Felser 2014 Toxicology I
| Felser A, Stoller A, Morand R, Schnell D, Donzelli M, Terracciano L, Bouitbir J, KrΓ€henbΓΌhl S (2014) Hepatic toxicity of dronedarone in mice: role of mitochondrial Ξ²-oxidation. Toxicology 323:1-9. |
Felser A, Stoller A, Morand R, Schnell D, Donzelli M, Terracciano L, Bouitbir J, Kraehenbuehl S (2014) Toxicology
Abstract: Dronedarone is an amiodarone-like antiarrhythmic drug associated with severe liver injury. Since dronedarone inhibits mitochondrial respiration and Ξ²-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 Ξ²-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 Ξ²-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 Ξ²-oxidation in and ex vivo, but not the respiratory chain. Jvs(+/-) mice are slightly more sensitive for the effect of dronedarone on mitochondrial Ξ²-oxidation than wild-type mice. The results suggest that inhibition of mitochondrial Ξ²-oxidation is an important mechanism of hepatotoxicity associated with dronedarone. β’ Keywords: Carnitine palmitoyltransferase 1a, Dronedarone, Juvenile visceral steatosis mice, Mitochondria, Ξ²-oxidation
β’ O2k-Network Lab: CH Basel Kraehenbuehl S
Labels: MiParea: Respiration, Genetic knockout;overexpression, Pharmacology;toxicology
Organism: Mouse
Tissue;cell: Liver
Preparation: Isolated mitochondria
Coupling state: LEAK, OXPHOS
Pathway: N, S
HRR: Oxygraph-2k, TPP
