Felser 2013 Toxicol Sci: Difference between revisions
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{{Publication | {{Publication | ||
|title=Felser A, Blum K, Lindinger PW, Bouitbir J, Kraehenbuehl S (2013) Mechanisms of hepatocellular toxicity associated with dronedarone - a comparison to amiodarone. Toxicol Sci 131: 480- | |title=Felser A, Blum K, Lindinger PW, Bouitbir J, Kraehenbuehl S (2013) Mechanisms of hepatocellular toxicity associated with dronedarone - a comparison to amiodarone. Toxicol Sci 131:480-90. | ||
|info=[http://www.ncbi.nlm.nih.gov/pubmed/23135547 PMID: 23135547] | |info=[http://www.ncbi.nlm.nih.gov/pubmed/23135547 PMID: 23135547] | ||
|authors=Felser A, Blum K, Lindinger PW, Bouitbir J, Kraehenbuehl S | |authors=Felser A, Blum K, Lindinger PW, Bouitbir J, Kraehenbuehl S | ||
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|organism=Human, Rat | |organism=Human, Rat | ||
|tissues=Liver | |tissues=Liver | ||
|preparations=Isolated | |preparations=Isolated mitochondria | ||
|enzymes=Complex I, Complex II; | |enzymes=Complex I, Complex II;succinate dehydrogenase | ||
|injuries=RONS | |injuries=Oxidative stress;RONS | ||
|diseases=Cancer | |diseases=Cancer | ||
|topics=Inhibitor, mt-Membrane potential, Fatty | |topics=Inhibitor, mt-Membrane potential, Fatty acid | ||
|substratestates=CI, CII, ETF | |substratestates=CI, CII, ETF | ||
|instruments=Oxygraph-2k | |instruments=Oxygraph-2k | ||
}} | }} |
Revision as of 10:34, 13 February 2015
Felser A, Blum K, Lindinger PW, Bouitbir J, Kraehenbuehl S (2013) Mechanisms of hepatocellular toxicity associated with dronedarone - a comparison to amiodarone. Toxicol Sci 131:480-90. |
Felser A, Blum K, Lindinger PW, Bouitbir J, Kraehenbuehl S (2013) Toxicol Sci
Abstract: Dronedarone is a new antiarrhythmic drug with an amiodarone-like benzofuran structure. Shortly after its introduction, dronedarone became implicated in causing severe liver injury. Amiodarone is a well-known mitochondrial toxicant. The aim of our study was to investigate mechanisms of hepatotoxicity of dronedarone in vitro and to compare them with amiodarone. We used isolated rat liver mitochondria, primary human hepatocytes, and the human hepatoma cell line HepG2, which were exposed acutely or up to 24h. After exposure of primary hepatocytes or HepG2 cells for 24h, dronedarone and amiodarone caused cytotoxicity and apoptosis starting at 20 and 50ยตM, respectively. The cellular ATP content started to decrease at 20ยตM for both drugs, suggesting mitochondrial toxicity. Inhibition of the respiratory chain required concentrations of ~10ยตM and was caused by an impairment of complexes I and II for both drugs. In parallel, mitochondrial accumulation of reactive oxygen species (ROS) was observed. In isolated rat liver mitochondria, acute treatment with dronedarone decreased the mitochondrial membrane potential, inhibited complex I, and uncoupled the respiratory chain. Furthermore, in acutely treated rat liver mitochondria and in HepG2 cells exposed for 24h, dronedarone started to inhibit mitochondrial ฮฒ-oxidation at 10ยตM and amiodarone at 20ยตM. Similar to amiodarone, dronedarone is an uncoupler and an inhibitor of the mitochondrial respiratory chain and of ฮฒ-oxidation both acutely and after exposure for 24h. Inhibition of mitochondrial function leads to accumulation of ROS and fatty acids, eventually leading to apoptosis and/or necrosis of hepatocytes. Mitochondrial toxicity may be an explanation for hepatotoxicity of dronedarone in vivo. โข Keywords: Dronedarone, Amiodarone, Hepatotoxicity, HepG2
โข O2k-Network Lab: CH_Basel_Kraehenbuehl_S
Labels: MiParea: Respiration, mt-Medicine, Pharmacology;toxicology
Pathology: Cancer
Stress:Oxidative stress;RONS
Organism: Human, Rat
Tissue;cell: Liver
Preparation: Isolated mitochondria
Enzyme: Complex I, Complex II;succinate dehydrogenase
Regulation: Inhibitor, mt-Membrane potential, Fatty acid
HRR: Oxygraph-2k