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Singlet oxygen and hydroperoxides in chemical and biological systems

Grant number: 06/59458-2
Support type:Research Projects - Thematic Grants
Duration: August 01, 2007 - January 31, 2012
Field of knowledge:Biological Sciences - Biochemistry - Metabolism and Bioenergetics
Principal Investigator:Paolo Di Mascio
Grantee:Paolo Di Mascio
Home Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Studies on the peroxidation of lipids has increased in the last few years due to discoveries about the role of lipidic hydroperoxides (LOOH) in skin cancer induced by UV, arteriosclerosis, neurodegenerative diseases and several other pathologies. LOOHs are potentially harmful compounds capable of promoting damage in bio-molecules, including proteins and DNA. As they have a longer half-life than free radical precursors, they enable translocations in the cell, between cells, or between lipoproteins and cells. In this way, the toxicity of the LOOHs and their action as enablers can manifest themselves in locations of the cell more distant than their place of formation. Another important aspect of the biological action of LOOHs, which is only beginning to be uncovered, is related to the role of LOOHs in signal transduction. Recent studies suggest that LOOHs are involved in the initial events responsible for the release of cytochrome c of mitochondria and induction of apoptosis. Such signaling could determine whether a cell is going to survive, or not, in the face of an oxidative insult. A large part of the cytotoxic and genotoxic effects of LOOH have been attributed to the formation of free radicals and of secondary and tertiary products resulting from their decomposition. Detection techniques HPLC coupled with Tandem mass spectrometry (HPLC-MS/MS), clearly demonstrated that LOOHs can interact with metals and other oxidants, such as peroxinitrite, generating singlet oxygen (102), a highly reactive species involved in several cell processes. This study aims to investigate the formation of singlet oxygen via hydroperoxides of lipids, proteins and DNA in biological systems. Reactions of singlet oxygen with bio-molecules and the biological mechanisms associated with the formation of this species will also be investigated. The formation and characterization of the reactions involved in the cytotoxic and genotoxic mechanisms by the ROOHs (LOOH and other non-lipidic hydroperoxides) in biological systems are also the object of this project. With this approach methodologies will be developed for the detection and quantification of different classes of ROOH, based on HPLC-MS/MS using isotopically marked compounds as internal standards. We will also characterize damage to proteins, in particular to cytochrome c, and to mitochondrial DNA resulting from the interaction with ROOH. (AU)