Difference between revisions of "Felser 2014 Toxicology I"
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{{Publication | {{Publication | ||
|title=Felser A, Stoller A, Morand R, Schnell D, Donzelli M, Terracciano L, Bouitbir J, Krähenbühl S (2014) Hepatic toxicity of dronedarone in mice: role of mitochondrial β-oxidation. Toxicology 323:1-9. | |title=Felser A, Stoller A, Morand R, Schnell D, Donzelli M, Terracciano L, Bouitbir J, Krähenbühl S (2014) Hepatic toxicity of dronedarone in mice: role of mitochondrial β-oxidation. Toxicology 323:1-9. | ||
|info=[http://www.ncbi.nlm.nih.gov/pubmed/24881592 PMID: 24881592] | |info=[http://www.ncbi.nlm.nih.gov/pubmed/24881592 PMID: 24881592] | ||
|authors=Felser A, Stoller A, Morand R, Schnell D, Donzelli M, Terracciano L, Bouitbir J, Kraehenbuehl S | |authors=Felser A, Stoller A, Morand R, Schnell D, Donzelli M, Terracciano L, Bouitbir J, Kraehenbuehl S | ||
|year=2014 | |year=2014 | ||
|journal=Toxicology | |journal=Toxicology | ||
|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. | |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. | ||
|keywords=Carnitine palmitoyltransferase 1a, Dronedarone, Juvenile visceral steatosis mice, Mitochondria, β-oxidation | |keywords=Carnitine palmitoyltransferase 1a, Dronedarone, Juvenile visceral steatosis mice, Mitochondria, β-oxidation | ||
|mipnetlab=CH Basel Kraehenbuehl S | |mipnetlab=CH Basel Kraehenbuehl S | ||
}} | }} | ||
{{Labeling | {{Labeling | ||
|area=Respiration, Pharmacology;toxicology | |area=Respiration, Genetic knockout;overexpression, Pharmacology;toxicology | ||
|organism=Mouse | |organism=Mouse | ||
|tissues=Liver | |tissues=Liver | ||
|preparations=Isolated mitochondria | |preparations=Isolated mitochondria | ||
|couplingstates=LEAK, OXPHOS | |couplingstates=LEAK, OXPHOS | ||
|substratestates=CI, CII | |substratestates=CI, CII | ||
|instruments=Oxygraph-2k, TPP | |instruments=Oxygraph-2k, TPP | ||
}} | }} | ||
Revision as of 12:59, 15 December 2015
| Felser A, Stoller A, Morand R, Schnell D, Donzelli M, Terracciano L, Bouitbir J, Krähenbühl S (2014) Hepatic toxicity of dronedarone in mice: role of mitochondrial β-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 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. • Keywords: Carnitine palmitoyltransferase 1a, Dronedarone, Juvenile visceral steatosis mice, Mitochondria, β-oxidation
• 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
HRR: Oxygraph-2k, TPP
