title: Hepatic toxicity of dronedarone in mice: role of mitochondrial β-oxidation.
abstract: Dronedarone is an amiodarone-like antiarrhythmic drug associated with severe liver injury. Since dronedarone inhibits mitochondrial respiration and β-oxidation in vitro, mitochondrial toxicity may also explain dronedarone-associated hepatotoxicity in vivo. We therefore studied hepatotoxicity of dronedarone (200mg/kg/day for 2 weeks or 400mg/kg/day for 1 week by intragastric gavage) in heterozygous juvenile visceral steatosis (jvs(+/-)) and wild-type mice. Jvs(+/-) mice have reduced carnitine stores and are sensitive for mitochondrial β-oxidation inhibitors. Treatment with dronedarone 200mg/kg/day had no effect on body weight, serum transaminases and bilirubin, and hepatic mitochondrial function in both wild-type and jvs(+/-) mice. In contrast, dronedarone 400mg/kg/day was associated with a 10-15% drop in body weight, and a 3-5-fold increase in transaminases and bilirubin in wild-type mice and, more accentuated, in jvs(+/-) mice. In vivo metabolism of intraperitoneal (14)C-palmitate was impaired in wild-type, and, more accentuated, in jvs(+/-) mice treated with 400mg/kg/day dronedarone compared to vehicle-treated mice. Impaired β-oxidation was also found in isolated mitochondria ex vivo. A likely explanation for these findings was a reduced activity of carnitine palmitoyltransferase 1a in liver mitochondria from dronedarone-treated mice. In contrast, dronedarone did not affect the activity of the respiratory chain ex vivo. We conclude that dronedarone inhibits mitochondrial β-oxidation in and ex vivo, but not the respiratory chain. Jvs(+/-) mice are slightly more sensitive for the effect of dronedarone on mitochondrial β-oxidation than wild-type mice. The results suggest that inhibition of mitochondrial β-oxidation is an important mechanism of hepatotoxicity associated with dronedarone.
authors.affiliation: Clinical Pharmacology and Toxicology, University Hospital Basel, Switzerland; Department of Biomedicine, University of Basel, Switzerland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Felser
authors.affiliation: Clinical Pharmacology and Toxicology, University Hospital Basel, Switzerland; Department of Biomedicine, University of Basel, Switzerland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Stoller
authors.affiliation: Clinical Pharmacology and Toxicology, University Hospital Basel, Switzerland; Department of Biomedicine, University of Basel, Switzerland.
authors.forename: Réjane
authors.initials: R
authors.lastname: Morand
authors.affiliation: Clinical Pharmacology and Toxicology, University Hospital Basel, Switzerland; Department of Biomedicine, University of Basel, Switzerland.
authors.forename: Dominik
authors.initials: D
authors.lastname: Schnell
authors.affiliation: Clinical Pharmacology and Toxicology, University Hospital Basel, Switzerland; Department of Biomedicine, University of Basel, Switzerland.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Donzelli
authors.affiliation: Institute of Pathology, University Hospital Basel, Switzerland; Swiss Centre for Applied Human Toxicology (SCAHT), Switzerland.
authors.forename: Luigi
authors.initials: L
authors.lastname: Terracciano
authors.affiliation: Clinical Pharmacology and Toxicology, University Hospital Basel, Switzerland; Department of Biomedicine, University of Basel, Switzerland; Swiss Centre for Applied Human Toxicology (SCAHT), Switzerland.
authors.forename: Jamal
authors.initials: J
authors.lastname: Bouitbir
authors.affiliation: Clinical Pharmacology and Toxicology, University Hospital Basel, Switzerland; Department of Biomedicine, University of Basel, Switzerland; Swiss Centre for Applied Human Toxicology (SCAHT), Switzerland. Electronic address: stephan.kraehenbuehl@usb.ch.
authors.forename: Stephan
authors.initials: S
authors.lastname: Krähenbühl
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000638:Amiodarone / Q000031:analogs & derivatives* / Q000633:toxicity; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000633:toxicity*; D004195:Disease Models, Animal; D000077764:Dronedarone; D005227:Fatty Acids / Q000378:metabolism; D005234:Fatty Liver; D008099:Liver / Q000033:anatomy & histology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008930:Mitochondria, Liver / Q000187:drug effects / Q000502:physiology; D010084:Oxidation-Reduction; D010101:Oxygen Consumption; D019308:Palmitic Acid / Q000494:pharmacology; D010172:Palmitoylcarnitine / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000235:genetics
chemical_list: D000889:Anti-Arrhythmia Agents; C494827:Bax protein, mouse; D005227:Fatty Acids; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D051028:bcl-2-Associated X Protein; D010172:Palmitoylcarnitine; D019308:Palmitic Acid; D000410:Alanine Transaminase; D000077764:Dronedarone; D000638:Amiodarone
keywords: Carnitine palmitoyltransferase 1a; Dronedarone; Juvenile visceral steatosis mice; Mitochondria; β-oxidation