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

Author(s)

Cruz, Thiago S. ^[1] ; Faria, Priscila A. ^{[2, 1]} ; Santana, Debora P. ^[1] ; Ferreira, Juliana C. ^[3] ; Oliveira, Vitor ^[3] ; Nascimento, Otaciro R. ^[4] ; Cerchiaro, Giselle ^[2] ; Curti, Carlos ^[5] ; Nantes, Iseli L. ^{[2, 1]} ; Rodrigues, Tiago ^{[2, 1]}

Affiliation

^[1] UMC, Ctr Interdisciplinar Invest Bioquim, Mogi Das Cruzes, SP - Brazil

^[2] Univ Fed ABC, Ctr Ciencias Nat & Humanas, BR-09210170 Santo Andre, SP - Brazil

^[3] Univ Fed Sao Paulo, Dept Biofis, Sao Paulo, SP - Brazil

^[4] Univ Sao Paulo, Inst Fis Sao Carlos, BR-14049 Ribeirao Preto, SP - Brazil

^[5] Univ Sao Paulo, Fac Ciencias Farmaceut Ribeirao Preto, BR-14049 Ribeirao Preto, SP - Brazil

• Document type: Journal article
• Source: Biochemical Pharmacology; v. 80, n. 8, p. 1284-1295, OCT 15 2010.
• Web of Science Citations: 25

Abstract

Phenothiazines (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 Mg(2+) 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 Ca(2+) 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. (AU)

• FAPESP's process: 08/01724-4 - Characterization of the Antioxidant Properties of Plant Extracts against the Oxidative Stress in Isolated Mitochondria and Cultured Cells
• Grantee: Tiago Rodrigues
• Support Opportunities: Regular Research Grants
• FAPESP's process: 06/00995-9 - Characterization of the antitumoral properties of excited and ground state phenothiazines by focusing their action on mitochondria, lysosomes and biological membranes
• Grantee: Tiago Rodrigues
• Support Opportunities: Regular Research Grants