Felser 2013 Toxicol Sci

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Publications in the MiPMap
Felser A, Blum K, Lindinger PW, Bouitbir J, Kraehenbuehl S (2013) Mechanisms of hepatocellular toxicity associated with dronedarone - a comparison to amiodarone. Toxicol Sci 131:480-90.

Β» PMID: 23135547 Open Access

Felser A, Blum K, Lindinger PW, Bouitbir J, Kraehenbuehl S (2013) Toxicol Sci

Abstract: Dronedarone is a new antiarrhythmic drug with an amiodarone-like benzofuran structure. Shortly after its introduction, dronedarone became implicated in causing severe liver injury. Amiodarone is a well-known mitochondrial toxicant. The aim of our study was to investigate mechanisms of hepatotoxicity of dronedarone in vitro and to compare them with amiodarone. We used isolated rat liver mitochondria, primary human hepatocytes, and the human hepatoma cell line HepG2, which were exposed acutely or up to 24h. After exposure of primary hepatocytes or HepG2 cells for 24h, dronedarone and amiodarone caused cytotoxicity and apoptosis starting at 20 and 50Β΅M, respectively. The cellular ATP content started to decrease at 20Β΅M for both drugs, suggesting mitochondrial toxicity. Inhibition of the respiratory chain required concentrations of ~10Β΅M and was caused by an impairment of complexes I and II for both drugs. In parallel, mitochondrial accumulation of reactive oxygen species (ROS) was observed. In isolated rat liver mitochondria, acute treatment with dronedarone decreased the mitochondrial membrane potential, inhibited complex I, and uncoupled the respiratory chain. Furthermore, in acutely treated rat liver mitochondria and in HepG2 cells exposed for 24h, dronedarone started to inhibit mitochondrial Ξ²-oxidation at 10Β΅M and amiodarone at 20Β΅M. Similar to amiodarone, dronedarone is an uncoupler and an inhibitor of the mitochondrial respiratory chain and of Ξ²-oxidation both acutely and after exposure for 24h. Inhibition of mitochondrial function leads to accumulation of ROS and fatty acids, eventually leading to apoptosis and/or necrosis of hepatocytes. Mitochondrial toxicity may be an explanation for hepatotoxicity of dronedarone in vivo. β€’ Keywords: Dronedarone, Amiodarone, Hepatotoxicity, HepG2, Benzofuran derivatives, Mitochondria, Uncoupling, Electron transport chain, Apoptosis

β€’ O2k-Network Lab: CH Basel Kraehenbuehl S

Labels: MiParea: Respiration, mt-Medicine, Pharmacology;toxicology  Pathology: Cancer  Stress:Oxidative stress;RONS  Organism: Human, Rat  Tissue;cell: Liver  Preparation: Isolated mitochondria  Enzyme: Complex I, Complex II;succinate dehydrogenase  Regulation: Inhibitor, mt-Membrane potential, Fatty acid 

Pathway: F, N, S  HRR: Oxygraph-2k 

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