Nitrosation of Uric Acid by Peroxynitrite. FORMATION OF A VASOACTIVE NITRIC OXIDE DONOR (original) (raw)
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Uric Acid and Oxidative Stress
Current Pharmaceutical Design, 2005
U'c acid is the final product of purine metabolism in humans. The final two reactions of its production catalyzingthe conversion ofhypoxanthineto xanthine and the latter.to uric.acid are catalysed by the enzyme xanthine oxidoreductme, which may attaln tlvo rnter-convertible forms, namely xanthine dehydrogenase or xanthine oxidase The latter uses molecular oxygen as electron acceptor and generates superoxide anion and other reactive oxygen products The role of uric acid in conditions associated with o;idative stress is not entirely clear. Evidence mainly based on epidemiotogical studies suggests that increased serum levels of uric acid are a risk factor for cardiovascular disease where oxidative stress plays an important pathophysiological role. Also, allopurinol, a xanthine oxidoreductase inhibitor that lowers serum levels of uric acid exerts protective;ffects in situations associated with oxidative stress (e g ischaemiareperfusion in1ury, cardiovascular disease). However, there is increasing experimental and clinical evidence showing that uric acid has an important role in vivo as an antioxidant'
Towards the physiological function of uric acid
Free Radical Biology and Medicine, 1993
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 physiological value. However, this ubiquitous compound has proven to be a 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 oxidisable cosubstrate for the enzyme cyclooxygenase. As shown for the coronary system, a major site of production of urate is the microvascular endothelium, and there is generally a net release ofurate 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 oxidative 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.
Chemico-Biological Interactions, 1990
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. HOCI 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/H202 systems also oxidized uric acid to allantoin, oxonic/oxaluric acid and traces of parabanic acid. Addition of ascorbic acid to the Fe2+-EDTA/H202 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 H202 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 (Cu 2÷) 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.
Review of Concepts and Controversies of Uric Acid as Antioxidant and Pro-Oxidant
Uric acid, the end product of purine catabolism in humans and is known for its crystal deposition at higher concentrations (>7 mg/dl) in gout. Less is known about its antioxidant property and the beneficial effects in various diseases. It is thought that high concentration of uric acid in humans is an evolutionary advantage and it is also hypothesized that high concentration of uric acid is to compensate the antioxidant capacity of ascorbic acid which is lost in humans during the course of evolution. In the extracelluar environment, uric acid can scavenge free radicals like hydroxyl radical, singlet oxygen and peroxynitrite radical therefore, it is considered as a powerful antioxidant. On the other hand uric acid depending upon the chemical milieu, changing its property and at times it acts as pro oxidant and is associated with the pathobiochemistry in developing various diseases like hypertension, cardio vascular diseases, ischemia reperfusion injury, diabetes mellitus, non alcoholic fatty liver disorders etc. In this review, we tried to summarize the evolutionary advantages of hyperuricaemia, effects of both antioxidant property and pro-oxidant nature of uric acid in various disease conditions.
Free radical biology & medicine, 2018
Uric acid is the final product of purine metabolism in humans and is considered to be quantitatively the main antioxidant in plasma. In vitro studies showed that the oxidation of uric acid by peroxidases, in presence of superoxide, generates urate free radical and urate hydroperoxide. Urate hydroperoxide is a strong oxidant and might be a relevant intermediate in inflammatory conditions. However, the identification of urate hydroperoxide in cells and biological samples has been a challenge due to its high reactivity. By using mass spectrometry, we undoubtedly demonstrated the formation of urate hydroperoxide and its corresponding alcohol, hydroxyisourate during the respiratory burst in peripheral blood neutrophils and in human leukemic cells differentiated in neutrophils (dHL-60). The respiratory burst was induced by phorbol myristate acetate (PMA) and greatly increased oxygen consumption and superoxide production. Both oxygen consumption and superoxide production were further augme...
Uric acid and oxidative stress: Relative impact on cardiovascular risk
Nutrition, Metabolism and Cardiovascular Diseases, 2007
Post-hoc analyses of the GREACE and the LIFE trials have renewed the interest in elevated serum uric acid (SUA) as a factor contributing to atherosclerotic cardiovascular disease (CVD) and in the possible benefit derived from its pharmacological reduction. The results of these trials are consistent with reports indicating favourable effects of SUA lowering treatment with allopurinol on the rate of cardiovascular complications in patients with coronary heart disease, congestive heart failure and dilated cardiomyopathy.
Archives of Biochemistry and Biophysics, 2000
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°C, pH 7.4) giving a pseudo-first-order rate constant in blood plasma k Urate /plasma ؍ 0.05 s ؊1 (T ؍ 37°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 CO2 /plasma ؍ 46 s ؊1 (T ؍ 37°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.
Uric Acid and Oxidative Stress—Relationship with Cardiovascular, Metabolic, and Renal Impairment
International Journal of Molecular Sciences, 2022
Background: The connection between uric acid (UA) and renal impairment is well known due to the urate capacity to precipitate within the tubules or extra-renal system. Emerging studies allege a new hypothesis concerning UA and renal impairment involving a pro-inflammatory status, endothelial dysfunction, and excessive activation of renin–angiotensin–aldosterone system (RAAS). Additionally, hyperuricemia associated with oxidative stress is incriminated in DNA damage, oxidations, inflammatory cytokine production, and even cell apoptosis. There is also increasing evidence regarding the association of hyperuricemia with chronic kidney disease (CKD), cardiovascular disease, and metabolic syndrome or diabetes mellitus. Conclusions: Important aspects need to be clarified regarding hyperuricemia predisposition to oxidative stress and its effects in order to initiate the proper treatment to determine the optimal maintenance of UA level, improving patients’ long-term prognosis and their quali...
Uric acid and serum antioxidant capacity: a reaction to atherosclerosis
Atherosclerosis, 2000
Background: the evidence of a potential beneficial role of antioxidants in preventing atherosclerotic disease is not entirely consistent. Objecti6e: to assess the longitudinal association of serum total antioxidant capacity and serum antioxidants with the presence of subclinical carotid atherosclerosis. Methods: Prospective case-control study nested within an historical cohort. Cases were 150 individuals with elevated carotid intimal-medial thickness measured by B-mode ultrasound at the first two examinations of the Atherosclerosis Risk in Communities Study (1987 -92). Controls were 150 age -gender-matched individuals with low carotid intimal-medial thickness. Serum antioxidant vitamins, uric acid, and serum total antioxidant capacity were measured in frozen serum samples collected from the same individuals in 1974 (13 -15 years prior to the determination of case-control status). Results: Compared to controls, atherosclerosis cases had significantly higher levels of serum total antioxidant capacity in 1974 than controls. This difference was almost entirely explained by increased serum concentration of uric acid in cases. In contrast with cross-sectional results, uric acid serum concentration in 1974, was significantly higher in cases than in controls, even after adjusting for the main cardiovascular risk factors. Cases had significantly lower levels of a-carotene in the 1974 sera than controls, but no other differences in serum antioxidant vitamin concentrations were observed. Conclusions: The higher serum uric acid concentration seemed associated with elevated total serum antioxidant capacity among individuals with atherosclerosis. This finding is consistent with experimental evidence suggesting that hyperuricemia may be a compensatory mechanism to counteract oxidative damage related to atherosclerosis and aging in humans.