Review articleNitrogen dioxide and carbonate radical anion: two emerging radicals in biology
Introduction
The discovery that the free radical nitric oxide is synthesized and used as a major transducer molecule by mammalian cells [1], [2] has promoted paradigmatic changes in the field of free radical research, leading to the present view that free radicals and oxidants play a role in cell homeostasis, and not only in cell injury, as previously emphasized [3], [4], [5]. In addition, it has brought into focus reactive species that were practically ignored in biology up to the 90s, such as peroxynitrite, nitrogen dioxide, and carbonate radical anion.
Peroxynitrite was a chemical curiosity in 1990 when a seminal work was published by Beckman and co-workers [6]. They proposed that this potent oxidant was likely to be produced in vivo by the rapid reaction between two relatively unreactive but biologically ubiquitous free radicals, nitric oxide and superoxide anion (Eqn. 1), and to participate in endothelial cell injury. This hypothesis inspired many investigators, and the chemistry and biology of peroxynitrite have been extensively studied in the last decade (for recent reviews, see, [7], [8], [9], [10]). Presently, there is solid evidence supporting the formation of peroxynitrite in vivo and its contribution to cell and tissue injury associated with several pathologies such as inflammatory conditions, vascular diseases, and neurodegeneration.
In contrast to peroxynitrite that was ignored in biology up until the 90s, nitrogen dioxide and the carbonate radical anion had received some previous attention. The importance of nitrogen dioxide as a pollutant discharged into the air from automobile exhausts, power plant emission, and general combustion processes had long been recognized, and several studies of the interaction of nitrogen dioxide with biomolecules and biological fluids have been reported ([11] and references therein). The carbonate radical anion, generally considered up until 1999 to be protonated at physiological pHs [12] and named carbonate radical (HCO3•), has been less studied in biological systems than nitrogen dioxide. Production of the carbonate radical as a secondary product of acetaldehyde oxidation by xanthine oxidase was proposed in 1977 [13] and its effects in mediating biological oxidative damage have been reported occasionally [14], [15], [16], [17], [18], [19]. Although the interest in the carbonate radical anion was expected to be immense because of the high concentrations of bicarbonate (≥ 24 mM) in most biological fluids, the difficulties in detecting the radical under physiological conditions may have contributed to the sporadic attention it has received so far from biological investigators.
The interest in both nitrogen dioxide and carbonate radical anion is being renewed as a consequence of the recent understanding of the biochemical reactions of nitric oxide and its derived oxidants that include nitrogen dioxide itself and peroxynitrite. The relevance of nitrogen dioxide and carbonate radical anion in biology is also supported by recent studies demonstrating the efficiency of classical antioxidants such as urate [20], [21], [22] and nitroxides [23], [24], [25], [26] in protecting cells and whole animals against the injury associated with an overproduction of nitric oxide. The high protective effects of these antioxidants are still poorly defined at the mechanistic level but, in our view, some of them can be rationalized by considering their efficiency in scavenging nitrogen dioxide and carbonate radical anion. Here, we review the potential physiological sources and biochemical reactions of these radicals, and discuss current evidence supporting their role as biological mediators.
Section snippets
General considerations
A survey of the chemical properties of nitrogen dioxide and carbonate radical anion provides the framework to discuss their potential sources (Fig. 1) and fates under physiological conditions. Both are oxidizing radicals and therefore do not react with oxygen to produce superoxide anion. The carbonate radical anion in particular is a potent one-electron oxidant whose reducing potential at pH 7.0 (E = 1.78 V) [23], [24], [25], [26], [27], [28], [29] is not much smaller than that of the hydroxyl
Nitric oxide autoxidation
As discussed above, there are more potential routes for the production of nitrogen dioxide than carbonate radical anion under physiological conditions (Fig. 1). Nitrogen dioxide can be produced directly from nitric oxide autoxidation, which produces nitrite as the final product in aqueous solutions , , [101], [102], [103], [104]. Since the autoxidation reaction rate depends on the square of nitric oxide
General considerations
The toxicity of nitrogen dioxide, a long recognized pollutant, has been examined in humans and in vitro and in vivo models (see above). Pathophysiological effects resulting from endogenously produced nitrogen dioxide have started to be considered recently [67], [68], [69], [70], [71], [72], [73], [116], [117], [118], [121], [122], and endogenously produced carbonate radical anion remains largely ignored. This is justified by the many potential routes for nitrogen dioxide production under
Summary
The recent understanding of the biochemical reactions of nitric oxide and its derived oxidants has renewed the interest in nitrogen dioxide and carbonate radical anion. Both radicals are oxidizing species and therefore they do not react with oxygen to produce superoxide anion. The carbonate radical anion (E = 1.78 V) is more oxidizing than nitrogen dioxide (E = 0.99 V) and this property limits carbonate radical anion formation to a few biological routes. Among them, the most important are
Acknowledgements
This work was supported by grants from the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), Conselho Nacional de Desenvolvimento Cientı́fico e Tecnológico (CNPq), and Financiadora de Estudos e Projetos (FINEP).
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Ohara Augusto is Full Professor of Biochemistry at the Departamento de Bioquı́mica, Instituto de Quı́mica, Universidade de São Paulo, São Paulo, SP, Brazil. She received her undergraduate (B.S. in Chemistry) and graduate (Ph.D. in Biochemistry) titles in the same Institution and did postdoctoral work at the University of California, Berkeley and University of California, San Francisco, USA. Her research interests are focused on the Biochemistry of free radicals and oxidants, molecular toxicology and the uses of electron paramagnetic resonance (EPR) to detect and identify free radicals under biological conditions.
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Marcelo G. Bonini (B.S. in Chemistry), Edlaine Linares (B.S. in Pharmacy), Célio C. X. Santos (B.S. in Biology) and Silvia L. De Menezes (B.S. in Chemistry) are graduate students presently working with Dr. Augusto. Angélica M. Amanso is an undergraduate student (Pharmacy School) also working in the group.