Assessing the Molecular Basis for Rat-Selective Induction of the Mitochondrial Permeability Transition by Norbormide

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Show simple item record Zulian, A en Petronilli, V en Bova, S en Dabbeni-Sala, F en Cargnelli, G en Cavalli, M en Rennison, David en Stäb, J en Laita, Olivia en Lee, Danny en Brimble, Margaret en Hopkins, Brian en Bernardi, P en Ricchelli, F en 2011-09-19T01:40:46Z en 2007 en
dc.identifier.citation Biochim Biophys Acta 1767(7):980-988 Jul 2007 en
dc.identifier.issn 0005-2728 en
dc.identifier.uri en
dc.description.abstract It was recently demonstrated that the rat-selective toxicant norbormide also induces rat-selective opening of the permeability transition pore (PTP) in isolated mitochondria. Norbormide is a mixture of endo and exo stereoisomers; however, only the endo forms are lethal to rats. In the present study we tested both endo and exo isomers as well as neutral and cationic derivatives of norbormide to: (i) verify if the PTP-regulatory activity by norbormide is stereospecific; (ii) define the structural features of norbormide responsible for PTP-activation, (iii) elucidate the basis for the drug species-specificity. Our results show that: (i) norbormide isomers affect PTP in a rat-selective fashion; however, no relevant differences between lethal and non-lethal forms are observed suggesting that drug regulation of PTP-activity and lethality in rats are unrelated phenomena; (ii) a (phenylvinyl)pyridine moiety represents the key element conferring the PTP-activating effect; (iii) cationic derivatives of rat-active compounds accumulate in the matrix via the membrane potential and activate the PTP also in mouse and guinea pig mitochondria. These findings suggest that the norbormide-sensitive PTP-target is present in all species examined, and is presumably located on the matrix side. The species-selectivity may depend on the unique properties of a transport system allowing drug internalisation in rat mitochondria. en
dc.language EN en
dc.publisher Elsevier B.V. en
dc.relation.ispartofseries Biochimica et Biophysica Acta-Bioenergetics en
dc.rights Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. Details obtained from en
dc.rights.uri en
dc.subject norbormide en
dc.subject rat-toxicant en
dc.subject mitochondria en
dc.subject permeability transition en
dc.subject species-specificity en
dc.subject BLOCKING en
dc.title Assessing the Molecular Basis for Rat-Selective Induction of the Mitochondrial Permeability Transition by Norbormide en
dc.type Journal Article en
dc.identifier.doi 10.1016/j.bbabio.2007.04.002 en
pubs.issue 7 en
pubs.begin-page 980 en
pubs.volume 1767 en
dc.rights.holder Copyright: 2007 Elsevier B.V. en
dc.identifier.pmid 17509521 en
pubs.end-page 988 en
dc.rights.accessrights en
pubs.subtype Article en
pubs.elements-id 74188 en Science en Chemistry en Science Research en Maurice Wilkins Centre (2010-2014) en
pubs.record-created-at-source-date 2010-09-01 en
pubs.dimensions-id 17509521 en

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