title: Dual effect of ebselen on mitochondrial permeability transition.
abstract: This study reports an investigation on the effect of the seleno-organic compound ebselen on rat liver mitochondria. We show that low concentrations of ebselen induced an increase in rat liver mitochondrial membrane permeability, resulting in swelling and loss of membrane potential. These effects were mediated by the opening of the permeability transition pore. They required Ca(2+), were independent of pyridine nucleotide oxidation, and involved the oxidation of thiol groups. Ebselen pore induction is apparently promoted by the glutathione peroxidase mimicking activity of the drug. Opposite effects, that is, inhibition of both pore opening and thiol oxidation, were observed when concentrations higher than 20 micro M were used. These data demonstrate that ebselen is able to modulate the opening of the permeability transition pore and that it might be a critical event for both the proapoptotic and cytoprotective activities of the drug.
authors.affiliation: Laboratoire de Pharmacologie, Faculté de Médecine, Créteil, France. morin@univ-paris12.fr
authors.forename: Didier
authors.initials: D
authors.lastname: Morin
authors.forename: Roland
authors.initials: R
authors.lastname: Zini
authors.forename: Heidi
authors.initials: H
authors.lastname: Ligeret
authors.forename: Wendi
authors.initials: W
authors.lastname: Neckameyer
authors.forename: Serge
authors.initials: S
authors.lastname: Labidalle
authors.forename: Jean Paul
authors.initials: JP
authors.lastname: Tillement
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001393:Azoles / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D007425:Intracellular Membranes / Q000187:drug effects* / Q000502:physiology; D054833:Isoindoles; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008665:Metalloporphyrins / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D008933:Mitochondrial Swelling / Q000187:drug effects*; D009249:NADP / Q000378:metabolism; D016566:Organoselenium Compounds / Q000494:pharmacology*; D010084:Oxidation-Reduction; D010539:Permeability / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D013438:Sulfhydryl Compounds / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D001393:Azoles; D054833:Isoindoles; D008665:Metalloporphyrins; D016566:Organoselenium Compounds; D013438:Sulfhydryl Compounds; C107919:platinum meso-tetra(4-caroboxyphenyl)porphine; C042986:ebselen; D009249:NADP; D002118:Calcium