The kinetics of the oxidation of l-ascorbic acid by peroxynitrite

Bartlett, Delland; Church, Daniel F.; Bounds, Patricia L.; Koppenol, Willem H.

doi:10.1016/0891-5849(94)e0133-4

Cited by 180 publications

(101 citation statements)

References 32 publications

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“…This conclusion is somewhat surprising because AA is known to react with most biologically relevant reactive species, including ONOO − [12][13][14][15][16][17]. Although various reports have shown that AA is an efficient scavenger of ONOO − in itro [18], it is still unclear whether cells with an increased content of AA are more resistant than control cells to the lethal response mediated by ONOO − .…”

Section: Resultsmentioning

confidence: 57%

“…AA is a major water-soluble antioxidant, found in the aqueous compartments of cells and extracellular fluids, that is capable of scavenging reactive oxygen [12][13][14] and nitrogen [15][16][17] species. However, although various papers have shown that AA is an efficient scavenger of ONOO − in in itro systems [18], it is still unclear whether intracellular AA mitigates the lethal response mediated by ONOO − .…”

Section: Introductionmentioning

confidence: 99%

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Intracellular ascorbic acid enhances the DNA single-strand breakage and toxicity induced by peroxynitrite in U937 cells

et al. 2001

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A well-established protocol to increase the intracellular content of ascorbic acid was used to investigate the effects of the vitamin on DNA single-strand breakage and toxicity mediated by authentic peroxynitrite (ONOO-) in U937 cells. This protocol involved exposure for 60 min to 100 muM dehydroascorbic acid, which was taken up by the cells and converted into ascorbic acid via a GSH-independent mechanism. At the time of exposure to ONOO-, which was performed in fresh saline immediately after loading with dehydroascorbic acid, the vitamin present in the cells was all in its reduced form. It was found that, in cells that are otherwise ascorbate-deficient, an increase in their ascorbic acid content does not prevent, but rather enhances, the DNA-damaging and lethal responses mediated by exogenous ONOO-. These results therefore suggest that acute supplementation of ascorbic acid can be detrimental for individuals with pathologies associated with a decrease in ascorbic acid and in which ONOO- is known to promote deleterious effects

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Section: Resultsmentioning

confidence: 57%

Section: Introductionmentioning

confidence: 99%

Intracellular ascorbic acid enhances the DNA single-strand breakage and toxicity induced by peroxynitrite in U937 cells

et al. 2001

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“…After incubation for 15 min at 30°C and separation on 12% SDS͞PAGE, autoradiography was performed. (1,075 Ci͞mmol). After labeling, the cells were processed as described (19).…”

Section: Methodsmentioning

confidence: 99%

“…A ctivated macrophages produce large amounts of nitric oxide (NO), which induces cytostasis and cytotoxicity to tumor cells both in vitro and in vivo (1)(2)(3)(4)(5)(6)(7)(8). Macrophages also play a significant role in host resistance to tumors (7)(8)(9).…”

mentioning

confidence: 99%

Nitric oxide-induced cytostasis and cell cycle arrest of a human breast cancer cell line (MDA-MB-231): Potential role of cyclin D1

Pervin

Singh

Chaudhuri

2001

Proc. Natl. Acad. Sci. U.S.A.

159

113

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DETA-NONOate, a nitric oxide (NO) donor, induced cytostasis in the human breast cancer cells MDA-MB-231, and the cells were arrested in the G 1 phase of the cell cycle. This cytostatic effect of the NO donor was associated with the down-regulation of cyclin D1 and hypophosphorylation of the retinoblastoma protein. No changes in the levels of cyclin E or the catalytic partners of these cyclins, CDK2, CDK4, or CDK6, were observed. This NO-induced cytostasis and decrease in cyclin D1 was reversible for up to 48 h of DETA-NONOate (1 mM) treatment. DETA-NONOate (1 mM) produced a steady-state concentration of 0.5 M of NO over a 24-h period. Synchronized population of the cells exposed to DETANONOate remained arrested at the G 1 phase of the cell cycle whereas untreated control cells progressed through the cell cycle after serum stimulation. The cells arrested at the G 1 phase after exposure to the NO donor had low cyclin D1 levels compared with the control cells. The levels of cyclin E and CDK4, however, were similar to the control cells. The decline in cyclin D1 protein preceded the decrease of its mRNA. This decline of cyclin D1 was due to a decrease in its synthesis induced by the NO donor and not due to an increase in its degradation. We conclude that down-regulation of cyclin D1 protein by DETA-NONOate played an important role in the cytostasis and arrest of these tumor cells in the G 1 phase of the cell cycle.A ctivated macrophages produce large amounts of nitric oxide (NO), which induces cytostasis and cytotoxicity to tumor cells both in vitro and in vivo (1-8). Macrophages also play a significant role in host resistance to tumors (7-9). Tumor cells cocultured with activated macrophages rapidly develop cytostasis, which precedes the cytotoxic effects (5, 10).It has been reported that NO-induced early cytostasis begins with a rapid and reversible inhibition of ribonucleotide reductase (RR) (10). However, the possibility of targets other than RR being involved in the NO-induced long-lasting cytostasis was suggested by other investigators (10). Hydroxyurea, a specific inhibitor of RR (10), decreased thymidine incorporation in cultured cells and, after its removal, the thymidine incorporation rapidly returned to control values. The rate of recovery was much faster after withdrawal of hydroxyurea when compared with the rate of recovery observed in cells that initially were exposed either to activated macrophages or to a NO donor and then kept in a NO-free environment. On this basis, it was suggested that targets other than RR may be responsible for producing long-lasting cytostasis in target cells exposed to NO (5,10,11). This long-lasting cytostasis, therefore, would be associated with metabolic alterations in target cells, producing long-lasting growth inhibition and requiring a longer time for these cells to resume their normal rate of proliferation.Because the precise mechanism(s) by which NO induces this long-lasting cytostasis is not completely known, the present work was undertaken to assess this mechanism(s)...

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“…1 Consequently, peroxynitrite has been implicated in many pathological conditions including stroke (3), heart disease (4), and atherosclerosis (5,6). The potential cellular targets for peroxynitrite cytotoxicity include the antioxidants ascorbate, ␣-tocopherol, and uric acid (7)(8)(9)(10), protein and non-protein sulfhydryls (11), DNA (12), and membrane phospholipids (13). Decomposition of peroxynitrite is complex (14,15).…”

mentioning

confidence: 99%

Metabolic Fate of Peroxynitrite in Aqueous Solution

Pfeiffer

Gorren

Schmidt

et al. 1997

Journal of Biological Chemistry

298

162

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Peroxynitrite, the reaction product of nitric oxide (NO) and superoxide (O 2 . ) is assumed to decompose upon protonation in a first order process via intramolecular rearrangement to NO 3 ؊ . The present study was carried out to elucidate the origin of NO 2 ؊ found in decomposed peroxynitrite solutions. As revealed by stopped-flow spectroscopy, the decay of peroxynitrite followed firstorder kinetics and exhibited a pK a of 6.8 ؎ 0.1. The reaction of peroxynitrite with NO was considered as one possible source of NO 2 ؊ , but the calculated second order rate constant of 9.1 ؋ 10 4 M ؊1 s ؊1 is probably too small to explain NO 2 ؊ formation under physiological conditions. Moreover, pure peroxynitrite decomposed to NO 2 ؊ without apparent release of NO. Determination of NO 2 ؊ and NO 3 ؊ in solutions of decomposed peroxynitrite showed that the relative amount of NO 2 ؊ increased with increasing pH, with NO 2 ؊ accounting for about 30% of decomposition products at pH 7.5 and NO 3 ؊ being the sole metabolite at pH 3.0. Formation of NO 2 ؊ was accompanied by release of stoichiometric amounts of O 2 (0.495 mol/mol of NO 2 ؊ ). The two reactions yielding NO 2 ؊ and NO 3 ؊ showed distinct temperature dependences from which a difference in E act of 26.2 ؎ 0.9 kJ mol ؊1 was calculated. The present results demonstrate that peroxynitrite decomposes with significant rates to NO 2 ؊ plus O 2 at physiological pH. Through formation of biologically active intermediates, this novel pathway of peroxynitrite decomposition may contribute to the physiology and/or cytotoxicity of NO and superoxide.The reaction between nitric oxide (NO) and superoxide anion (O 2 . ) yields peroxynitrite with a second order rate constant near the diffusion-controlled limit (k ϭ 4.3-6.7 ϫ 10 9 M Ϫ1 s Ϫ1 ) (1, 2). The reaction constitutes an important sink for O 2 . because it is about twice as fast as the maximum velocity of SOD. 1 Consequently, peroxynitrite has been implicated in many pathological conditions including stroke (3), heart disease (4), and atherosclerosis (5, 6). The potential cellular targets for peroxynitrite cytotoxicity include the antioxidants ascorbate, ␣-tocopherol, and uric acid (7-10), protein and non-protein sulfhydryls (11), DNA (12), and membrane phospholipids (13). Decomposition of peroxynitrite is complex (14, 15). The anion is rather stable in alkaline solutions but decomposes rapidly (t 1/2 ϭ 1 s at pH 7.4, 37°C) upon protonation to peroxynitrous acid (ONOOH) (pK a ϭ 6.8) (16). Two pathways of ONOOH decomposition have been proposed. Some studies have argued that ONOOH is cleaved homolytically to generate hydroxyl and NO 2 radicals. This hypothesis is based on the sensitivity to hydroxyl radical scavengers of certain peroxynitrite-induced reactions, including the formation of malondialdehyde from deoxyribose and the hydroxylation on the benzene ring of sodium benzoate, phenylalanine, and tyrosine (16, 17). Studies on decomposition of peroxynitrite by electron paramagnetic resonance spectroscopy with the spin traps 5,5-dime...

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The kinetics of the oxidation of l-ascorbic acid by peroxynitrite

Cited by 180 publications

References 32 publications

Intracellular ascorbic acid enhances the DNA single-strand breakage and toxicity induced by peroxynitrite in U937 cells

Intracellular ascorbic acid enhances the DNA single-strand breakage and toxicity induced by peroxynitrite in U937 cells

Nitric oxide-induced cytostasis and cell cycle arrest of a human breast cancer cell line (MDA-MB-231): Potential role of cyclin D1

Metabolic Fate of Peroxynitrite in Aqueous Solution

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