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Phisical and photochemical effects of phenothiazines on membrane models and mitochondrial membranes

Grant number: 07/07287-2
Support Opportunities:Scholarships in Brazil - Scientific Initiation
Effective date (Start): February 01, 2008
Effective date (End): January 31, 2010
Field of knowledge:Biological Sciences - Biophysics - Radiology and Photobiology
Principal Investigator:Iseli Lourenço Nantes Cardoso
Grantee:Marcelo Buscariolli Domingues Borges
Host Institution: Pró-Reitoria de Pesquisa, Pós-Graduação e Extensão e Assuntos Comunitários. Universidade de Mogi das Cruzes (UMC). Mogi das Cruzes , SP, Brazil


Phenothiazines are drugs used in the treatment of psichoses such as squizophrenia. The photochemical effects of these drugs became interesting after reports about photosensitization in pacients under treatment with phenothiazines. Literature data have also demonstrated pro-apoptótic effects of phenothiazines in cells of tumoral lineage that points the possibility to use such drugs in the cancer treatment. Studies published by our research group characterized the photochemical behavior of thioridazine (TR), fluphenazine (FP) e trifluorperazine (TFP) modulated by the aggregation state of these drugs as well as the prooxidant effects on mitochondrial membranes exhibited by the photochemically-generated cation radical derived from phenothiazines. In the absence of membranes, it has been observed that the cation radical is stabilized in the phenothiazine aggregates and can even protect cytochrome c against the deleterious effects of UV irradiation. In the present project, we intend to characterize, systematically the photochemical behavior of the thiazinic nucleous (PH) in comparison with TR, FP and TFP in membrane models (liposomos with different compositions) and in mitochondrial membranes. The use of liposomes in this study will give support for the compreension of the effects of the phenothiazine cation radical on membrane lipids as well as for the use of liposomes as phenothiaze carriers. The photochemical characterization will encompass: i) titration of liposomal and mitochondrial membranes with phenothiazines to verify possible spectral changes suggesting aggregation and microenvironment changes; ii) in liposomes, analisis of the absorption electronic spectra during the irradiation with UV light in different drug concentrations as determined before; iii) photoproduct analysis by FTIR and mass spectrometry; iv) in liposomes containing unsaturated lipids and in mitochondrial membranes, characterization of the lipid oxidation products (aldehydes reactive with thiobarbituric acid and lipid peroxides) formed during irradiation with UV light, in the presence and in the absence of molecular oxygen; v) EPR measurements in the presence of spin label to characterize caracterizar changes in the lipid organization and fluidity and EPR measurements at 11 Kelvin to detect the cation radical of phenothiazines in membranes.

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