Aryl radical involvement in amiodarone-induced pulmonary toxicity: Investigation of protection by spin-trapping nitrones

Journal Article · Sun Apr 01 04:00:00 EDT 2007 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2006.12.031· OSTI ID:20976898

Nicolescu, Adrian C ^[1]; Comeau, Jeannette L ^[1]; Hill, Bruce C ^[2]; Bedard, Leanne L ^[1]; Takahashi, Takashi ^[3]; Brien, James F ^[1]; Racz, William J ^[1]; 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), 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{sub 50} = 8 {mu}M) than AM (LC{sub 50} = 146 {mu}M), whereas DDIA cytotoxicity was intermediate (LC{sub 50} = 26 {mu}M) 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.

• OSTI ID: 20976898
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 1 Vol. 220; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
AQUEOUS SOLUTIONS
ARYL RADICALS
BROMIDES
DRUGS
ELECTRON SPIN RESONANCE
FIBROSIS
HAMSTERS
IN VIVO
LUNGS
OXIDES
OXYGEN
PHOTOLYSIS
SAFETY
SPECTROSCOPY
SPIN
TETRAZOLIUM
THIAZOLES
TOXICITY
TRAPPING