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Mechanisms of hepatocellular toxicity associated with dronedarone and other mitochondrial toxicants

Felser, Andrea Debora. Mechanisms of hepatocellular toxicity associated with dronedarone and other mitochondrial toxicants. 2014, PhD Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_10779

Abstract

Idiosyncratic drug-induced liver injury is a rare toxic event that typically occurs at therapeutic doses, which are generally safe to the majority of patients. Because there are hardly any reliable preclinical in vitro or animal models available to predict this adverse reaction, it represents a substantial problem for the pharmaceutical industry and can have important consequences, such as drug withdrawals or warnings by drug agencies. Although the mechanisms are not fully understood, drug-induced mitochondrial dysfunction and reactive metabolite formation are believed to be major contributors. Severe inhibition of mitochondrial function can trigger accumulation of reactive oxygen species, microvesicular steatosis, hypoglycemia, coma, and death. It is thus important to characterize drugs for their potential interactions with mitochondrial function.
The present work consists of three projects investigating molecular mechanisms of mitochondrial dysfunction in vitro and in vivo, and is emphasizing on the new antiarrhythmic dronedarone and its structural derivatives.
The aim of the first project was to understand the molecular mechanism of dronedarone-induced hepatotoxicity in vitro, and to compare it to amiodarone, a well-known mitochondrial disruptor. We investigated acutely exposed rat liver mitochondria, and primary human hepatocytes and HepG2 cells treated for up to 24h. We performed cytotoxicity experiments, measured the capacity of the respiratory chain and fatty acid beta-oxidation, and assessed markers of hepatocyte apoptosis/necrosis. Our investigations demonstrate that similar to amiodarone, dronedarone inhibited the electron transport chain and beta-oxidation and uncoupled oxidative phosphorylation of liver mitochondria. We thus suggested that mitochondrial toxicity might explain hepatotoxicity of dronedarone in vivo.
The focus of the second project was to expand the knowledge of dronedarone-associated liver toxicity to the in vivo situation. We studied hepatotoxicity of dronedarone in wild-type and heterozygous juvenile visceral steatosis mice, a model with higher susceptibility to mitochondrial inhibitors. The animals were treated by oral gavage with two different doses of dronedarone, and mitochondrial function was assessed in vivo and ex vivo. We found that dronedarone acts as an inhibitor of mitochondrial fatty acid beta-oxidation both in vivo and ex vivo, whereas the electron transport chain was not inhibited. Furthermore, juvenile visceral steatosis mice appeared to be more sensitive to the hepatotoxic effects of dronedarone than wild-type mice. We concluded that inhibition of hepatic mitochondrial fatty acid beta-oxidation may be an important mechanism of dronedarone-associated hepatotoxicity in humans and underlying defects in hepatic beta-oxidation may represent susceptibility factors for this adverse drug reaction.
In the last project we aimed to improve our understanding of the molecular mechanisms of benzbromarone associated liver toxicity. We used HepG2 cells and performed cytotoxicity experiments, measured the capacity of the respiratory chain and fatty acid beta-oxidation. In addition, we also investigated adaptive effects on mitochondrial structure. We observed that benzbromarone was associated with uncoupling of oxidative phosphorylation, inhibition of the respiratory chain and inhibition of mitochondrial beta-oxidation. Furthermore we found that benzbromarone induced profound changes in mitochondrial network, which may be associated with hepatocyte apoptosis.
Advisors:Krähenbühl, Stephan
Committee Members:Huwyler, Jörg
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Clinical Pharmacology (Krähenbühl)
Item Type:Thesis
Thesis no:10779
Bibsysno:Link to catalogue
Number of Pages:125 p.
Language:English
Identification Number:
Last Modified:30 Jun 2016 10:55
Deposited On:23 May 2014 12:17

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