Department of Pediatrics, United Arab Emirates University , Al Ain , UAE.
Toxicol Mech Methods. 2013 Oct;23(8):610-6. doi: 10.3109/15376516.2013.812170. Epub 2013 Oct 7.
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.
This study was designed primarily to explore whether amiodarone impairs lung tissue cellular bioenergetics in BALB/c and Taylor Outbred mice.
Cellular respiration (mitochondrial O2 consumption), ATP, caspase activity and glutathione were measured in lung fragments incubated in vitro with 22 µM amiodarone for several hours.
Without amiodarone, lung tissue cellular mitochondrial O2 consumption decayed exponentially with time, showing two distinct phases sharply separated at t ≥ 150 min. The rate of cellular respiration was 6-10-fold higher in the late phase compared to the early phase (p<0.0001). Lung tissue ATP also decayed exponentially with time, suggesting "uncoupling oxidative phosphorylation" was the responsible mechanism (low cellular ATP with high mitochondrial O2 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 (N-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(-1) (n=12) and for treated tissue was 490 ± 226 pmol mg(-1) (n=12, p=0.5106).
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.
胺碘酮（一种碘苯并呋喃）是一种 III 类抗心律失常药物，可导致明显的肺部疾病。这种细胞毒性的提出机制包括坏死、细胞凋亡、线粒体功能障碍和谷胱甘肽耗竭。
本研究旨在主要探讨胺碘酮是否会损害 BALB/c 和 Taylor 近交系小鼠的肺组织细胞生物能学。
用 22µM 胺碘酮孵育体外肺组织片段数小时，测量细胞呼吸（线粒体 O2 消耗）、ATP、半胱天冬酶活性和谷胱甘肽。
在没有胺碘酮的情况下，肺组织细胞线粒体 O2 消耗随时间呈指数衰减，在 t≥150min 时明显分为两个阶段。与早期阶段相比，晚期阶段的细胞呼吸速率高 6-10 倍（p<0.0001）。肺组织 ATP 也随时间呈指数衰减，表明“氧化磷酸化解偶联”是负责的机制（细胞内 ATP 低而线粒体 O2 消耗高，导致细胞代谢燃料迅速耗尽）。尽管细胞内半胱天冬酶活性随时间呈指数增加，但全半胱天冬酶抑制剂 zVAD-fmk（N-苯甲氧基羰基-缬氨酰-丙氨酰-天冬氨酸（O-甲基）-氟甲基酮）不能阻止解偶联。在存在胺碘酮的情况下也注意到相同的谱，但细胞 ATP 衰减速度快 50%。未经处理的组织细胞谷胱甘肽为 560±287pmol·mg-1（n=12），处理组织为 490±226pmol·mg-1（n=12，p=0.5106）。
在未处理的小鼠肺组织中证明了氧化磷酸化解偶联。胺碘酮降低了细胞内的 ATP。需要进一步研究来探讨肺对这些有害影响的易感性及其与人类疾病的相关性。
