title: S-15176 and its methylated derivative suppress the CsA-insensitive mitochondrial permeability transition and subsequent cytochrome c release induced by silver ion, and show weak protonophoric activity.
abstract: A recent report has described that S-15176 (N-[(3,5-di-tert-butyl-4-hydroxy-1-thiophenyl)]-3-propyl-N'-(2,3,4-trimethoxybenzyl) piperazine), an anti-ischemic agent, inhibits the mitochondrial permeability transition (PT) induced by not only Ca(2+) and inorganic phosphate, but also by tert-butylhydroperoxide or phenylarsine oxide [Morin et al. (Biochem Pharmacol 72:911-918, 2006)]. In the present study, we tested the effects of S-15176 on the PT induced by Ag(+), PT of which is not suppressed by cyclosporin A or oligomycin. S-15176 was effective in suppressing the PT and the subsequent cytochrome c release induced by Ag(+), and hence, it was concluded to be a more universal PT inhibitor than cyclosporin A or oligomycin. In addition to the PT-suppression activity, S-15176 also showed weak protonophoric activity. Thus, we further tested to investigate whether the hydroxyl group of S-15176 was involved in its PT-suppression or weak protonophoric activities. The methylated derivative of S-15176 also showed both PT suppression and weak protonophoric activities; hence, the hydroxyl group of S-15176 was concluded not to be involved in these activities.
authors.affiliation: Institute for Genome Research, University of Tokushima, Kuramotocho-3, Tokushima 770-8503, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kawashima
authors.forename: Takenori
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Yuka
authors.initials: Y
authors.lastname: Horiuchi
authors.forename: Kengo
authors.initials: K
authors.lastname: Fujiwara
authors.forename: Shunichi
authors.initials: S
authors.lastname: Gouda
authors.forename: Yuya
authors.initials: Y
authors.lastname: Yoshimura
authors.forename: Atsushi
authors.initials: A
authors.lastname: Yamamoto
authors.forename: Yuki
authors.initials: Y
authors.lastname: Inotani
authors.forename: Kikuji
authors.initials: K
authors.lastname: Yamashita
authors.forename: Seiichiro
authors.initials: S
authors.lastname: Kitamura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Terada
authors.forename: Makoto
authors.initials: M
authors.lastname: Kanematsu
authors.forename: Kozo
authors.initials: K
authors.lastname: Shishido
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Shinohara
mesh_terms: D000818:Animals; D002118:Calcium / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology*; D045304:Cytochromes c / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D007477:Ions; D008297:Male; D008745:Methylation / Q000187:drug effects; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D009391:Nephelometry and Turbidimetry; D009840:Oligomycins / Q000494:pharmacology; D010879:Piperazines / Q000378:metabolism* / Q000494:pharmacology*; D011522:Protons; D051381:Rats; D017208:Rats, Wistar; D012834:Silver / Q000494:pharmacology*
chemical_list: D007477:Ions; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D009840:Oligomycins; D010879:Piperazines; D011522:Protons; C416838:S 15176; D012834:Silver; D016572:Cyclosporine; D045304:Cytochromes c; D002118:Calcium