat Mar 15 04:00:00 EDT 2008 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2007.12.009· OSTI ID:21077952

Ji, Yanbin; Comeau, Jeannette L ^[1]; Hill, Bruce C ^[2]; Takahashi, Takashi ^[3]; Brien, James F; Racz, William J; Massey, Thomas E ^[1]

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1. Department of Pharmacology and Toxicology, Queen's University, Kingston, ON, K7L 3N6 (Canada)
2. Department of Biochemistry, Queen's University, Kingston, ON, K7L 3N6 (Canada)
3. Division of Molecular Carcinogenesis, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya 466-8550 (Japan)

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 ({>=} 6 h) of HPL1A cells with 100 {mu}M 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 (registered) 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.

• OSTI ID: 21077952
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 3 Vol. 227; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ARYL RADICALS
CARBOXYLIC ACIDS
ELECTRON SPIN RESONANCE
GROWTH FACTORS
LUNGS
MITOCHONDRIA
OXIDES
SPECTROSCOPY
TOXICITY