title: Mechanisms of hepatocellular toxicity associated with dronedarone--a comparison to amiodarone.
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 50 µM, respectively. The cellular ATP content started to decrease at 20 µM for both drugs, suggesting mitochondrial toxicity. Inhibition of the respiratory chain required concentrations of ~10 µM 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 β-oxidation at 10 µM and amiodarone at 20 µM. Similar to amiodarone, dronedarone is an uncoupler and an inhibitor of the mitochondrial respiratory chain and of β-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.
authors.affiliation: Department of Clinical Pharmacology & Toxicology, University Hospital, 4031 Basel, Switzerland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Felser
authors.forename: Kim
authors.initials: K
authors.lastname: Blum
authors.forename: Peter W
authors.initials: PW
authors.lastname: Lindinger
authors.forename: Jamal
authors.initials: J
authors.lastname: Bouitbir
authors.forename: Stephan
authors.initials: S
authors.lastname: Krähenbühl
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000638:Amiodarone / Q000031:analogs & derivatives* / Q000633:toxicity*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000633:toxicity*; D001483:Base Sequence; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000378:metabolism; D017931:DNA Primers; D000077764:Dronedarone; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D010084:Oxidation-Reduction; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D000889:Anti-Arrhythmia Agents; D017931:DNA Primers; D000255:Adenosine Triphosphate; D045304:Cytochromes c; D053148:Caspase 3; D053179:Caspase 7; D000077764:Dronedarone; D000638:Amiodarone