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Reaction of uric acid with peroxynitrite and implications for the mechanism of neuroprotection by uric acid 总被引:12,自引:0,他引:12
Squadrito GL Cueto R Splenser AE Valavanidis A Zhang H Uppu RM Pryor WA 《Archives of biochemistry and biophysics》2000,376(2):333-337
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. 相似文献
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Towards the physiological function of uric acid 总被引:48,自引:0,他引:48
Uric acid, or more correctly (at physiological pH values), its monoanion urate, is traditionally considered to be a metabolically inert end-product of purine metabolism in man, without any physiology value. However, this ubiquitous compound has proven to be selective antioxidant, capable especially of reaction with hydroxyl radicals and hypochlorous acid, itself being converted to innocuous products (allantoin, allantoate, glyoxylate, urea, oxalate). There is now evidence for such processes not only in vitro and in isolated organs, but also in the human lung in vivo. Urate may also serve as an oxidase cosubstrate for the enzyme cyclooxygenase. As shown for the coronary system, a major site of production of urates is the microvascular endothelium, and there is generally a net release of urate from the human myocardium in vivo. In isolated organ preparations, urate protects against reperfusion damage induced by activated granulocytes, cells known to produce a variety of radicals and oxidants. Intriguingly, urate prevents inactivation of endothelial enzymes (cyclooxygenase, angiotensin converting enzyme) and preserves the ability of the endothelium to mediate vascular dilatation in the face of oxidative stress, suggesting a particular relationship between the site of urate formation and the need for a biologically potent radical scavenger and antioxidant. 相似文献
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Summary Obesity, alcohol consumption, and hematocrit provide an index of plasma uric acid, which in path analysis has a cultural heritability of 0.11 in children and 0.23 in parents, a small maternal effect, and a genetic heritability of 0.25 in both generations. Preliminary evidence for a major locus is destroyed by the omission of one exceptional child. There is no evidence against the polygenic hypothesis for hyperuricemia in the Japanese-American population studied. 相似文献
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Action of biologically-relevant oxidizing species upon uric acid. Identification of uric acid oxidation products 总被引:4,自引:0,他引:4
Uric acid is an end-product of purine metabolism in Man, and has been suggested to act as an antioxidant in vivo. Products of attack upon uric acid by various oxidants were measured by high performance liquid chromatography. Hypochlorous acid rapidly oxidized uric acid, forming allantoin, oxonic/oxaluric and parabanic acids, as well as several unidentified products. HOCl could oxidize all these products further. Hydrogen peroxide did not oxidize uric acid at detectable rates, although it rapidly oxidized oxonic acid and slowly oxidized allantoin and parabanic acids. Hydroxyl radicals generated by hypoxanthine/xanthine oxidase or Fe2(+)-EDTA/H2O2 systems also oxidized uric acid to allantoin, oxonic/oxaluric acid and traces of parabanic acid. Addition of ascorbic acid to the Fe2(+)-EDTA/H2O2 system did not increase formation of oxidation products from uric acid, possibly because ascorbic acid can 'repair' the radicals resulting from initial attack of hydroxyl radicals upon uric acid. Mixtures of methaemoglobin or metmyoglobin and H2O2 also oxidized uric acid: allantoin was the major product, but some parabanic and oxonic/oxaluric acids were also produced. Caeruloplasmin did not oxidize uric acid under physiological conditions, although simple copper (Cu2+) ions could, but this was prevented by albumin or histidine. The possibility of using oxidation products of uric acid, such as allantoin, as an index of oxidant generation in vivo in humans is discussed. 相似文献
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A general procedure to obtain tetra-substituted uric acid by stepwise N-alkylation is described. 2,6-Dichloropurine (1) was condensed with 1-propanol by Mitsunobu reaction to give 9-propyl congener (2). Treatment of 2 with ammonia gave adenine derivative (4a), which was converted to the 8-oxoadenine (5b) in 3 steps. Methylation of 5b proceeded site-specifically to give 6-amino-2-chloro-7,8-dihydro-7-methyl-9-propylpurin-8-one (6) as a sole product. Compound 6 was successively treated with NaNO2 and iodomethane to give 2-chloro-1,6,7,8-tetrahydro-1,7-dimethyl-9-propylpurin-6,8-dione (9) accompanied by the O6-methyl product (8) in 75% and 6.9%, respectively. After nucleophilic substitution of 9 with NaOAc, the product (11) was reacted with iodomethane to give the uric acid (12) and the 2-methoxy product (13) in 46% and 15.5%, respectively. However, the reaction of 11 with the benzylating agents gave only O-benzyl products (14a,b). 相似文献
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Infection of erythrocytes with the Plasmodium parasite causes the pathologies associated with malaria, which result in at least one million deaths annually. The rupture of infected erythrocytes triggers an inflammatory response, which is induced by parasite-derived factors that still are not fully characterized. Induced secretion of inflammatory cytokines by these factors is considered a major cause of malaria pathogenesis. In particular, the inflammatory cytokine tumor necrosis factor (TNF) is thought to mediate most of the life-threatening pathologies of the disease. Here we describe the molecular characterization of a novel pathway that results in the secretion of TNF by host cells. We found that erythrocytes infected by Plasmodium accumulate high concentrations of hypoxanthine and xanthine. Degradation of Plasmodium-derived hypoxanthine/xanthine results in the formation of uric acid, which triggers the secretion of TNF. Since uric acid is considered a "danger signal" released by dying cells to alert the immune system, Plasmodium appears to have co-evolved to exploit this warning system. Identifying the mechanisms used by the parasite to induce the host inflammatory response is essential to develop urgently needed therapies against this disease. 相似文献
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Free radical metabolite of uric acid 总被引:2,自引:0,他引:2
Uric acid has previously been shown to act as a water-soluble antioxidant. Although the antioxidant activity of uric acid has been attributed to its ability to scavenge free radicals, the one-electron uric acid oxidation product of such a scavenging reaction has not been detected. It order to determine whether a free radical metabolite of uric acid could be formed via one-electron redox processes, we oxidized uric acid with potassium permanganate, horseradish peroxidase/hydrogen peroxide, and hematin/hydrogen peroxide systems. With the use of the rapid-mixing, continuous-flow electron spin resonance technique, we were able to detect the urate anion free radical in all three radical-generating systems. Based on N15-isotopic-labeling experiments, we show that the unpaired electron of this radical is located primarily on the five-membered ring of the purine structure. We were also able to demonstrate that this radical could be scavenged by ascorbic acid. 相似文献
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Stibůrková B Pospísilová E Kmoch S Sebesta I 《Nucleosides, nucleotides & nucleic acids》2006,25(9-11):1301-1304
Excretion fraction of uric acid (EFUA), is one of the most important hallmarks for diagnosis of familial juvenile hyperuricemic nephropathy (FJHN) and hereditary renal hypouricemia. EFUA was measured in 20 patients with FJHN. However, low excretion fraction (<6%) was found also in healthy FJHN family members and healthy controls (ref. ranges EFUA: men 6-12%, women 6-20%). Similar finding of low EFUA was reported recently. Distribution of EFUA was further studied in 2,416 healthy controls, which were selected from 6,000 samples and divided according to age. In conclusion, finding of low EFUA in family members is a risk factor for renal damage and indication for purine metabolic investigations with subsequent molecular biology analysis. As EFUA could be found also in healthy controls--it should be interpreted with care and other features of FJHN (such as hyperuricemia, progressive renal disease in family) should be taken to account. 相似文献