Reactive species derived from oxygen, nitrogen and carbon. Interactions and pathophysiological significance

Abstract

Reactive oxygen and nitrogen intermediates are now widely recognized to play important roles in a variety of physiological and pathological processes. Reduced oxygen species such as the superoxide anion and hydrogen peroxide are continuously produced by aerobic cells. Nitric oxide is a gaseous free radical synthesized enzymatically from the aminoacid arginine and it plays a role in several physiological processes including blood pressure control neurotransmission and immune response. Excessive production of superoxide anion and nitric oxide individually has been associated with several pathologies but only recently bas it been hypothesized that interactions between them may also be important in the etiology of many human diseases including atherosclerosis, neurodegenerative diseases and cancer. Peroxynitrite, nitrogen dioxide and the carbonate radical anion are examples of reactive species that were virtually unknown in Biology but are presently recognized as products of free radical and oxidant interactions underphysiological conditions. Also overlooked in the past have been the addition and recombination reactions between free radicals and oxidizing intermediates with biomolecules. Indeed, free radical chain reactions leading to biomolecule degradation have been more explored due to historical reasons. However, it is becoming increasingly recognized that stable products of addition and recombination reactions (protein and DNA adducts; nitrated and nitrosylated proteins, etc.), may be important mediators of the biological effects of free radicals and oxidizing species.In this context, and to further contribute to the understanding of the palhophysiological roles of free radicals, we are presently studying three general problems:(i) the chemistry and biology of peroxynitrite; (ii) the roles of the carbonate radical anion in oxidative stress conditions; (iii) biomolecule alkylation by free radical mechanisms. These problems are being studied by a multidisciplinary experimental approach employing general chemical and biochemical techniques with special emphasis on EPR and EPR-spin trapping. The experiments are being performed in vitro (test tubes, cell cultures) and in vivo (mice infected with Leishmania amazonensis and rats intoxicated with ethanol, acetaldehyde and tert-butylhydroperoxide). It is expected that the project will provide information about the biochemistry of peroxynitrite, the biological effects of protein nitration, the cellular defenses against reactive nitrogen species, the genotoxicity of some xenobiotics (ethanol, tert-butylhydroperoxide) and potential biomarkes of nitrogen species. (AU)