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

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 microM 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 PTP 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 PTZ give rise to cation radicals chemically by the action of peroxidases and cyanide inhibited the PTZ-induced swelling, we propose that PTZ bury in the inner mitochondrial membrane and the chemically generated PTZ 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 MPT induction and may have implications for the cell death induced by PTZ.

journal_name

Biochem Pharmacol

journal_title

Biochemical pharmacology

authors

Cruz TS,Faria PA,Santana DP,Ferreira JC,Oliveira V,Nascimento OR,Cerchiaro G,Curti C,Nantes IL,Rodrigues T

doi

10.1016/j.bcp.2010.06.052

subject

Has Abstract

pub_date

2010-10-15 00:00:00

pages

1284-95

issue

eissn

0006-2952

issn

1873-2968

pii

S0006-2952(10)00486-7

journal_volume

pub_type

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