Mitochondrial oxidative stress and respiratory chain dysfunction account for liver toxicity during amiodarone but not dronedarone administration

作者：Serviddio Gaetano^*; Bellanti Francesco; Giudetti Anna Maria; Gnoni Gabriele Vincenzo; Capitanio Nazzareno; Tamborra Rosanna; Romano Antonino Davide; Quinto Maurizio; Blonda Maria; Vendemiale Gianluigi; Altomare Emanuele

来源：Free Radical Biology and Medicine, 2011, 51(12): 2234-2242.

DOI：10.1016/j.freeradbiomed.2011.09.004

• Mitochondrial dysfunction
• Lipid peroxidation
• Antioxidants
• Drugs
• Hepatotoxicity
• Free radicals

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.

• 出版日期2011-12-15