title: Mitochondrial oxidative stress and respiratory chain dysfunction account for liver toxicity during amiodarone but not dronedarone administration.
abstract: 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.
authors.affiliation: CURE Center for Liver Disease Research and Treatment, Institute of Internal Medicine, Department of Medical and Occupational Sciences, University of Foggia, 71122 Foggia, Italy. g.serviddio@unifg.it
authors.forename: Gaetano
authors.initials: G
authors.lastname: Serviddio
authors.forename: Francesco
authors.initials: F
authors.lastname: Bellanti
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Giudetti
authors.forename: Gabriele Vincenzo
authors.initials: GV
authors.lastname: Gnoni
authors.forename: Nazzareno
authors.initials: N
authors.lastname: Capitanio
authors.forename: Rosanna
authors.initials: R
authors.lastname: Tamborra
authors.forename: Antonino Davide
authors.initials: AD
authors.lastname: Romano
authors.forename: Maurizio
authors.initials: M
authors.lastname: Quinto
authors.forename: Maria
authors.initials: M
authors.lastname: Blonda
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Vendemiale
authors.forename: Emanuele
authors.initials: E
authors.lastname: Altomare
mesh_terms: D000638:Amiodarone / Q000008:administration & dosage* / Q000031:analogs & derivatives; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology*; D000077764:Dronedarone; D006861:Hydrogen Peroxide / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D010743:Phospholipids / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
chemical_list: D010743:Phospholipids; D006861:Hydrogen Peroxide; D000077764:Dronedarone; D000638:Amiodarone