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Mechanisms and Efficiencies of Antioxidation Action of Ortho, Meta and Para Manganese Meso-Tetrakis Porphyrins in Biomimetic Membrane Systems and in Culture Cells

Abstract

Meso-tetrakis porphyrins have been studied because their pro and antioxidant properties, dependent on the medium, the central metal and its meso-substituents. MnTMPyP (Manganese(III)(meso-tetrakis [N-methyl-4-pyridyl])porphyrin)is a cationic porphyrin that has attracted the attention of researchers in the chemistry and biology areas because of its catalytic and antioxidant properties. These properties are correlated with the redox potential of the central metal which, in turn, is modulated by the type of porphyrin isomer (ortho, meta and para), by the pH and by association with negatively charged interfaces. We previously investigated the para MnTMPyP isomer properties in association with liposomes containing cardiolipin, phosphatidylcholine and phosphatidylserine, by experimental and theoretical work.These studies were extended to rat liver mitochondria and mitoplastos isolated that showed the antioxidant properties of the para MnTMPyP isomer, which is the less efficient isomeric form, can be improved by combination with negatively charged interfaces. This effect is due to the change in redox potential of the porphyrin which is shifted to more positive values. It was also demonstrated that the para MnTMPyP operates as an antioxidant mechanism glutathione peroxidase (GPx)-like, and thus, is more efficient in cell conditions without glutathione depletion. More recent studies submitted to Scientific Reports Journal have demonstrated the Fe3+ cytochrome c-like activity of Mn3+TMPyP and that the porphyrin anti- and pro-oxidant activity switch can be modulated by the delivery mechanism. The MnTMPyP pro-oxidant activity was demonstrated in a study of the mechanisms involved in the action of MnTMPyP in mitochondria.In this study it was discussed that the protective effect of Mn3+TMPyP against superoxide ions and peroxides is limited by GSH levels because this porphyrin acts as GPx against peroxides. Thus, in highly pro-oxidant conditions in which a significant depletion of NADPH/GSH was installed in association with the increase LOOH, Mn3+TMPyP can act as a peroxidase of peroxide lipids and contribute to oxidative stress. In this project, we intend to extend the previous studies, comparatively, to the ortho and meta MnTMPyP isomers. In this project, we also intend to invest in the determination of antioxidant and pro-oxidant mechanisms of the three MnTMPyP isomers in cell culture focused on its effects on mitochondrial bioenergetics. Therefore, rabbit aortic smooth muscle cells (SMCs) are challenged by superoxide ion generating systems such as hypoxia followed by reoxygenation in the presence and absence of these porphyrins, which will be directly delivered to cells or associated with liposomes. Thus, with the techniques of fluorescence microscopy and flow cytometry we will investigate the effects of these treatments on the mitochondrial membrane potential and cell death mechanisms. The project also involves physico-chemical studies of affinity for lipid membranes that involve the absorbance techniques UV-visible spectrometry, fluorescence spectrometry, zeta potential and cyclic voltammetry, because these studies will be made in comparison with the free forms of porphyrins and associated with liposomes. Theoretical calculations will be made to understand the effects of porphyrin/liposomes association with resulting from the interaction of these molecules, with repercussions in the electron transfer mechanisms. These studies contribute for application in catalysis and design of new drugs. (AU)