Abstract
Amiodarone (AM) is an efficacious antidysrhythmic agent that can cause numerous adverse effects, including potentially life-threatening pulmonary fibrosis. The current study was undertaken to investigate potential protective mechanisms of vitamin E against AM-induced pulmonary toxicity (AIPT) in the hamster. Three weeks after intratracheal administration of AM (1.83 μmol), increased pulmonary hydroxyproline content and histological damage were observed, indicative of fibrosis. These effects were preceded by increased pulmonary levels of transforming growth factor (TGF)-β1mRNA at 1 week post-AM, which remained elevated 3 weeks post-AM. Dietary supplementation with vitamin E resulted in rapid pulmonary accumulation of the vitamin, and prevention of AM-induced increases in TGF-β1, hydroxyproline, and histological damage. Although dietary supplementation also markedly elevated lung mitochondrial vitamin E content, it did not attenuate AM-induced inhibition of mitochondrial respiration or disruption of mitochondrial membrane potential in vitro, or lung mitochondrial respiratory inhibition resulting from in vivo AM administration. These results suggest that vitamin E reduces the extent of pulmonary damage after AM administration via down-regulating TGF-β1 overexpression but that it does not modify AM-induced mitochondrial dysfunction, a potential initiating event in AIPT.
Footnotes
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This research was supported by Operating Grant MT-13257 from the Canadian Institutes of Health Research. J.W.C. was the recipient of a Canadian Institutes of Health Research Doctoral Research Award and the Procter and Gamble Graduate Student Fellowship from the Society of Toxicology. Portions of this work have been presented in abstract form under the following citations: Card JW, Racz WJ, Brien JF, Margolin SB, and Massey TE (2001) Anti-fibrotic studies in the hamster model of amiodarone-induced pulmonary fibrosis. Proc Soc Toxicol Canada; and Card JW, Steenbakkers MJ, Beard KM, Racz WJ, Brien JF, Bennett BM, and Massey TE (2000) Dietary vitamin E supplementation does not prevent lung mitochondrial dysfunction induced by in vitro amiodarone and N-desethylamiodarone.Toxicologist54 (1-S):319.
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DOI: 10.1124/jpet.102.043208
- Abbreviations:
- AM
- amiodarone
- AIPT
- AM-induced pulmonary toxicity
- DEA
- N-desethylamiodarone
- TGF
- transforming growth factor
- RCR
- respiratory control ratio
- ADP:O
- ratio of adenosine diphosphate to oxygen
- Received August 14, 2002.
- Accepted September 19, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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