Chapter 11
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Peroxynitrite and Nitroxidative Stress: Detection Probes and Micro-Sensors. A Case of a Nanostructured Catalytic Film Serban F. Peteu,1,3,4 Saleem Banihani,1 Mutha M. Gunesekera,1 Pubudu Peiris,1 Oana A. Sicuia,5 and Mekki Bayachou*,1,2 1Chemistry
Department, Cleveland State University, 2399 Euclid Ave., Cleveland, Ohio 44115, United States 2Lerner Research Institute, Cleveland Clinic, 9500 Euclid Ave. NB21, Cleveland, Ohio 44195, United States 3National Institute for Chemistry Research and Development, Bucharest 300224, Romania 4Chemical Engineering & Materials Science, Michigan State University, East Lansing, Michigan 48824, United States 5Institute for Crop Protection Research and Development, 8 Ion Ionescu dela Brad Blvd., Bucharest 013813, Romania *E-mail:
[email protected] Peroxynitrite, the primary product of the reaction of superoxide ion and nitric oxide, emerged as an important species with profound biological roles. Relatively speaking, it is a new member of the nitroxidative array of reactive metabolites, and details of its actions, impact on biological systems in health and disease states are still accumulating. It has already been linked to a host of pathological conditions. At the same time, its cytoprotective roles including redox regulation of critical signaling pathways are also reported. Assessment of peroxynitrite’s deleterious versus potential protective/signaling roles strongly depends on the possibility to accurately measure and monitor its concentration. This will help build a clearer understanding of its physiological roles. However, peroxynitrite’s extremely short half-life under physiological conditions and its very complex reactivity with many cellular targets create a major analytical chemistry
© 2011 American Chemical Society In Oxidative Stress: Diagnostics, Prevention, and Therapy; Andreescu, S., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2011.
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challenge, particularly at the single cell level. The dynamic concentration of peroxynitrite versus other reactive species generated in situ under various conditions modulates its role in many vital cell functions. In this chapter, we give a brief overview of peroxynitrite biochemistry, physiology, and related therapeutic efforts to control its impact under pathological conditions. We then discuss the challenges and accomplishments in terms of major analytical methods developed for peroxynitrite’s sensing up-to-date, as well as opportunities for the future.
1. Introduction Peroxynitrite emerged as a potent cytotoxic compound since early 1990s (1, 2) after the identification of nitric oxide as the main player involved in many physiological processes including vasodilation (3). It turned out to be the direct culprit for much what was wrongly assigned as nitric oxide’s pathology. A plethora of physiologically relevant reactions, ranging from deleterious to protective ones, is subject of extensive research. In fact, the list of reports implicating this molecule in pathologic conditions and, more recently, as potentially involved in basic signaling or ensuring protective roles, is growing (4–10). Peroxynitrite (Formula: ONOO–, Abbreviation: PON; PON will be mostly used in this text; however, the full name will also be used interchangeably at times when emphasis on the name is needed) is the product of the reaction of superoxide ion (O2•–) and nitric oxide free radical (NO•) (2, 11–14). Nitric oxide is generated in a two-step catalytic oxidation of L-arginine by nitric oxide synthases (NOSs), while superoxide ion can be leaked by many oxidases, by enzyme complexes of the respiratory chain associated with mitochondria, or by simple intrinsic uncoupling of endothelial NOS (eNOS), Figure 1. Proinflammatory conditions may exacerbate the levels of superoxide ion released, and thus the levels of PON formed. Nitric oxide and superoxide ion react very fast in a diffusion-controlled reaction (reported rates ~3-20 x109 M-1s-1). A reaction rate of this magnitude outperforms even the natural enzymatic sink for superoxide ion, i.e. the catalytic detoxification by superoxide dismutases. The only case where the rate of the reaction with CO2 is challenged is under conditions of high density of target cells, which essentially reduces the diffusion distance from a given PON source (15). Given the relatively large diffusion range of NO (16, 17), the order of magnitude reported for the rate of reaction between nitric oxide and superoxide ion guarantees the formation of ONOO– any time NO comes across a source of superoxide ion. Peroxynitrite chemistry is strongly dependent on pH, and is further complicated by the complexity of the biological milieu and the myriad of possible cellular targets. PON anion can act as a direct oxidant of many cellular targets. At pH 7.4, 80% of ONOO– is present as the anionic form while the complementary fraction is protonated in the form of peroxynitrous acid (ONOOH, pKa = 6.8). 312 In Oxidative Stress: Diagnostics, Prevention, and Therapy; Andreescu, S., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2011.
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The anionic form can react with many targets. For instance it reacts with CO2 to form nitrosoperoxycarbonate adduct (ONOOCO2–), Figure 1. The O-O bond homolysis in both ONOOH (the conjugate acid of PON) and ONOOCO2– generates deleterious radicals (•OH, •NO2, CO3•–), which highlights another indirect deleterious torrent that drives peroxynitrite’s pathological impacts (2, 12, 13, 17, 18) (Figure 1). Hydroxyl radicals (•OH), nitrogen dioxide (•NO2) and carbonate radicals are behind irreversible insults on cell components such as disruption of membrane lipids, nucleobase oxidation/nitration and DNA strand breaks, and protein nitrations (19–21). Given its direct and indirect decay pathways, PON is relatively short-lived (
