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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{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 PBNmore » 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.« less

Authors:
 [1];  [1];  [2];  [1];  [3];  [1];  [1];  [4]
  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)
  4. Department of Pharmacology and Toxicology, Queen's University, Kingston, ON, K7L 3N6 (Canada). E-mail: masseyt@post.queensu.ca
Publication Date:
OSTI Identifier:
20976898
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 220; Journal Issue: 1; Other Information: DOI: 10.1016/j.taap.2006.12.031; PII: S0041-008X(06)00497-2; Copyright (c) 2007 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
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

Citation Formats

Nicolescu, Adrian C., Comeau, Jeannette L., Hill, Bruce C., Bedard, Leanne L., Takahashi, Takashi, Brien, James F., Racz, William J., and Massey, Thomas E.. Aryl radical involvement in amiodarone-induced pulmonary toxicity: Investigation of protection by spin-trapping nitrones. United States: N. p., 2007. Web. doi:10.1016/j.taap.2006.12.031.
Nicolescu, Adrian C., Comeau, Jeannette L., Hill, Bruce C., Bedard, Leanne L., Takahashi, Takashi, Brien, James F., Racz, William J., & Massey, Thomas E.. Aryl radical involvement in amiodarone-induced pulmonary toxicity: Investigation of protection by spin-trapping nitrones. United States. doi:10.1016/j.taap.2006.12.031.
Nicolescu, Adrian C., Comeau, Jeannette L., Hill, Bruce C., Bedard, Leanne L., Takahashi, Takashi, Brien, James F., Racz, William J., and Massey, Thomas E.. Sun . "Aryl radical involvement in amiodarone-induced pulmonary toxicity: Investigation of protection by spin-trapping nitrones". United States. doi:10.1016/j.taap.2006.12.031.
@article{osti_20976898,
title = {Aryl radical involvement in amiodarone-induced pulmonary toxicity: Investigation of protection by spin-trapping nitrones},
author = {Nicolescu, Adrian C. and Comeau, Jeannette L. and Hill, Bruce C. and Bedard, Leanne L. and Takahashi, Takashi and Brien, James F. and Racz, William J. and Massey, Thomas E.},
abstractNote = {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.},
doi = {10.1016/j.taap.2006.12.031},
journal = {Toxicology and Applied Pharmacology},
number = 1,
volume = 220,
place = {United States},
year = {Sun Apr 01 00:00:00 EDT 2007},
month = {Sun Apr 01 00:00:00 EDT 2007}
}