Nitrosation by Peroxynitrite: Use of Phenol as a Probe

Uppu, Rao M.; Lemercier, Jean-Noël; Squadrito, G; Zhang, Houwen; Bolzan, Rachel M.; Pryor, William A.

doi:10.1006/abbi.1998.0825

Cited by 54 publications

(43 citation statements)

References 87 publications

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“…Like most oxidation 13 and nitration 7,14 reactions mediated by PN/ CO 2 , the nitrosation reaction levels off with a maximum yield that is only about 0.2 mol/mol of PN used ( Figure 1B). 15 This confirms the existence of competing steps 8,10,13,14 in which PN Lippton, H.;Edwards, J. C.;Baricos, W. H.;Hyman, A. L.;Kadowitz, P. J.; Greutter, C. A. J. Pharmacol. Exp.…”

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confidence: 65%

“…7,14 Both ionic and free radical mechanisms have been postulated to explain nitrosation of nucleophiles by PN/CO 2 . 8 We find that azide ions inhibit nitrosation of 4 by nitrous acid ( Figure 1D, curve a) but not by PN/CO 2 (curve b). The ability of N 3 -to inhibit nitrosation in the HNO 2 reaction indicates that azide can trap protonated nitrous acid (H 2 O + -NO) and/or N 2 O 3 .…”

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confidence: 73%

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Nitrosation of 1,2-Phenylenediamine by Peroxynitrite/CO₂: Evidence for a Free Radical Mechanism

Uppu

Pryor

1999

J. Am. Chem. Soc.

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Nitric oxide and S-nitrosothiols function as critical signaling species. 1 S-Nitrosothiols have a longer half-life 2 than does • NO, and typical concentrations of S-nitrosothiols in blood plasma are 3-4 orders of magnitude higher than those of • NO. 3 Thus, nitrosation can lead to the formation of S-nitrosothiols, which can serve as carriers of • NO; however, since • NO itself does not nitrosate, 4 the mechanism by which nitrosation occurs in vivo is still unclear. 5 We have recently shown that peroxynitrite (PN), 6 an oxidant formed in the down-regulation of • NO, 7 can nitrosate phenol 8 in a CO 2 -dependent pathway. The nitrosating species was suggested to be a nitrosonium ion (NO + ) carrier X-NdO (where X can be -ONO, -ONO 2 , -O 2 NO 2 , or -OCO 2 -) or the free radicals CO 3 •-and • NO, all 8 of which can be formed from the reactions of PN 9 and its adduct with CO 2 , ONOOCO 2 -10 (Scheme 1). We here present unequivocal evidence for nitrosation of nucleophiles by PN/CO 2 based on the oxidation of 1,2-phenylenediamine (4), which gives up to 20 mol % yield of 1,2,3-benzotriazole (9). The inhibitory effects of azide support a free radical mechanism for the reaction.A characteristic probe for nitrosation involves the reaction of a vicinal diamine such as 4 or 2,3-diaminonaphthalene 11 to give a triazole (9), formed as a result of an intramolecular nucleophilic displacement on the diazo hydroxide (8) by the neighboring amino group (Scheme 2). Reactions of this type give quantitative yields of nitrosation under mildly acidic, neutral, or even somewhat alkaline conditions. Figure 1A shows the typical product profile for the reaction of PN with 4 in the presence of trace amounts of CO 2 (curve a). One of the major products of this reaction, 12 which elutes with a retention time of 8.0 min, has been identified as 9 based on coelution with authentic 1,2,3-benzotriazole ( Figure 1A, curve b) as well as GC/MS/EI analysis giving ions at m/z 119, 91, and 64, corresponding to M + (C 6 H 5 N 3 •+ ), and fragmentation to C 6 H 5 N •+ (loss of N 2 ) and C 5 H 4 •+ (further loss of HCN).The pH profile of the yields of 9 in the PN/CO 2 /4 system parallels the formation of NO 2 -(in the absence of 4) ( Figure 1B), confirming 8-10 that the nitrosation reaction is mechanistically related to the pathways that produce NO 2 -(Scheme 1, eqs e-h). Like most oxidation 13 and nitration 7,14 reactions mediated by PN/ CO 2 , the nitrosation reaction levels off with a maximum yield that is only about 0.2 mol/mol of PN used ( Figure 1B). 15 This confirms the existence of competing steps 8,10,13,14 in which PN Lippton, H.;Edwards, J. C.;Baricos, W. H.;Hyman, A. L.;Kadowitz, P. J.; Greutter, C. A. J. Pharmacol. Exp. Ther. 1981, 218, 739. (3) Stamler, J. S.; Jaraki, O.; Osborne, J.; Simon, D. I.; Keaney, J.; Vita, J.; Singel, D.; Valeri, C. R.; Loscalzo, J. . van der Vliet, A.; Hoen, P. A. C.; Wong, P. S.-Y.; Bast, A.; Cross, C. E. J. Biol. Chem. 1998, 273, 30255.(6) The term PN refers to the sum of PN anion (ONOO -) and its acid, ONOOH (...

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Nitrosation of 1,2-Phenylenediamine by Peroxynitrite/CO₂: Evidence for a Free Radical Mechanism

Uppu

Pryor

1999

J. Am. Chem. Soc.

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“…Peroxynitrite (ONOO) is a potent oxidant exhibiting unique chemical reactivities such as hydroxylation and nitration of aromatic species (Beckman et al, 1994), DNA-strand breakage and direct oxidation of purines and pyrimidines (Maeda and Akaike, 1998) and nitrosation of nucleophiles (Uppu et al, 1998). Peroxynitrite decomposes with a half-life of < I s at physiological pH at 37~ (Pasquat et al, 1996), which allows it to diffuse away from the site of its formation and reach critical targets.…”

Section: Reactive Nitrogen Species (Rns)mentioning

confidence: 99%

“…Recently, it became evident that S-nitrosothiols constitute an important class of compounds whose analysis may help in understanding of both cyto(neuro)toxicity and cytoprotection by NO ~ and its derivative ONOO-in vivo. S-nitrosothiols (RSNO) may be an endogenous source of NO ~ (Singh et al, 1996), a convenient form for NO~ and transport in biological systems (Vanin, 1998) and critical signal transduction species (Uppu et al, 1998).…”

Section: Reactive Nitrogen Species (Rns)mentioning

confidence: 99%

“…Peroxynitrite can promote the nitrosation of nucleophiles (phenolic compounds) (Uppu et al, 1998). The concentration-dependent effect of CO2 observed before in the hydroxylation and nitration of phenol by ONOO-, clearly indicates the involvement of: (i) intermediates -peroxynitrite/CO2-adduct, nitrocarbonate anion and carbonate radical, in the transfer of NO + to the phenolate ion; and (ii) free radicals -phenoxyl (PhO ~ and nitrosyldioxyl (ONOO~ In the authors' view, the role of these products in the cytotoxic effects of peroxynitrite cannot be neglected, having in mind that the toxic effects of NO ~ are suspect as part of S-nitrosation reactions (Mollina et al, 1992).…”

Section: Reactive Nitrogen Species (Rns)mentioning

confidence: 99%

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Reactive oxygen species and reactive nitrogen species: Relevance to cyto(neuro)toxic events and neurologic disorders. An overview

1999

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Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are formed under physiological conditions in the human body and are removed by cellular antioxidant defense systems. During oxidative stress their increased formation leads to tissue damage and cell death. This process may be especially important in the central nervous system (CNS) which is vulnerable to ROS and RNS damage as the result of high 02 consumption, high lipid content and the relatively low antioxidant defenses in brain, compared with other tissues.Recently there has been an increased number of reports suggesting the involvement of free radicals and their non-radical derivatives in a variety of pathological events and multistage disorders including neurotoxicity, apoptotic death of neurons, and neural disorders: Alzheimer's (AD), Parkinson's disease (PD) and schizophrenia. Taking into consideration the basic molecular chemistry of ROS and RNS, their overall generation and location, in order to control or supress their action it is essential to understand the fundamental aspects of this problem. In this presentation we review and summarize the basics of all the recently known and important properties, mechanisms, molecular targets, possible involvement in cellular (neural) degeneration and apoptotic death and in pathogenesis of AD, PD and schizophrenia.The aim of this article is to provide an overview of our current knowledge of this problem and to inspire experimental strategies for the evaluation of optimum innovative therapeutic trials. Another purpose of this work is to shed some light on one of the most exciting recent advances in our understanding of the CNS: the realisation that RNS pathway is highly relevant to normal brain metabolism and to neurologic disorders as well. The interactions of RNS and ROS, their interconversions and the ratio of RNS/ ROS could be an important neural tissue injury mechanism(s) involved into etiology and pathogenesis of AD, PD and schizophrenia.It might be possible to direct therapeutic efforts at oxidative events in the pathway of neuronal degeneration and apoptotic death. From reviewed data, no single substance can be recommended for use in human studies. Some of the recent therapeutic strategies and neuroprotective trials need further development particularly those of antioxidants enhancement. Such an approach should also consider using combinations of radical(s) scavengers rather than a single substance.

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Reactivity of Peroxynitrite with Melatonin as a Function of pH and CO2 Content

et al. 2003

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Peroxynitrite is known to be a strong oxidant and a nitrating agent of aromatic phenolic or heterocyclic rings, depending on its form in aqueous solutions: the anion ONOO − , its conjugate acid ONOOH, or its CO 2 adduct ONOOCO 2 − . Various reactions have been observed with melatonin (1), a tryptophan derivative, in phosphate-buffered solutions. Melatonin (1) is recognized as a scavenger of several strong oxidants (HO · , H 2 O 2 , ...) accounting for its biological and pharmacological effects. Here we describe two oxidation routes that give rise to indol-2-ones 2 (probably via a 2,3-epoxyindole) and kynuramines 6 (by cleavage of the pyrrole ring), attributable to reactions of ONOOH and ONOO − , respectively, according to the effects of pH and CO 2 content. At pH = 7.6 and in the presence of CO 2 , an important conversion is the cyclization of the lateral amide function, giving 3-substituted pyrroloindoles 4. At neutral pH, therefore, all routes coexist, with a balance between indol-2-ones 2 and pyrroloindoles 4 on the one side and kynuramines 6 on the other, depending on the

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Nitrosation by Peroxynitrite: Use of Phenol as a Probe

Cited by 54 publications

References 87 publications

Nitrosation of 1,2-Phenylenediamine by Peroxynitrite/CO₂: Evidence for a Free Radical Mechanism

Nitrosation of 1,2-Phenylenediamine by Peroxynitrite/CO₂: Evidence for a Free Radical Mechanism

Reactive oxygen species and reactive nitrogen species: Relevance to cyto(neuro)toxic events and neurologic disorders. An overview

Reactivity of Peroxynitrite with Melatonin as a Function of pH and CO2 Content

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Nitrosation by Peroxynitrite: Use of Phenol as a Probe

Cited by 54 publications

References 87 publications

Nitrosation of 1,2-Phenylenediamine by Peroxynitrite/CO2: Evidence for a Free Radical Mechanism

Nitrosation of 1,2-Phenylenediamine by Peroxynitrite/CO2: Evidence for a Free Radical Mechanism

Reactive oxygen species and reactive nitrogen species: Relevance to cyto(neuro)toxic events and neurologic disorders. An overview

Reactivity of Peroxynitrite with Melatonin as a Function of pH and CO2 Content

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Nitrosation of 1,2-Phenylenediamine by Peroxynitrite/CO₂: Evidence for a Free Radical Mechanism

Nitrosation of 1,2-Phenylenediamine by Peroxynitrite/CO₂: Evidence for a Free Radical Mechanism