On the mechanisms of phenothiazine-induced mitochondrial permeability transition: Thiol oxidation, strict Ca2+ dependence, and cyt c release

Página do item simplificado
dc.contributor.authorCruz, Thiago S.
dc.contributor.authorFaria, Priscila A.
dc.contributor.authorSantana, Debora P.
dc.contributor.authorFerreira, Juliana C. [UNIFESP]
dc.contributor.authorOliveira, Vitor [UNIFESP]
dc.contributor.authorNascimento, Otaciro R.
dc.contributor.authorCerchiaro, Giselle
dc.contributor.authorCurti, Carlos
dc.contributor.authorNantes, Iseli L.
dc.contributor.authorRodrigues, Tiago
dc.contributor.institutionUMC
dc.contributor.institutionUniversidade Federal do ABC (UFABC)
dc.contributor.institutionUniversidade Federal de São Paulo (UNIFESP)
dc.contributor.institutionUniversidade de São Paulo (USP)
dc.date.accessioned2016-01-24T14:05:34Z
dc.date.available2016-01-24T14:05:34Z
dc.date.issued2010-10-15
dc.description.abstractPhenothiazines (PTZ) are drugs widely used in the treatment of schizophrenia. Trifluoperazine, a piperazinic PTZ derivative, has been described as inhibitor of the mitochondrial permeability transition (MPT). We reported previously the antioxidant activity of thioridazine at relatively low concentrations associated to the inhibition of the MPT (Brit. J. Pharmacol., 2002;136:136-142). in this study, it was investigated the induction of MPT by PTZ derivatives at concentrations higher than 10 mu M focusing on the molecular mechanism involved. PTZ promoted a dose-response mitochondrial swelling accompanied by mitochondrial transmembrane potential dissipation and calcium release, being thioridazine the most potent derivative. PTZ-induced MPT was partially inhibited by CsA or Mg2+ and completely abolished by the abstraction of calcium. the oxidation of reduced thiol group of mitochondrial membrane proteins by PTZ was upstream the VIP opening and it was not sufficient to promote the opening of PTP that only occurred when calcium was present in the mitochondrial matrix. EPR experiments using DMPO as spin trapping excluded the participation of reactive oxygen species on the PTZ-induced MPT. Since 117 give rise to cation radicals chemically by the action of peroxidases and cyanide inhibited the PTZ-induced swelling, we propose that VIZ bury in the inner mitochondrial membrane and the chemically generated 117 cation radicals modify specific thiol groups that in the presence of Ca2+ result in MPT associated to cytochrome c release. These findings contribute for the understanding of mechanisms of MET induction and may have implications for the cell death induced by PTZ. (C) 2010 Elsevier Inc. All rights reserved.en
dc.description.affiliationUMC, Ctr Interdisciplinar Invest Bioquim, Mogi Das Cruzes, SP, Brazil
dc.description.affiliationUniv Fed ABC, Ctr Ciencias Nat & Humanas, BR-09210170 Santo Andre, SP, Brazil
dc.description.affiliationUniversidade Federal de São Paulo, Dept Biofis, São Paulo, SP, Brazil
dc.description.affiliationUniv São Paulo, Inst Fis Sao Carlos, BR-14049 Ribeirao Preto, SP, Brazil
dc.description.affiliationUniv São Paulo, Fac Ciencias Farmaceut Ribeirao Preto, BR-14049 Ribeirao Preto, SP, Brazil
dc.description.affiliationUnifespUniversidade Federal de São Paulo, Dept Biofis, São Paulo, SP, Brazil
dc.description.sourceWeb of Science
dc.description.sponsorshipFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
dc.description.sponsorshipIDFAPESP: 2006/00995-9
dc.description.sponsorshipIDFAPESP: 2008/01724-4
dc.format.extent1284-1295
dc.identifierhttp://dx.doi.org/10.1016/j.bcp.2010.06.052
dc.identifier.citationBiochemical Pharmacology. Oxford: Pergamon-Elsevier B.V., v. 80, n. 8, p. 1284-1295, 2010.
dc.identifier.doi10.1016/j.bcp.2010.06.052
dc.identifier.issn0006-2952
dc.identifier.urihttp://repositorio.unifesp.br/handle/11600/32991
dc.identifier.wosWOS:000281936800019
dc.language.isoeng
dc.publisherElsevier B.V.
dc.relation.ispartofBiochemical Pharmacology
dc.rightsinfo:eu-repo/semantics/restrictedAccess
dc.rights.licensehttp://www.elsevier.com/about/open-access/open-access-policies/article-posting-policy
dc.subjectPhenothiazinesen
dc.subjectCation radicalsen
dc.subjectThiol oxidationen
dc.subjectCalcium dependenceen
dc.subjectMitochondrial permeability transitionen
dc.subjectHepatotoxicityen
dc.titleOn the mechanisms of phenothiazine-induced mitochondrial permeability transition: Thiol oxidation, strict Ca2+ dependence, and cyt c releaseen
dc.typeinfo:eu-repo/semantics/article
Arquivos
Coleções
EPM - Artigos