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PubMed2005

Nitration and photonitration of naphthalene in aqueous systems.

The nitration of naphthalene was studied in aqueous solution to gain insight into the processes leading to the nitration of aromatic compounds in atmospheric hydrometeors. Reactants used were nitric acid, nitrogen dioxide and peroxynitrous acid in the dark, nitrate, and nitrite/nitrous acid under illumination. Naphthalene nitration can lead to two possible isomers, 1- and 2-nitronaphthalene. The former nitrocompound preferentially forms upon electrophilic processes and in the presence of nitrogen dioxide. Electrophilic nitration of naphthalene takes place in the presence of concentrated nitric acid, but nitration with nitric acid and oxidants (charge-transfer nitration) occurs under much milder conditions than with nitric acid alone. Charge-transfer nitration may have some environmental significance in particular cases, e.g. in acidic aerosols in the presence of HNO3 and oxidants. Nitrogen dioxide is thought to have a role in PAH nitration in the Antarctic particulate matter. In previous papers we have found that nitration induced by peroxynitrous acid, HOONO, can follow two pathways, the former electrophilic (leading for instance to the formation of nitrophenols from phenol) and the latter probably involving HOONO itself (accounting for the formation of nitrobenzene from benzene). In the case of naphthalene and HOONO the electrophilic pathway mainly leads to 1-nitronaphthalene, while the other one preferentially yields 2-nitronaphthalene. The nitration of naphthalene in the presence of nitrite/nitrous acid under irradiation leads to both nitroisomers in similar ratios, and the process is not inhibited by hydroxyl scavengers. This excludes nitrogen dioxide as reactive species for nitration and marks a difference with phenol photonitration and a similarity with the behavior of benzene under comparable conditions. Nitrite photochemistry (and nitrite-induced photonitration as well) is expected to be relevant in fog and cloudwater in polluted areas. An important difference with the gas-phase nitration is that the radicals OH and NO3 are unlikely to play a relevant role in the nitration of naphthalene in aqueous solution.

Benzene↗
PubMed2005

An ab initio molecular orbital study of the mechanism for the gas-phase water-mediated decomposition and the formation of hydrates of peroxyacetyl nitrate (PAN).

There is uncertainty in the mechanism for the hydrolysis of peroxyacetyl nitrate (PAN), and experimental attempts to detect products of the direct reaction have been unsuccessful. Ab initio calculations are used to examine the energetics of water-mediated decomposition of gas-phase PAN into acetic acid and peroxynitric acid. On the basis of ab initio calculations, an alternative reaction mechanism for the decomposition of PAN is proposed. The calculations indicate that the barrier for one water addition to PAN is large. However, including additional water molecules reveals a substantially lower energy route. The calculations suggest that the formation of PAN hydrate complexes are energetically favorable and stable. Additional waters are increasingly efficient at stabilizing hydrated PAN.

Journal Article↗
PubMed2000

The quantitative oxidation of methionine to methionine sulfoxide by peroxynitrite.

Both peroxynitrous acid and peroxynitrite react with methionine, k(acid) = (1.7 +/- 0.1) x 10(3) M(-1) s(-1) and k(anion) = 8.6 +/- 0.2 M(-1) s(-1), respectively, and with N-acetylmethionine k(acid) = (2.8 +/- 0.1) x 10(3) M(-1) s(-1) and k(anion) = 10.0 +/- 0.1 M(-1) s(-1), respectively, to form sulfoxides. In contrast to the results of Pryor et al. (1994, Proc. Natl. Acad. Sci. USA 91, 11173-11177), a linear correlation between k(obs) and [met] was obtained. Surprisingly, for every two sulfoxides and nitrites formed, one peroxynitrite is converted to nitrate. Thus, methionine also catalyzes the isomerization of peroxynitrite to nitrate. Neither the pH nor the concentration of methionine affected the distribution of the yields of nitrite, nitrate, and methionine sulfoxide, which were the only products detected. No products other than nitrite, nitrate, and methioninesulfoxide could be detected. The reactions of methionine and N-acetylmethionine with peroxynitrous acid and peroxynitrite are simple bimolecular reactions that do not involve an activated form of peroxynitrous acid or of peroxynitrite. Nitrite, produced together with methionine sulfoxide, or present as a contamination in the peroxynitrite preparation, is not innocuous, but oxidizes methionine by one electron, which leads to the formation of methional and ethylene.

Aldehydes↗
PubMed2003

New processes in the environmental chemistry of nitrite. 2. The role of hydrogen peroxide.

The oxidation of nitrite and nitrous acid to *NO2 upon irradiation of dissolved Fe(III), ferric (hydr)oxides, and nitrate has previously been shown to enhance phenol nitration. This allowed the proposal of a new role for nitrite and nitrous acid in natural waters and atmospheric aerosols. This paper deals with the interaction between hydrogen peroxide, a key environmental factor in atmospheric oxidative chemistry, and nitrite/nitrous acid. The reaction between nitrous acid and hydrogen peroxide yields peroxynitrous acid, a powerful nitrating agent and an important intermediate in atmospheric chemistry. The kinetics of this reaction is compatible with a rate-determining step involving either H3O2+ and HNO2 or H2O2 and protonated nitrous acid. In the former case the rate constant between the two species would be 179.6 +/- 1.4 M(-1) s(-1), in the latter case it would be as high as (1.68 +/- 0.01) x 10(10) M(-1) s(-1) (diffusion-controlled reaction). Due to the more reasonable value of the rate constant, the reaction between H3O2+ and HNO2 seems more likely. In the presence of HNO2 + H2O2 the nitration of phenol is strongly enhanced when compared with HNO2 alone. The nitration rate of phenol in the presence of peroxynitrous acid decreases as pH increases, thus HOONO is a potential source of atmospheric nitroaromatic compounds in acidic water droplets. The mixture Fe(II) + H2O2 (Fenton reagent) can oxidize nitrite and nitrous acid to nitrogen dioxide, which results in phenol nitration. The nitration in the presence of Fe(II) + H2O2 + NO2-/HNO2 occurs more rapidly than the one with H2O2 + NO2-/HNO2 at pH 5, where little HNO2 is available to directly react with hydrogen peroxide. Both systems, however, are more effective than NO2-/HNO2 alone in producing nitrophenols from phenol. Another process leading to the oxidation of nitrite to nitrogen dioxide is the photo-Fenton one. It can be relevant at pH > or = 6, as nitrite does not react with H2O2 at room temperature. Under such conditions the source of Fe(II) is the photolysis of ferric (hydr)oxides (heterogeneous photo-Fenton reaction). In the presence of nitrite this reaction induces very effective nitrophenol formation from phenol.

Aerosols↗
PubMed1995

Desferrioxamine inhibition of the hydroxyl radical-like reactivity of peroxynitrite: role of the hydroxamic groups.

Nitric oxide reacts with superoxide to form peroxynitrite, a strong oxidizing species. Peroxynitrite can either directly oxidize molecules such as thiols or protonate to peroxynitrous acid, which can yield an oxidant with a reactivity similar to that of hydroxyl radical in a transition metal-independent mechanism. This oxidative chemistry of peroxynitrite, however, is inhibited by the metal chelator desferrioxamine. Indeed, desferrioxamine, was a potent inhibitor of dimethylsulfoxide, hydrogen peroxide, 5,5-dimethyl-1-pyrroline-N-oxide, and luminol oxidation, whereas the metal chelator diethylenetriaminepentaacetic acid, and ferrioxamine, the iron complex of desferioxamine, were not. Two other hydroxamates, acetohydroxamate and salicylhydroxamate, were also effective inhibitors. Stopped-flow experiments showed that there is no direct reaction between peroxynitrite anion or cis-peroxynitrous acid with desferrioxamine. Electron paramagnetic resonance (EPR) studies showed the formation of the desferrioxamine nitroxide radical in incubations containing desferrioxamine, but not ferrioxamine, indicating that the hydroxamic group acts as a one-electron donor to peroxynitrite-derived oxidants. Taken together, our results led us to propose that desferrioxamine can inhibit the oxidative chemistry of peroxynitrite by reaction of the hydroxamic acid moieties with trans-peroxynitrous acid.

Cyclic N-Oxides↗
PubMed1998

Determination of optimal conditions for synthesis of peroxynitrite by mixing acidified hydrogen peroxide with nitrite.

The measured parameters for the formation of peroxynitrous acid via the reaction of acidified hydrogen peroxide with nitrous acid and its self-decomposition corroborate with an earlier suggested mechanism in which H2NO2+ nitrosates H2O2. The activation energies for the formation and decay of peroxynitrous acid have been determined to be 15 and 19 kcal/mol, respectively. We found that perchlorate, nitrate, sulfate and phosphate ions have no effect on the formation and decay rates, whereas chloride ions enhance the rate of the formation of peroxynitrous acid at low peroxide concentrations, and have no effect at high peroxide concentrations. This suggests that at relatively low concentration of H2O2, Cl- competes with H2O2 for H2NO+ to yield NOCl, which may also nitrosate H2O2. Simulation of the experimentally observed parameters for the decay and formation rates suggests that it is not possible to obtain 100% yield of peroxynitrite under any condition. High yields of peroxynitrite were obtained at room temperature using an efficient double mixer where acidified peroxide was mixed with nitrite; after an appropriate delay, the reaction was quenched with strong alkali. An excess of more than 10% of H2O2 over nitrite, or vice versa, is sufficient to get ca. 85-90% of peroxynitrite, almost free from nitrite or H2O2, respectively. The results also suggest that conventional use of ice-cold solutions of the reactants and the alkali solutions is not required if an efficient mixer and appropriate quenching times are available.

Cold Temperature↗
PubMed1994

Lactate-dependent killing of Escherichia coli by nitrite plus hydrogen peroxide: a possible role of nitrogen dioxide.

The killing of Escherichia coli by nitrite plus hydrogen peroxide was observed in lactate, but not in phosphate or acetate. Although nitrite or hydrogen peroxide alone caused a slight decrease in bacterial survival, nitrite plus hydrogen peroxide killed bacteria synergistically in time-, dose-, and pH-dependent manners. The killing was increased with decreasing pH. The plot of viable cells versus [nitrous acid] was linear. Among the hydroxyl radical scavengers used, only benzoate and formate at concentrations higher than that of lactate inhibited the killing by nitrite plus hydrogen peroxide, whereas dimethyl sulfoxide enhanced it. The generation of peroxynitrous acid during the reaction of nitrite and hydrogen peroxide was confirmed by the formation of malondialdehyde using deoxyribose as a hydroxyl radical-like oxidant detector. The nitration of glycyl-tryosine was observed only in lactate buffer, but not in phosphate and acetate buffers. Benzoate and formate inhibited the nitration, whereas dimethyl sulfoxide and ethanol enhanced it. No evidence for the formation of nitric oxide and superoxide during the reaction of nitrite and hydrogen peroxide was found. These data suggest that nitrogen dioxide from the decomposition of peroxynitrous acid or secondary oxidants formed from the reaction of peroxynitrous acid with lactate is responsible for the lactate-dependent killing of E. coli induced by the reaction of protonated nitrite and hydrogen peroxide.

Animals↗
PubMed1997

Peroxynitrite-mediated oxidation of D,L-selenomethionine: kinetics, mechanism and the role of carbon dioxide.

Peroxynitrite oxidizes D,L-selenomethionine (MetSe) by two competing mechanisms, a one-electron oxidation that leads to ethylene and a two-electron oxidation that gives methionine selenoxide (MetSeO). Kinetic modeling of the experimental data suggests that both peroxynitrous acid and the peroxynitrite anion react with MetSe to form MetSeO with rate constants of 20,460 +/- 440 M-1 s-1 and 200 +/- 170 M-1 s-1, respectively at 25 degrees C. The enthalpy (delta H++) and entropy (delta S++) of activation for the reaction of peroxynitrous acid with MetSe at pH 4.6 are 2.55 +/- 0.08 kcal mol-1 and -30.5 +/- 0.3 cal mol-1 K-1, respectively. With increasing concentrations of MetSe at pH 7.4, the yield of ethylene decreases and that of MetSeO increases, suggesting, as with methionine, the reactions leading to ethylene and MetSeO have different kinetic orders. We propose that the activated form of peroxynitrous acid, HOONO*, is the one-electron oxidant and ground-state peroxynitrite is the two-electron oxidant in the reaction of peroxynitrite with MetSe. The peroxynitrite anion rapidly adds to CO2 to form an adduct, O = N-OO-CO2- (1), capable of generating potent reactive species, and we therefore examined the role of CO2 in the peroxynitrite/MetSe system. In presence of added bicarbonate, the yield of ethylene obtained from the reaction of 0.4 mM peroxynitrite with 1.0 mM MetSe increases slightly with an increase in the concentration of bicarbonate from 0 to 5.0 mM and remains constant with a further increase of bicarbonate up to 20 mM. The yield of MetSeO, from the reaction of 10 mM peroxynitrite with 10 mM MetSe, decreases by 35% with an increase in the concentration of bicarbonate from 0 to 25 mM. Kinetic simulations show that the decrease in the yield of MetSeO is due to reaction of the peroxynitrite anion with CO2. These results suggest that CO2 partially protects MetSe from peroxynitrite-mediated oxidation and that 1 or its derivatives do not mediate the oxidation of MetSe to MetSeO.

Carbon Dioxide↗
PubMed2000

Kinetic analysis of the M1 RNA folding pathway.

The biological activity of large RNAs is dependent on the formation of complex folded structures that determine function. Typically the creation of such structures requires divalent magnesium and in many cases the folding process takes place over the course of several minutes. It has been proposed that the folding paths of large RNAs proceed through discrete intermediates but the nature of these intermediates is not known in most cases. Here, we describe our studies on the folding of the M1 RNA sub-unit of Escherichia coli RNase P. We performed kinetic footprinting studies of M1 RNA folding with the chemical footprinting reagent peroxynitrous acid to provide a detailed description of the folding pathway of RNase P RNA. Our results indicate that, in contrast to the Group I ribozyme, the M1 RNA folds into its catalytically active structure through the formation of two separately folded domains and that the folding of each proceeds through a discrete series of intermediates. Similar rates of folding were observed for regions believed to form the interface between the two domains. This observation is consistent with a kinetic trap which occurs by interaction of the domains during folding.

Binding Sites↗
PubMed2000

The nitration of platelet cytosolic proteins during agonist-induced activation of platelets.

The nitration of protein tyrosine residues by peroxynitrous acid has been associated with pathological conditions. Here it is shown, using a sensitive competitive enzyme-linked immunosorbent assay and immunoblotting for nitrotyrosine, that spontaneous nitration of specific proteins occurs during a physiological process, the activation of platelets by collagen. One of the main proteins nitrated is vasodilator-stimulated phosphoprotein. Endogenous synthesis of nitric oxide and activity of cyclo-oxygenase were required for the nitration of tyrosine. The nitration was mimicked by addition of peroxynitrite to unstimulated platelets, although the level of nitrotyrosine formation was greater and its distribution among the proteins was less specific.

Aspirin↗
PubMed1991

Peroxynitrite-induced membrane lipid peroxidation: the cytotoxic potential of superoxide and nitric oxide.

Endothelial cells, macrophages, neutrophils, and neuronal cells generate superoxide (O2-) and nitric oxide (.NO) which can combine to form peroxynitrite anion (ONOO-). Peroxynitrite, known to oxidize sulfhydryls and to yield products indicative of hydroxyl radical (.OH) reaction with deoxyribose and dimethyl sulfoxide, is shown herein to induce membrane lipid peroxidation. Peroxynitrite addition to soybean phosphatidylcholine liposomes resulted in malondialdehyde and conjugated diene formation, as well as oxygen consumption. Lipid peroxidation was greater at acidic and neutral pH, with no significant lipid peroxidation occurring above pH 9.5. Addition of ferrous (Fe+2) or ferric (Fe+3) iron did not enhance lipid peroxide formation over that attributable to peroxynitrite alone. Diethylenetetraminepentacetic acid (DTPA) or iron removal from solutions by ion-exchange chromatography decreased conjugated diene formation by 25-50%. Iron did not play an essential role in initiating lipid peroxidation, since DTPA and iron depletion of reaction systems were only partially inhibitory. In contrast, desferrioxamine had an even greater concentration-dependent inhibitory effect, completely abolishing lipid peroxidation at 200 microM. The strong inhibitory effect of desferrioxamine on lipid peroxidation was due to direct reaction with peroxynitrous acid in addition to iron chelation. We conclude that the conjugate acid of peroxynitrite, peroxynitrous acid (ONOOH), and/or its decomposition products, i.e., .OH and nitrogen dioxide (.NO2), initiate lipid peroxidation without the requirement of iron. These observations demonstrate a potential mechanism contributing to O2-(-)and .NO-mediated cytotoxicity.

Free Radicals↗
PubMedDate not supplied

The reaction of 2-(methylseleno)benzanilide with peroxynitrite.

2-(Methylseleno)benzanilide (MeSe), a main metabolite of ebselen in vivo, rapidly reacts with peroxynitrite, yielding 2-(methylseleninyl)benzanilide (MeSe = O) as the sole selenium-containing product. The reaction proceeds efficiently at acidic pH where peroxynitrous acid (ONOOH) is predominant, suggesting that MeSe reacts faster with ONOOH than with the peroxynitrite anion (ONOO-). MeSe is much less reactive with hydrogen peroxide. The second-order rate constant for the reaction at 22 degrees C was estimated from the relationship between substrate consumption and peroxynitrite concentration as 2.2 x 10(4) M-1 s-1 and 2.7 x 10(3) M-1 s-1 at pH 3.9 and 7.0, respectively, and from intermolecular competition with ascorbic acid as 3.4 x 10(3) M-1 s-1 at pH 7.1. The rate constant is about 2 orders of magnitude lower than that for the reaction of ebselen with peroxynitrite, but about 1-2 orders of magnitude higher than that reported in the literature for methionine or ascorbate. The selenoxide can be reduced back to MeSe by thiols. MeSe has previously been considered to be an inert metabolite of ebselen, but may show antioxidant activity against peroxynitrite.

Anilides↗
PubMed1996

Direct and indirect oxidations by peroxynitrite, neither involving the hydroxyl radical.

A new mechanism (Mechanism III) that combines features of mechanisms suggested earlier (Goldstein and Czapski, Inorg. Chem. 34:4041-4048; 1995; Pryor, Jin, and Squadrito Proc. Natl. Acad. Sci. USA 91:11173-11177; 1994) is proposed for oxidations by peroxynitrite. In Mechanism III, oxidations by peroxynitrite can take place either directly by ground-state peroxynitrous acid, ONOOH, or indirectly by ONOOH*, where ONOOH* is an activated form of peroxynitrous acid. In the direct oxidation pathway the reaction is first order in peroxynitrite and first order in substrate, and the oxidation yield approaches 100%. In the indirect oxidation pathway the reaction is first order in peroxynitrite and zero order in substrate. In the presence of sufficient concentrations of a substrate that reacts by the indirect oxidation pathway, about 50-60% of the ONOOH directly isomerizes to nitric acid, and about 40-50% of the ONOOH is converted into ONOOH*. Thus, the oxidation yields by the indirect pathway will not exceed 40-50%, and there will always be a residual yield of nitrate even in the presence of very high concentrations of the substrate. Competitive inhibition studies with various free radical scavengers showed that in some cases these scavengers have no effect on oxidation yields. In others, only partial inhibition was observed, far less than that predicted from to the known rate constants for the reactions of these scavengers with the hydroxyl radical. There are some cases where the extent of inhibition correlates well with the known rate constants of the reactions of these scavengers with hydroxyl radical; nevertheless, even in these cases, the involvement of hydroxyl radicals in indirect oxidations by peroxynitrite is ruled our on the basis of kinetics and oxidation yields. Thus, direct oxidations by peroxynitrite are explained in terms of ONOOH, and indirect oxidations in terms of ONOOH*, and substrates can react by one or both of these pathways.

Chemical Phenomena↗
PubMed1997

Peroxynitrite-mediated decarboxylation of pyruvate to both carbon dioxide and carbon dioxide radical anion.

There has been a recent renewal of interest in the antioxidant properties of pyruvate which are usually attributed to its capacity to undergo oxidative decarboxylation in the presence of hydrogen peroxide. The interaction of pyruvate with other oxidizing biological intermediates, however, has been scarcely considered in the literature. Here we report that peroxynitrite, the oxidant produced by the reaction between superoxide anion and nitric oxide, reacts with pyruvate with an apparent second-order rate constant of 88 +/- 7 M-1 s-1 at pH 7.4 and 37 degrees C. Kinetic studies indicated that pyruvate reacts with peroxynitrite anion (k = 100 +/- 7 M-1 s-1, peroxynitrous acid (k = 49 +/- 7 M-1 s-1, and a highly oxidizing species derived from peroxynitrous acid. Pyruvate decarboxylation was proved by anion exchange chromatography detection of acetate in incubations of peroxynitrite and pyruvate at pH 7.4 and 5.5. Formation of carbon dioxide radical anion was ascertained by EPR spin-trapping studies in the presence of GSH and the spin-trap 5,5-dimethyl-1-pyrroline N-oxide (DMPO). The use of pyruvate labeled with 13C at the 1-position led to the detection of the labeled DMPO carbon dioxide radical anion adduct. In the absence of GSH, oxygen consumption studies confirmed that peroxynitrite mediates the decarboxylation of pyruvate to free radical intermediates. Comparing the yields of acetate and free radicals estimated from the oxygen uptake studies, it is concluded that pyruvate is oxidized by both one- and two-electron oxidation pathways, the latter being preponderant. Hydrogen peroxide-mediated pyruvate oxidation does not produce detectable levels of carbon dioxide radical anion except in the presence of iron(II)-ethylenediamine-N,N,N',N'-tetraacetate (EDTA). The apparent second-order rate constant of the reaction between pyruvate and hydrogen peroxide was determined to be 1 order of magnitude lower than that of the reaction between pyruvate and peroxynitrite. The latter process may contribute to the antioxidant properties of pyruvate.

Anions↗
PubMed2000

Kinetic and mechanistic studies of the peroxynitrite-mediated oxidation of oxymyoglobin and oxyhemoglobin.

Kinetic studies of the peroxynitrite-mediated oxidations of oxymyoglobin (MbFeO(2)) and oxyhemoglobin (HbFeO(2)) showed that the mechanisms of these reactions are more complex than what had previously been reported; both reactions proceed in two steps. For myoglobin, we found that the small amount of deoxymyoglobin (MbFe(II)) which is in equilibrium with MbFeO(2) is first oxidized by peroxynitrous acid to ferryl myoglobin (MbFe(IV)=O). Then, in the second step, MbFe(IV)=O is reduced by peroxynitrous acid to metmyoglobin (metMb). The second-order rate constant values obtained at pH 7.3 and 20 degrees C for the two steps are (5.4 +/- 0.2) x 10(4) and (2.2 +/- 0.1) x 10(4) M(-)(1) s(-)(1), respectively. Analogous studies with hemoglobin suggest that its reaction with peroxynitrite follows the same mechanism. In this case, the second-order rate constant values measured at pH 7.0 and 20 degrees C for the two steps are (8.8 +/- 0.4) x 10(4) and (9.4 +/- 0.7) x 10(4) M(-)(1) s(-)(1), respectively. A possible mechanism in the absence as well as in the presence of CO(2) and the relevance of these reactions in vivo are discussed.

Carbon Dioxide↗
PubMed2000

Reaction of uric acid with peroxynitrite and implications for the mechanism of neuroprotection by uric acid.

Peroxynitrite, a biological oxidant formed from the reaction of nitric oxide with the superoxide radical, is associated with many pathologies, including neurodegenerative diseases, such as multiple sclerosis (MS). Gout (hyperuricemic) and MS are almost mutually exclusive, and uric acid has therapeutic effects in mice with experimental allergic encephalomyelitis, an animal disease that models MS. This evidence suggests that uric acid may scavenge peroxynitrite and/or peroxynitrite-derived reactive species. Therefore, we studied the kinetics of the reactions of peroxynitrite with uric acid from pH 6.9 to 8.0. The data indicate that peroxynitrous acid (HOONO) reacts with the uric acid monoanion with k = 155 M(-1) s(-1) (T = 37 degrees C, pH 7.4) giving a pseudo-first-order rate constant in blood plasma k(U(rate))(/plasma) = 0.05 s(-1) (T = 37 degrees C, pH 7.4; assuming [uric acid](plasma) = 0.3 mM). Among the biological molecules in human plasma whose rates of reaction with peroxynitrite have been reported, CO(2) is one of the fastest with a pseudo-first-order rate constant k(CO(2))(/plasma) = 46 s(-1) (T = 37 degrees C, pH 7.4; assuming [CO(2)](plasma) = 1 mM). Thus peroxynitrite reacts with CO(2) in human blood plasma nearly 920 times faster than with uric acid. Therefore, uric acid does not directly scavenge peroxynitrite because uric acid can not compete for peroxynitrite with CO(2). The therapeutic effects of uric acid may be related to the scavenging of the radicals CO(*-)(3) and NO(*)(2) that are formed from the reaction of peroxynitrite with CO(2). We suggest that trapping secondary radicals that result from the fast reaction of peroxynitrite with CO(2) may represent a new and viable approach for ameliorating the adverse effects associated with peroxynitrite in many diseases.

Bicarbonates↗
PubMed1999

Reaction of peroxynitrite with melatonin: A mechanistic study.

The pH profile of the peroxynitrite/melatonin reaction suggests that both peroxynitrous acid (ONOOH) and its anion (ONOO-) are reactive toward melatonin, but at physiological pH most of the reaction with melatonin involves ONOOH and the activated form of peroxynitrous acid (ONOOH). The formation of hydroxylated products (mainly 6-hydroxymelatonin) suggests that melatonin also reacts with ONOOH. The overall peroxynitrite/melatonin reaction is first-order in melatonin and first-order in peroxynitrite, but the hydroxylation of melatonin is presumed to be zero-order in melatonin. Melatonin is metabolized in the liver, mainly to 6-hydroxymelatonin, so we do not think this metabolite is a useful biomarker for melatonin's antioxidant activity; however, 6-hydroxymelatonin is a better chain-breaking antioxidant than melatonin and may contribute to the beneficial effects of melatonin in vivo. As is now well-known, CO2 modulates the reactions of peroxynitrite. The reaction of peroxynitrite with melatonin in the absence of added bicarbonate produces mainly 6-hydroxymelatonin and 1,2,3,3a,8, 8a-hexahydro-1-acetyl-5-methoxy-8a-hydroxypyrrolo[2,3-b]indole, with some isomeric 1,2,3,3a,8, 8a-hexahydro-1-acetyl-5-methoxy-3a-hydroxypyrrolo[2,3-b]indole. In the presence of added bicarbonate, product yields decrease and 6-hydroxymelatonin is not formed. These facts suggest that melatonin scavenges reactive species (such as CO3*- and *NO2) that are produced from the peroxynitrite/CO2 reaction. The spectrum of the melatoninyl radical cation is observed both in the absence and in the presence of added bicarbonate, suggesting that the melatoninyl radical cation is the initial product and the hydroxypyrrolo[2, 3-b]indole products are derived from it. Unlike tyrosine, where both nitrated and hydroxylated products can be isolated, nitromelatonin is not found in the final products from the melatonin/peroxynitrite reaction in either the absence or presence of added bicarbonate. However, we suggest that 2-hydroxy-3-nitro- and/or 2-hydroxy-3-peroxynitro-2,3-dihydromelatonin are formed as intermediates and subsequently decompose to give 1,2,3,3a,8, 8a-hexahydro-1-acetyl-5-methoxy-8a-hydroxypyrrolo[2,3-b]indole. Since peroxynitrite/CO2 governs the reactions of peroxynitrite in vivo, we suggest that the hydroxypyrrolo[2,3-b]indole products are the main products from the oxidation of melatonin by peroxynitrite-derived species in vivo, and that these products may serve as indexes for melatonin's antioxidant activity.

Bicarbonates↗
PubMed1998

Slowing of peroxynitrite decomposition in the presence of mannitol and ethanol.

The kinetics of peroxynitrite decomposition in the presence of the hydroxyl radical scavengers mannitol and ethanol were studied by stopped-flow spectrophotometry. Mannitol and ethanol decreased the rate of peroxynitrite decomposition in a concentration-dependent manner, following a hyperbolic function. The decreases in peroxynitrite decay rates were observed all throughout the pH range 5.8 to 8.0. In the presence of 100 mM mannitol or ethanol, the first-order rate constant for peroxynitrite decomposition changed from 1.25 +/- 0.01 s-1 at 25 degrees C, to values of 0.83 +/- 0.01 s-1 and 0.95 +/- 0.01 s-1, respectively. One explanation for this decrease in the rate of peroxynitrite decay with mannitol and ethanol could be a stabilizing effect of the substrate by hydrogen bonding with peroxynitrite, analogous to what has been recently proposed for hydrogen peroxide (Alvarez, B., Denicola, A. and Radi, R. Chem. Res. Toxicol. 8:859-869; 1995). In this sense, kinetic data fitted a mechanism implying fast equilibria between peroxynitrite anion and peroxynitrous acid with the substrates to form the corresponding complexes. The equilibrium constants of complex dissociation were estimated to be (6.7 +/- 0.9) x 10(-3) M and (9.6 +/- 1.5) x 10(-3) M for mannitol and ethanol, respectively. When bonded to mannitol or ethanol, peroxynitrous acid could ionize, too, or decompose at a slower rate than in the absence of substrate, in part to a reactive intermediate which performs oxidations. While mannitol and ethanol inhibit oxidation and nitration processes that occur through the reaction of secondary reactive intermediates of peroxynitrite with target molecules, up to 0.5 M mannitol or ethanol failed to inhibit cysteine oxidation by peroxynitrite at pH 7.4 and 25 degrees C. Thus, the formation of stabilizing complexes would not divert the reaction yield of direct, second order reactions such as thiol oxidation, but highlights the importance of hydrogen bonding and solvent effects on peroxynitrite stability.

Buffers↗