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Zulian, Alessandra (2008) Assessing the molecular basis for rat-selective induction of the mitochondrial permeability transition by norbormide. [Ph.D. thesis]

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Abstract (english)

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.


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EPrint type:Ph.D. thesis
Tutor:Bova, Sergio
Supervisor:Ricchelli, Fernanda
Ph.D. course:Ciclo 20 > Corsi per il 20simo ciclo > FARMACOLOGIA MOLECOLARE E CELLULARE
Data di deposito della tesi:2008
Anno di Pubblicazione:2008
Key Words:mitochondria , norbormide, permeability transition
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/14 Farmacologia
Struttura di riferimento:Dipartimenti > pre 2012 - Dipartimento di Farmacologia ed Anestesiologia "E. Meneghetti"
Codice ID:390
Depositato il:17 Oct 2008
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