CURE Center for Liver Disease Research and Treatment, Institute of Internal Medicine, Department of Medical and Occupational Sciences, University of Foggia, 71122 Foggia, Italy.
Free Radic Biol Med. 2011 Dec 15;51(12):2234-42. doi: 10.1016/j.freeradbiomed.2011.09.004. Epub 2011 Sep 17.
The role played by oxidative stress in amiodarone-induced mitochondrial toxicity is debated. Dronedarone shows pharmacological properties similar to those of amiodarone but several differences in terms of toxicity. In this study, we analyzed the effects of the two drugs on liver mitochondrial function by administering an equivalent human dose to a rat model. Amiodarone increased mitochondrial H(2)O(2) synthesis, which in turn induced cardiolipin peroxidation. Moreover, amiodarone inhibited Complex I activity and uncoupled oxidative phosphorylation, leading to a reduction in the hepatic ATP content. We also observed a modification of membrane phospholipid composition after amiodarone administration. N-acetylcysteine completely prevented such effects. Although dronedarone shares with amiodarone the capacity to induce uncoupling of oxidative phosphorylation, it did not show any of the oxidative effects and did not impair mitochondrial bioenergetics. Our data provide important insights into the mechanism of mitochondrial toxicity induced by amiodarone. These results may greatly influence the clinical application and toxicity management of these two antiarrhythmic drugs.
氧化应激在胺碘酮诱导的线粒体毒性中的作用存在争议。多非利特在药理学特性上与胺碘酮相似，但在毒性方面存在一些差异。在这项研究中，我们通过给予大鼠模型等效的人体剂量来分析这两种药物对肝线粒体功能的影响。胺碘酮增加了线粒体 H2O2 的合成，进而诱导了心磷脂过氧化。此外，胺碘酮抑制了复合物 I 的活性并解偶联了氧化磷酸化，导致肝 ATP 含量减少。我们还观察到胺碘酮给药后膜磷脂组成的改变。N-乙酰半胱氨酸完全阻止了这些作用。虽然多非利特与胺碘酮一样具有诱导氧化磷酸化解偶联的能力，但它没有显示出任何氧化作用，也没有损害线粒体生物能量学。我们的数据为胺碘酮诱导的线粒体毒性的机制提供了重要的见解。这些结果可能会极大地影响这两种抗心律失常药物的临床应用和毒性管理。
