Assessing the molecular basis for rat-selective induction of the mitochondrial permeability transition by norbormide.
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.
Zulian
Alessandra
A
Department of Pharmacology and Anesthesiology/Pharmacology Division, University of Padova, Padova, Italy.
Petronilli
Valeria
V
Bova
Sergio
S
Dabbeni-Sala
Federica
F
Cargnelli
Gabriella
G
Cavalli
Maurizio
M
Rennison
David
D
Stäb
Jessica
J
Laita
Olivia
O
Lee
Dong Jun
DJ
Brimble
Margaret A
MA
Hopkins
Brian
B
Bernardi
Paolo
P
Ricchelli
Fernanda
F
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
D009636:Norbornanes; C005321:norbormide