In vitro study on the pulmonary cytotoxicity of amiodarone. (October 2013)

• Record Type: Journal Article
• Authors: Alsamri, Mohammed T.; Pramathan, Thachillath; Souid, Abdul-Kader
• Is Part Of: Toxicology mechanisms and methods. Volume 23:Number 8(2013)
• Page Start: 610
• Page End: 616
• Publication Date: 2013-10
• Subjects: Analytical toxicology -- Periodicals; Toxicology -- Periodicals; Toxicology -- Methodology -- Periodicals; 615.907
• DOI: 10.3109/15376516.2013.812170
• Languages: English
• ISSNs: 1537-6516

Abstract

<abstract> <title>Abstract</title> <p> <italic>Context</italic>: Amiodarone (an iodinated benzofuran) is a Class III antiarrhythmic drug that produces significant pulmonary disease. Proposed mechanisms of this cytotoxicity include necrosis, apoptosis, mitochondrial dysfunction and glutathione depletion.</p> <p> <italic>Objective:</italic> This study was designed primarily to explore whether amiodarone impairs lung tissue cellular bioenergetics in BALB/c and Taylor Outbred mice.</p> <p> <italic>Materials and methods:</italic> Cellular respiration (mitochondrial O<sub>2</sub> consumption), ATP, caspase activity and glutathione were measured in lung fragments incubated <italic>in vitro</italic> with 22 µM amiodarone for several hours.</p> <p> <italic>Results:</italic> Without amiodarone, lung tissue cellular mitochondrial O<sub>2</sub> consumption decayed exponentially with time, showing two distinct phases sharply separated at <italic>t</italic> ≥ 150 min. The rate of cellular respiration was 6–10-fold higher in the late phase compared to the early phase (<italic>p</italic> < 0.0001). Lung tissue ATP also decayed exponentially with time, suggesting "uncoupling oxidative phosphorylation" was the responsible mechanism (low cellular ATP with high mitochondrial O<sub>2</sub> consumption, resulting in rapid depletion of cellular metabolic fuels). Although intracellular caspase activity increased exponentially with time, the uncoupling was not prevented by the pancaspase inhibitor zVAD-fmk (<italic>N</italic>-benzyloxycarbonyl-val-ala-asp (O-methyl)-fluoromethylketone). The same profiles were noted in the presence of amiodarone; but cellular ATP decayed 50% faster. Cellular glutathione for untreated tissue was 560 ± 287 pmol mg<sup>−1</sup> (<italic>n</italic> = 12) and for treated tissue was 490 ± 226 pmol mg<sup>−1</sup> (<italic>n</italic> = 12, <italic>p</italic> = 0.5106).</p> <p> <italic>Conclusion</italic>: Uncoupling oxidative phosphorylation was demonstrated in untreated mouse lung tissues. Amiodarone lowered cellular ATP. Further studies are needed to explore the susceptibility of the lung to these deleterious insults and their relevance to human diseases.</p> </abstract>