Dual effect of ebselen on mitochondrial permeability transition.
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.
Morin
Didier
D
Laboratoire de Pharmacologie, Faculté de Médecine, Créteil, France. morin@univ-paris12.fr
Zini
Roland
R
Ligeret
Heidi
H
Neckameyer
Wendi
W
Labidalle
Serge
S
Tillement
Jean Paul
JP
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
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