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A small dose of toxicology : role of mitochondrial dysfunction in hepatic and skeletal muscle toxicity

Kaufmann, Priska M.. A small dose of toxicology : role of mitochondrial dysfunction in hepatic and skeletal muscle toxicity. 2005, PhD Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_7162

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Abstract

Research over the last decade has extended the prevailing view of mitochondrial function well
beyond its critical bioenergetic role in supplying ATP. Recently, it has been recognized that
mitochondria play a critical role in cell regulatory and signaling events, in the responses of cells to drug
effects, genetic stresses and cell death. Based on this, four studies were conducted in order to gain
more insight into several aspects of mitochondrial toxicity of drugs, consequences of mitochondrial
dysfunction and role of mitochondria in cell death induction.
Project 1 (Chapter 7) aimed to investigate the mechanisms leading to liver steatosis in rats
treated with trimethylhydraziniumpropionate, an inhibitor of butyrobetaine hydroxylase. Rats were
treated with trimethylhydraziniumpropionate for three or six weeks and were studied after 24h of
starvation. Beside the mechanisms leading to liver steatosis, we also investigated adaptive changes
secondary to a decrease in the hepatic carnitine pool and to impaired in vivo mitochondrial β-
oxidation. Our studies demonstrate that hepatic carnitine deficiency is the most important cause for
liver steatosis in trimethylhydraziniumpropionate-treated rats and suggest that reduced mitochondrial
fatty acid oxidation may be partially compensated by increased peroxisomal fatty acid metabolism due
to proliferation of peroxisomes.
Project 2 (Chapter 8) describes a study about hepatic toxicity of benzarone and
benzbromarone having its source in clinical findings. Both drugs have similar structural features like
amiodarone, a well-known mitochondrial toxin. Liver toxicity of benzarone and benzbromarone and of
the two analogues benzofuran and 2-butylbenzofuran was therefore investigated using freshly isolated
rat hepatocytes or freshly isolated rat liver mitochondria. In particular, we were interested in
mitochondrial mechanisms leading to cell damage or even death. We also investigated the structuretoxicity
relationship by including the molecular analogues benzofuran and 2-butylbenzofuran along
with amiodarone, benzarone and benzbromarone in our studies. We could show that benzarone,
benzbromarone as well as amiodarone are toxic to liver cells and liver mitochondria. The side chain at
position 2 enhances the toxic potential to some extent but does not fully explain it. Bromide atoms in
the p-hydroxybenzene moiety are not essential for the toxicity of these compounds but clearly
enhance the toxic potential. The benzofuran structure alone was not responsible for the toxic effects.
Hepatic injury associated with the ingestion of these drugs can be explained by mitochondrial damage
with subsequent induction of cell death.
Myotoxicity, rhabdomyolysis in particular, is a rare but severe adverse drug reaction of statins.
The aim of project 3 (Chapter 9) was to evaluate the mitochondrial toxicity of five different statins and
to assess their role in cell death induction in skeletal muscle cells. Lipophilic statins reduced cell
viability and impaired mitochondrial functions, such as β-oxidation and respiratory chain, which are
essential for cell survival. As a consequence, the mitochondrial membrane potential dissipated, the
mitochondrial permeability transition pore opened and apoptosis inducing factors were released.
Mitochondrial dysfunction and the subsequent release of mitochondrial proteins are tightly linked to
the process of programmed cell death, also called apoptosis. Consistently, induction of apoptosis
could be convincingly demonstrated, since lipophilic statins did cause DNA fragmentation and an
increase in annexin V stained cells. Myotoxicity, a known side effect after treatment with statins, in
particular rhabdomyolysis in response to lipophilic statin treatment can be explained at least in part by
mitochondrial toxicity and the subsequent induction of apoptosis of myocytes.
Project 4 (Chapter 10) was dealing with a putative drug-drug interaction. The aim of the study
was to investigate the mechanisms by which venoocclusive disease was provoked in a patient, who
was treated with immunodepressive doses of cyclophosphamide and roxithromycin. We therefore
determined first the effect of roxithromycin on the metabolism of cyclophosphamide in vitro.
Furthermore, by the use of cultured human umbilical endothelial cells, we could confirm the toxicity of
the cyclophosphamide/roxithromycin combination and were able to investigate the underlying
mechanisms of cell death induction. Roxithromycin causes an overall inhibition of hepatocyte
cyclophosphamide metabolism and inhibition of P-glycoprotein, leading to an accumulation of
cyclophosphamide in hepatocytes and possibly also endothelial cells. Apoptosis is the principle
mechanism of toxicity of cyclophosphamide in endothelial cells, most probably associated with
activation of the mitochondrial pathway of initiation of apoptosis.
Advisors:Krähenbühl, Stephan
Committee Members:Drewe, Jürgen
Faculties and Departments:05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Pharmazie > Pharmakologie (Krähenbühl)
Item Type:Thesis
Thesis no:7162
Bibsysno:Link to catalogue
Number of Pages:161
Language:English
Identification Number:
Last Modified:30 Jun 2016 10:41
Deposited On:13 Feb 2009 15:18

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