Superoxide and nitric oxide induced nitrosative processes may follow unusual and different dynamic behaviors

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by José Carlos Toledo

Possibly, most pathophysiological processes involving the radicals nitric oxide (NO) and superoxide (O₂•–) depend on their simultaneous production and their favorable co-reaction to produce peroxynitrite. Peroxynitrite is an oxidant itself but in the presence of carbon dioxide it gives origin to radical species such as carbonate anion (CO₃•–) and nitrogen dioxide (NO₂) radicals, both capable of stimulating oxidative and nitrosative events that damage biomolecules. The interplay of NO and O₂•– in biological environments is complex, though. Using a fluorescent probe molecule to monitor nitrosation in cells upon extracellular NO and O₂•– co-generation, Espey et al. [1] found an unexpected behavior shaped like a circumflex accent (^). That is, nitrosation increases, peaks and then decreases as NO levels grow in excess vs. a constant flux of O₂•–. The decreasing non-nitrosating phase was attributed to extracellular reactions of NO with CO₃•– and NO₂ radicals. Thus, unexpectedly, in the extracellular space NO both stimulates and may avoid nitrosation. But, that is not the whole story. Recent work from the CEPID-Redoxoma group led by Toledo and collaborators [2] adopted a strategy similar to that of Espey et al. [1], except that they did not generate O₂•– extracellularly and, as a result, observed a distinct behavior. Nitrosation requires intracellular O₂•–, but it increases until reaching a plateau and never falls when the NO grows in excess to O₂•– (generating a ramp-plateau behavior). The existence of the plateau phase led to the conclusion that NO cannot intercept CO₃•– and NO₂ intracellularly to prevent nitrosation due to competition with more abundant targets of these radicals, including the fluorescent probe. At the same time, this study shows that O₂•–-dependent nitrosative processes taking place by the same chemical mechanisms may exhibit distinct patterns in cells as NO levels increase. Nitrosation may occur by additional different mechanisms, but observation of either the circumflex accent or the ramp-plateau shaped profiles appear to be good indicators for the involvement of O₂•– in cellular nitrosation events.


  1. M. G. Espey, D. D. Thomas, K. M. Miranda, D. A. Wink.
    Focusing of nitric oxide mediated nitrosation and oxidative nitrosylation as a consequence of reaction with superoxide.
    Proceedings of the National Academy of Sciences of the United States of America, 99 (17): 11127-32, 2002. | http://dx.doi.org/10.1073/pnas.152157599
  2. F. C. Damasceno, R. R. Facci, T. M. Silva, J. C. Toledo Jr.
    Mechanisms and kinetic profiles of superoxide-stimulated nitrosative processes in cells using a diaminofluorescein probe.
    Free Radical Biology and Medicine, 77: 270-80, 2014. | http://dx.doi.org/10.1016/j.freeradbiomed.2014.09.012

José Carlos Toledo Jr, PhD.
Professor at Department of Chemistry,
Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto,
University of São Paulo, Brazil

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