Investigation of drug-induced mitochondrial toxicity using fluorescence-based oxygen-sensitive probes

Toxicological Sciences : an Official Journal of the Society of Toxicology
James HynesYvonne Will

Abstract

Mitochondrial dysfunction is a common mechanism of drug-induced toxicity. Early identification of new chemical entities (NCEs) that perturb mitochondrial function is of significant importance to avoid attrition in later stages of drug development. One of the most informative ways of assessing mitochondrial dysfunction is by measuring mitochondrial oxygen consumption. However, the conventional polarographic method of measuring oxygen consumption is not amenable to high sample throughput or automation. We present an alternative, low-bulk, high-throughput approach to the analysis of isolated-mitochondrial oxygen consumption using luminescent oxygen-sensitive probes. These probes are dispensable and are analyzed in standard microtitre plates on a fluorescence plate reader. Respiratory substrate and adenosine diphosphate (ADP) dependencies of mitochondrial oxygen consumption were assessed using the fluorescence-based method, and results compared favourably to conventional polarographic analysis. To assess assay performance, the method was then applied to the analysis of a panel of classical modulators of oxidative phosphorylation. The effect of uncoupler concentration was analyzed in detail to identify factors which would be importa...Continue Reading

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Citations

Jan 18, 2012·Cellular and Molecular Life Sciences : CMLS·Ruslan I Dmitriev, Dmitri B Papkovsky
Mar 18, 2008·Toxicological Sciences : an Official Journal of the Society of Toxicology·James A DykensYvonne Will
Apr 7, 2010·Molecular Interventions·Dean P JonesNeil Kaplowitz
Nov 27, 2008·American Journal of Physiology. Gastrointestinal and Liver Physiology·Thorsten EismannAlex B Lentsch
Jan 15, 2013·BMC Research Notes·Ahmed R AlsuwaidiAbdul-Kader Souid
Aug 29, 2014·Toxicological Sciences : an Official Journal of the Society of Toxicology·Nianyu LiPadma Kumar Narayanan
Apr 4, 2012·Expert Opinion on Drug Discovery·Craig E Thomas, Yvonne Will
Jul 16, 2014·Expert Opinion on Drug Metabolism & Toxicology·Yvonne Will, James Dykens
Jan 21, 2012·Toxicology in Vitro : an International Journal Published in Association with BIBRA·Willem G E J SchoonenG Jean Horbach
Jan 7, 2016·Chemical Research in Toxicology·Richard A ThompsonDominic P Williams
Jul 27, 2010·Toxicology in Vitro : an International Journal Published in Association with BIBRA·María José Gómez-LechónMaría Teresa Donato
May 12, 2009·Toxicology in Vitro : an International Journal Published in Association with BIBRA·Simone BeckersElmar Heinzle
Jul 11, 2013·Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism·Ai-Ling LinVeronica Galvan
Oct 28, 2008·Analytical Biochemistry·Anabela P RoloGino A Cortopassi
Oct 23, 2008·Toxicology in Vitro : an International Journal Published in Association with BIBRA·Hui ZhangSheng-Yong Yang
Sep 11, 2007·Drug Discovery Today·James A Dykens, Yvonne Will
Mar 10, 2007·Toxicology in Vitro : an International Journal Published in Association with BIBRA·Sashi NadanacivaYvonne Will
Apr 30, 2014·Journal of Applied Toxicology : JAT·Varun Ahuja, Sharad Sharma
Apr 2, 2016·Journal of Molecular Neuroscience : MN·Cécile MonpaysSylvain Grignon
Jul 25, 2015·Toxicological Sciences : an Official Journal of the Society of Toxicology·Falgun ShahMichael D Aleo
Apr 17, 2016·Toxicology in Vitro : an International Journal Published in Association with BIBRA·Julie EakinsPaul Walker
Dec 1, 2010·Journal of Neuroscience Methods·Fiachra B BolgerJohn P Lowry
Sep 22, 2009·Analytical Biochemistry·Caroline DiepartBernard Gallez
Jun 7, 2013·Toxicology Mechanisms and Methods·Mohammed T AlsamriAbdul-Kader Souid
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Apr 22, 2014·Toxicology in Vitro : an International Journal Published in Association with BIBRA·Sandra M A SantosAmália S Jurado
Jun 4, 2013·Toxicology in Vitro : an International Journal Published in Association with BIBRA·Rachel SwissYvonne Will
Nov 14, 2012·Toxicology in Vitro : an International Journal Published in Association with BIBRA·James HynesYvonne Will
Jul 3, 2013·Toxicology and Applied Pharmacology·Lauren P WillsRick G Schnellmann
Mar 3, 2012·Analytical Chemistry·Ruslan I DmitrievDmitri B Papkovsky
Oct 25, 2016·Biochimica Et Biophysica Acta·Otília MenyhártBalázs Győrffy
Oct 19, 2013·Toxicological Sciences : an Official Journal of the Society of Toxicology·Daphna LaifenfeldMichael Lawton

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