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Molecular mechanisms of mitochondrial toxicity of drugs

English title Molecular mechanisms of mitochondrial toxicity of drugs
Applicant Krähenbühl Stephan
Number 132992
Funding scheme Project funding
Research institution Klinische Pharmakologie und Toxikologie Universitätsspital Basel
Institution of higher education University of Basel - BS
Main discipline Pharmacology, Pharmacy
Start/End 01.10.2010 - 30.09.2013
Approved amount 300'000.00
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Keywords (5)

Mitochondria; adverse drug reactions; proteomics; metabolomics; metabolomics

Lay Summary (German)

Lead
Lay summary
LeadWir entwickeln intelligente menschliche Zellsysteme zur Untersuchung toxischer Effekte von Chemikalien an Mitochondrien. Nach dem Etablieren solcher Testsysteme validieren wir die Ergebnisse im Tiermodell. Mittels solcher Testsysteme können toxische Effekte und Mechanismen früh und schnell in menschlichem Material untersucht werden.HintergrundMitochondrien sind wichtige Ziele für die Toxizität von Arzneistoffen. Arzneistoffe können die viele Funktionen von Mitochondrien negativ beeinflussen, insbesondere die Funktion der Atmungskette, verschiedene metabolische Funktionen (z.B. Abbau von Fettsäuren und Kohlehydraten), die mitochondriale Synthese von DNA oder auch die mitochondriale Proteinsynthese. In vielen Fällen kommt es dabei zum Schwellen von Mitochondrien, was zum Untergang von Zellen durch Apoptose oder auch wegen eines Energiedefizits (Nekrose) führen kann. Die genauen Mechanismen, mit welchen die Mitochondrien durch chemische Substanzen geschädigt werden, sind nur für wenige Substanzen bekannt. Es fehlen gut validierte, einfache Zellsysteme, welche für solche Untersuchungen geeignet sind. Wir schlagen deshalb die Entwicklung intelligenter, menschlicher Zellsysteme vor, mit denen die Toxizität von Modellsubstanzen exakt untersucht werden kann. Die Ergebnisse werden in geeigneten Tiermodellen validiert, um aufzuzeigen, dass die entwickelten Systeme systemische Wirkungen voraussagen können.ZielDie molekularen Mechanismen toxischer Effekte auf Mitochondrien von ausgewählten Substanzen sollen mittels neu entwickelter humaner Zellsysteme untersucht werden. Nebst den üblichen Techniken wird auch die Analyse des mitochondrialen Proteoms angewandt. Mittels dieser Studien können auch Risikofaktoren für das Auftreten mitochondrialer Toxizität ermittelt und untersucht werden. Die toxischen Effekte werden dann in geeigneten Tiermodellen reproduziert, um die Zellsysteme zu validieren.BedeutungDie Ergebnisse werden unsere Kenntnisse über die Mechanismen erweitern, welche zu Funktionseinbussen von Mitochondrien führen und damit Auswirkung auf den Energiemetabolismus von Zellen und Organen haben. Damit können auch Risikofaktoren und Marker für das Auftreten dieser Toxizität gefunden werden, was für die Vermeidung und das Monitoring toxischer Effekte essentiell ist. Unsere Zellsysteme sollten auch für die Testung toxischer Effekte neu synthetisierter Substanzen verwendet werden können.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Effect of carnitine, acetyl-, and propionylcarnitine supplementation on the body carnitine pool, skeletal muscle composition, and physical performance in mice
Morand R Bouitbir J Felser A Hench J Handschin C Frank S Krähenbühl S. (2013), Effect of carnitine, acetyl-, and propionylcarnitine supplementation on the body carnitine pool, skeletal muscle composition, and physical performance in mice, in Eur J Nutr, Epub ahead of print, Epub ahead-Epub ahead.
Hepatic toxicity of dronedarone in mice: role of mitochondrial beta-oxidation
Felser Andrea, Stoller Andrea, Bourqui Rejane Morand, Bouitbir Jamal, Kraehenbuehl Stephan (2013), Hepatic toxicity of dronedarone in mice: role of mitochondrial beta-oxidation, in CLINICAL TOXICOLOGY, 51(4), 336-336.
Mechanisms of hepatocellular toxicity associated with dronedarone--a comparison to amiodarone.
Felser Andrea, Blum Kim, Lindinger Peter W, Bouitbir Jamal, Krähenbühl Stephan (2013), Mechanisms of hepatocellular toxicity associated with dronedarone--a comparison to amiodarone., in Toxicological sciences : an official journal of the Society of Toxicology, 131(2), 480-90.
Quantification of plasma carnitine and acylcarnitines by high-performance liquid chromatography-tandem mass spectrometry using online solid-phase extraction
Morand Rejane, Donzelli Massimiliano, Haschke Manuel, Kraehenbuehl Stephan (2013), Quantification of plasma carnitine and acylcarnitines by high-performance liquid chromatography-tandem mass spectrometry using online solid-phase extraction, in ANALYTICAL AND BIOANALYTICAL CHEMISTRY, 405(27), 8829-8836.
Toxicity of thienopyridines on human neutrophil granulocytes and lymphocytes
Maseneni Swarna, Donzelli Massimiliano, Brecht Karin, Kraehenbuehl Stephan (2013), Toxicity of thienopyridines on human neutrophil granulocytes and lymphocytes, in TOXICOLOGY, 308, 11-19.
Effect of short- and long-term treatment with valproate on carnitine homeostasis in humans.
Morand Réjane, Todesco Liliane, Donzelli Massimiliano, Fischer-Barnicol David, Mullen Peter J, Krähenbühl Stephan (2012), Effect of short- and long-term treatment with valproate on carnitine homeostasis in humans., in Therapeutic drug monitoring, 34(4), 406-14.
Toxicity of clopidogrel and ticlopidine on human myeloid progenitor cells: importance of metabolites.
Maseneni Swarna, Donzelli Massimiliano, Taegtmeyer Anne Barbara, Brecht Karin, Krähenbühl Stephan (2012), Toxicity of clopidogrel and ticlopidine on human myeloid progenitor cells: importance of metabolites., in Toxicology, 299(2-3), 139-45.

Collaboration

Group / person Country
Types of collaboration
Division of Molecular and Systems Toxicology Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure

Associated projects

Number Title Start Funding scheme
112483 Drug-drug interactions and toxicity of thienopyridine drugs 01.04.2006 Project funding
112483 Drug-drug interactions and toxicity of thienopyridine drugs 01.04.2006 Project funding
156270 Idiosyncratic drug-induced liver injury: hepatotoxicity of tyrosine kinase inhibitors and impairment of mitochondrial fatty acid metabolism 01.01.2015 Project funding

Abstract

Mitochondria are important targets for drug-associated organ toxicity. Clinically, mitochondrial toxicity most often represents as so called idiosyncratic toxicity, meaning that this type of toxicity is rare (usually not detected during drug development) and that the precise mechanisms are not known. The current concept assumes the presence of genetic and/or other risk factors rendering patients with idiosyncratic toxicity more sensitive to specific drugs.Considering the importance of mitochondria as a target for idiosyncratic toxicity, we propose A. to establish a framework allowing efficient screening of drugs for mitochondrial toxicity and B. to test the hypothesis that underlying mitochondrial diseases predispose for mitochondrial toxicity of drugs in animal models. Regarding project A, cultured cells (human cell lines, isolated human cells or cells derived from human stem cells) are used to assess cellular toxicity (by monitoring of oxygen consumption, lactate production, cellular ATP levels and cytotoxicity). If mitochondrial toxicity is detected; mitochondria are isolated from these cells and used for specific functional and biochemical assessments. In parallel, a proteomics approach is performed, involving protein separation and isolation with FPLC and gel electrophoresis and, finally, protein identification and quantification using Maldi-TOF. Most of these techniques are available in our laboratory or in laboratories at the university of Basel.Using these approaches, we plan to study first the effects of well known mitochondrial toxins (benzbromarone, hydroxy-cobalamin[c-lactam] and valproate) on mitochondria in human cell lines (HepG2 cells and HUH-7 cells). After its establishment, this technique will be suitable for the assessment of potential mitochondrial toxicity for any other compound. In project B, we propose to test two known mitochondrial toxicants, valproate and simvastatin, in animal models with known mitochondrial dysfunction, namely jvs+/- mice (mice with decreased tissue carnitine stores due to a mutation in the renal carnitine carrier OCTN2) and LCAD-/- (mice with a knock out of long-chain acyl-CoA dehydrogenase, an enzyme involved in the ß-oxidation of fatty acids). Doses of the toxicants known to be sub- or only slightly toxic for wild type mice will be administered and signs of toxicity compared between wild-type and experimental mice treated with such doses of the respective toxicant.The proposed projects will enlarge our understanding about the mechanisms involved in mitochondrial toxicity of drugs, in particular the interaction with mitochondrial proteins. We will be able to assess the consequences of toxicant exposure on the mitochondrial proteome, genome and/or metabolome, possibly leading to the identification of specific drug targets. This will lead to the detection of possible biomarkers, the construction of “intelligent” cellular systems suitable for screening for mitochondrial toxicity and to the identification of patients at risk for developing idiosyncratic toxicity.
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