title: Aryl radical involvement in amiodarone-induced pulmonary toxicity: investigation of protection by spin-trapping nitrones.
abstract: Amiodarone (AM), an antidysrrhythmic drug, can produce serious adverse effects, including potentially fatal AM-induced pulmonary toxicity (AIPT). AM-induced cytotoxicity and pulmonary fibrosis are well recognized, but poorly understood mechanistically. The hypothesis of aryl radical involvement in AM toxicity was tested in non-biological and biological systems. Photolysis of anaerobic aqueous solutions of AM, or N-desethylamiodarone (DEA) resulted in the formation of an aryl radical, as determined by spin-trapping and electron paramagnetic resonance (EPR) spectroscopy experiments. The non-iodinated AM analogue, didesiodoamiodarone (DDIA), did not form aryl radicals under identical conditions. The toxic susceptibility of human lung epithelioid HPL1A cells to AM, DEA, and DDIA showed time- and concentration-dependence. DEA had a more rapid and potent toxic effect (LC(50)=8 microM) than AM (LC(50)=146 microM), whereas DDIA cytotoxicity was intermediate (LC(50)=26 microM) suggesting a minor contribution of the iodine atoms. Incubation of human lung epithelial cells with the spin-trapping nitrones alpha-phenyl-N-t-butylnitrone (PBN, 10 mM) or alpha-(4-pyridyl N-oxide)-N-t-butylnitrone (POBN, 5.0 mM) did not significantly protect against AM, DEA, or DDIA cytotoxicity. Intratracheal administration of AM to hamsters produced pulmonary fibrosis at day 21, which was not prevented by 4 days of treatment with 150 mg/kg/day PBN or 164 mg/kg/day POBN. However, the body weight loss in AM-treated animals was counteracted by PBN. These results suggest that, although AM can generate an aryl radical photochemically, its in vivo formation may not be a major contributor to AM toxicity, and that spin-trapping reagents do not halt the onset of AM toxicity.
authors.affiliation: Department of Pharmacology and Toxicology, Queen's University, Kingston, ON, Canada K7L 3N6.
authors.forename: Adrian C
authors.initials: AC
authors.lastname: Nicolescu
authors.forename: Jeannette L
authors.initials: JL
authors.lastname: Comeau
authors.forename: Bruce C
authors.initials: BC
authors.lastname: Hill
authors.forename: Leanne L
authors.initials: LL
authors.lastname: Bedard
authors.forename: Takashi
authors.initials: T
authors.lastname: Takahashi
authors.forename: James F
authors.initials: JF
authors.lastname: Brien
authors.forename: William J
authors.initials: WJ
authors.lastname: Racz
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Massey
mesh_terms: D000638:Amiodarone / Q000633:toxicity*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000633:toxicity*; D006224:Cricetinae; D003497:Cyclic N-Oxides / Q000494:pharmacology*; D004578:Electron Spin Resonance Spectroscopy; D005609:Free Radicals; D006909:Hydroxyproline / Q000032:analysis; D008168:Lung / Q000737:chemistry / Q000187:drug effects* / Q000473:pathology; D008297:Male; D008647:Mesocricetus; D010777:Photochemistry; D011725:Pyridines / Q000494:pharmacology*
chemical_list: D000889:Anti-Arrhythmia Agents; D003497:Cyclic N-Oxides; D005609:Free Radicals; D011725:Pyridines; C043438:alpha-(4-pyridyl-1-oxide)-N-tert-butylnitrone; C029217:phenyl-N-tert-butylnitrone; D000638:Amiodarone; D006909:Hydroxyproline