title: Assessing the molecular basis for rat-selective induction of the mitochondrial permeability transition by norbormide.
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.
authors.affiliation: Department of Pharmacology and Anesthesiology/Pharmacology Division, University of Padova, Padova, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Zulian
authors.forename: Valeria
authors.initials: V
authors.lastname: Petronilli
authors.forename: Sergio
authors.initials: S
authors.lastname: Bova
authors.forename: Federica
authors.initials: F
authors.lastname: Dabbeni-Sala
authors.forename: Gabriella
authors.initials: G
authors.lastname: Cargnelli
authors.forename: Maurizio
authors.initials: M
authors.lastname: Cavalli
authors.forename: David
authors.initials: D
authors.lastname: Rennison
authors.forename: Jessica
authors.initials: J
authors.lastname: Stäb
authors.forename: Olivia
authors.initials: O
authors.lastname: Laita
authors.forename: Dong Jun
authors.initials: DJ
authors.lastname: Lee
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Brimble
authors.forename: Brian
authors.initials: B
authors.lastname: Hopkins
authors.forename: Paolo
authors.initials: P
authors.lastname: Bernardi
authors.forename: Fernanda
authors.initials: F
authors.lastname: Ricchelli
mesh_terms: D000818:Animals; D006168:Guinea Pigs; D007536:Isomerism; D051379:Mice; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism*; D009636:Norbornanes / Q000737:chemistry / Q000633:toxicity*; D010539:Permeability / Q000187:drug effects; D051381:Rats
chemical_list: D009636:Norbornanes; C005321:norbormide