Hepatic toxicity of dronedarone in mice: role of mitochondrial β-oxidation.

Toxicology (2014-06-03)
Andrea Felser, Andrea Stoller, Réjane Morand, Dominik Schnell, Massimiliano Donzelli, Luigi Terracciano, Jamal Bouitbir, Stephan Krähenbühl
RESUMEN

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.

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Sigma-Aldrich
Palmitic acid, ≥99%
Sigma-Aldrich
Palmitic acid, BioXtra, ≥99%
Supelco
Palmitic acid, analytical standard
Supelco
Palmitic acid, Pharmaceutical Secondary Standard; Certified Reference Material
Sigma-Aldrich
Palmitic acid, ≥95%, FCC, FG
Sigma-Aldrich
Palmitic acid, ≥98% palmitic acid basis (GC)
USP
Palmitic acid, United States Pharmacopeia (USP) Reference Standard
Palmitic acid, European Pharmacopoeia (EP) Reference Standard
Sigma-Aldrich
Palmitic acid, natural, 98%, FG
Supelco
Palmitic acid, certified reference material, TraceCERT®

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