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: Andrea Felser, Andrea Stoller, Réjane Morand, Dominik Schnell, Massimiliano Donzelli, Luigi Terracciano, Jamal Bouitbir, Stephan Krähenbühl
• Journal: Toxicology (Toxicology) Vol. 323 Pg. 1-9 (Sep 02 2014) ISSN: 1879-3185 [Electronic] Ireland
• PMID: 24881592 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Anti-Arrhythmia Agents
• Bax protein, mouse
• Fatty Acids
• Proto-Oncogene Proteins c-bcl-2
• RNA, Messenger
• bcl-2-Associated X Protein
• Palmitoylcarnitine
• Palmitic Acid
• Alanine Transaminase
• Dronedarone
• Amiodarone

Topics

• Alanine Transaminase (blood)
• Amiodarone (analogs & derivatives, toxicity)
• Animals
• Anti-Arrhythmia Agents (toxicity)
• Disease Models, Animal
• Dronedarone
• Fatty Acids (metabolism)
• Fatty Liver
• Liver (anatomy & histology, drug effects, metabolism)
• Male
• Membrane Potential, Mitochondrial
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Mitochondria, Liver (drug effects, physiology)
• Oxidation-Reduction
• Oxygen Consumption
• Palmitic Acid (pharmacology)
• Palmitoylcarnitine (pharmacology)
• Proto-Oncogene Proteins c-bcl-2 (genetics)
• RNA, Messenger (metabolism)
• bcl-2-Associated X Protein (genetics)