Assessing the molecular basis for rat-selective induction of the mitochondrial permeability transition by norbormide

Biochimica Et Biophysica Acta
Alessandra ZulianFernanda Ricchelli


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, an...Continue Reading


Aug 1, 1986·Journal of Biochemical and Biophysical Methods·T C Tomov
Jul 1, 1966·Journal of Medicinal Chemistry·G I PoosA P Roszkowski
May 8, 2004·Acta Crystallographica. Section C, Crystal Structure Communications·Peter J SteelDavid Rennison
Jun 15, 2005·Biochimica Et Biophysica Acta·Fernanda RicchelliSergio Bova
May 3, 2006·The FEBS Journal·Paolo BernardiMichael A Forte
Feb 27, 2007·Bioorganic & Medicinal Chemistry·David RennisonMargaret A Brimble

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