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Free radicals in biological systems: mechanisms of generation and production of structural lesions and molecules and cell microstructures

Grant number: 91/00514-3
Support Opportunities:Research Projects - Thematic Grants
Duration: December 01, 1991 - November 30, 1996
Field of knowledge:Biological Sciences - Biochemistry
Principal Investigator:Rogerio Meneghini
Grantee:Rogerio Meneghini
Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

In the last few years there has been growing evidence that free radical species can originate in biological systems through various processes and that these can play important roles in physiological and pathological phenomena. This project is centered on the idea that multiple approaches of chemistry, biochemistry and molecular biology can permit the understanding of how free radicals are generated and act in cells. Various forms of initiation of oxidative stress (a situation in which the balance between pro-oxidants versus antioxidants favors the former and which frequently leads to the formation of radical species) will be investigated, both for endogenous and exogenous species. Thus we will investigate how certain exogenous compounds, such as derivatives of hydrazine (a carcinogenetic agent) and antiparasitics (principally primaquine and chloroquine) produce free radicals during their metabolisms. The role of transition metals long recognized as important in the production of radicals, will be dealt with, highlighting the importance that the metabolism of intracellular Fe and its complexes with bio-molecules can have in this process. Endogenous forms of production of radicals will be investigated from two aspects: generation through the activation of phagocytes and production through aminoketonic intermediaries of the metabolism of aminoacids. The modern methodological potentialities, including Electron Paramagnetic Resonance Spectroscopy, will be explored in the attempt to elucidate the nature of radicals formed in the cells, which include oxygen radicals and carbon-centered radicals. The structural alterations which various bio-molecules suffer through the action of radicals will be investigated as to the mechanism involved as well as the consequences they can produce. Among these bio-molecules DNA will have a central role. We will investigate how processes mediated by Fe ions and hydroxyl radicals can injure the DNA in the cell. Carbon radicals can attack the DNA and particularly the 8-methylguanine lesion will be investigated as to the production through methyl radicals generated metabolically. The possibility of the latter being generated by activated phagocytes as well as the possible consequences of this for the transformation of cells will be one of the topics explored. Products derived from lipoperoxidation can also attack the DNA and this fact should be focused on, there being interest in verifying the consequences of the alterations caused in terms of mutagenesis. Among microstructures potentially affected by oxidative stress mitochondria play an important role. We will investigate the possibility that aminoketons accumulated in the defective metabolism of aminoacids causes oxidative stress responsible for mitochondrial lesions and that therein might reside the origin of problems related to dysfunctions of the porphyria type and metabolic defects of threonine. The study of metabolic generation of radicals based on antiparasitics will be directed in two aspects: the possibilities of designing pharmacologically more powerful molecules and of obtaining synergistic therapeutic effects with simultaneous action of oxygen enriched atmosphere. Still within the therapeutic field it is currently recognized as very important the possibility of oxidative stress being involved in cardiovascular accidents. In humans it is difficult to test this hypothesis. Here occurs the interesting possibility of using the ascorbyl radical, formed in plasma, as a natural marker of oxidative stress, through the ERE technique. This opens up the possibility of effectively measuring the protective effect of superoxide dismutase and catalysis against lesions supposedly originating from oxidative stress. (AU)

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