Inhibition by Uric Acid of Free Radicals that Damage Biological Molecules

Muraoka, Sanae; Miura, Toshiaki

doi:10.1111/j.1600-0773.2003.pto930606.x

Cited by 115 publications

(77 citation statements)

References 31 publications

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“…UA effectively blocks peroxynitrite-mediated tyrosine nitration in vitro by a reaction with second-order kinetics (21). On the other hand, UA enhances the oxidation of low-density lipoproteins by peroxynitrite in vitro (39) and has variable effects on lipid peroxidation by other radicals (45). In an EAE model, where peroxynitrite makes a major contribution to pathology, UA treatment inhibits tyrosine nitration in lesions (24) but fails to significantly reduce lipid peroxidation (38).…”

Section: Discussionmentioning

confidence: 99%

Uric acid protects against secondary damage after spinal cord injury

Scott

Cuzzocrea

Genovese

et al. 2005

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

114

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Peroxynitrite contributes to the pathogenesis of various neurodegenerative disorders through multiple mechanisms and is thought to mediate secondary neuronal cell death after spinal cord injury (SCI). Here we establish that physiologically relevant levels of uric acid (UA), a selective inhibitor of certain peroxynitrite-mediated reactions, block the toxic effects of peroxynitrite on primary spinal cord neurons in vitro. Furthermore, administration of UA at the onset of SCI in a mouse model inhibits several pathological changes in the spinal cord including general tissue damage, nitrotyrosine formation, lipid peroxidation, activation of poly(ADP-ribose) polymerase, and neutrophil invasion. More importantly, UA treatment improves functional recovery from the injury. Taken together, our findings support the concept that peroxynitrite contributes to the pathophysiology of secondary damage after SCI. They also raise the possibility that elevating UA levels may provide a therapeutic approach for the treatment of SCI as well as other neurological diseases with a peroxynitrite-mediated pathological component.blood-brain barrier ͉ neutrophils ͉ peroxynitrite ͉ spinal cord neurons ͉ cytotoxicity A cascade of pathophysiological processes rapidly follows mechanical trauma to the spinal cord, resulting in secondary neuronal damage that can significantly exacerbate the original injury (1). An acute inflammatory response at the site of the initial lesion is at least partly responsible for this secondary spinal cord pathology (e.g., refs. 2-4). Among the inflammatory cells recruited to the injured area are macrophages͞microglia and neutrophils that can mediate tissue damage by producing a variety of cytotoxic factors including reactive nitrogen species (3-7). Several studies have implicated peroxynitrite, a molecule generated when nitric oxide and superoxide combine, in secondary neuronal damage after spinal cord injury (SCI) (5-7). Not only has evidence of peroxynitrite production been detected in spinal cord tissues from rats after traumatic injury (5-7), but administration of a peroxynitrite donor directly into the rat spinal cord has been shown to cause neuronal cell death and neurological deficit (8). In addition, a number of previous reports have demonstrated that peroxynitrite is toxic for neurons, including primary spinal cord neurons, and neuronal cell lines in vitro (9-13).Peroxynitrite is known to mediate several potentially destructive chemical reactions, including tyrosine nitration and lipid peroxidation (14). Mitochondrial respiration is directly inhibited by peroxynitrite and is an early marker of its cytotoxic effects (9,14). In addition, peroxynitrite causes DNA strand breakage, which activates the enzyme poly(ADP-ribose) polymerase (PARP), which in turn triggers a cascade of processes that often lead to cell death (14). Because increased nitrotyrosine formation, lipid peroxidation, and PARP activation have all been associated with secondary damage in spinal cord trauma (5-7, 14-20), it is possible that second...

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Section: Discussionmentioning

confidence: 99%

Uric acid protects against secondary damage after spinal cord injury

Scott

Cuzzocrea

Genovese

et al. 2005

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

114

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“…[37] Uric acid is a powerful scavenger of carbon-centered and peroxyl radicals in the hydrophilic environment but loses an ability to scavenge lipophilic radicals and cannot break the radical chain propagation within lipid membranes. [38] At the same time, peroxynitrous radicals are extremely diffusible through the membrane, [39] and the hydrophobic environment is also more favorable for tyrosine nitration. [40,41] Thus, these physicochemical findings could explain why the antioxidant effects of uric acid are manifested only in the hydrophilic environment of biological fluids, such as plasma.…”

Section: Antioxidant Function Of Uric Acid and Its Limitationsmentioning

confidence: 99%

“…[45] Thus, uric acid can become a pro-oxidant by forming radicals in reactions with other oxidants, and these radicals seem to target predominantly lipids (LDL and membranes) rather than other cellular components. At the same time, the hydrophobic environment created by lipids is unfavorable for the antioxidant effects of uric acid, [38] and oxidized lipids can even convert uric acid into an oxidant.[45] Given this background and association of hyperuricemia with obesity one may infer that uric acid has a direct effect on the adipose tissue, and this effect might have a redox-dependent component.Well-established model of adipocytes differentiated in vitro from the mouse embryonic fibroblast cell line 3T3-L1 [46,47] were used to characterize the effects of uric acid. An interesting phenotypic feature of differentiated adipocytes is a substantial uptake rate for urate, an expression of the urate transporters of OAT family URAT1 and OAT4, and high basal level Sautin and Johnson Page 3 Nucleosides Nucleotides Nucleic Acids.…”

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confidence: 99%

Uric Acid: The Oxidant-Antioxidant Paradox

Sautin

Johnson

2008

Nucleosides, Nucleotides and Nucleic Acids

724

549

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Uric acid, despite being a major antioxidant in the human plasma, both correlates and predicts development of obesity, hypertension, and cardiovascular disease, conditions associated with oxidative stress. While one explanation for this paradox could be that a rise in uric acid represents an attempted protective response by the host, we review the evidence that uric acid may function either as an antioxidant (primarily in plasma) or pro-oxidant (primarily within the cell). We suggest that it is the pro-oxidative effects of uric acid that occur in cardiovascular disease and may have a contributory role in the pathogenesis of these conditions. KeywordsUric acid; redox homeostasis; metabolic syndrome; cardiovascular disease Uric acid is a final enzymatic product in the degradation of purine nucleosides and free bases in humans and Great Apes. The pathway of purine catabolism in humans is shortest among vertebrates because about 8-20 million years ago during primate evolution the activity of urate oxidase (uricase, an enzyme catalyzing conversion of uric acid to allantoin) was lost in a twostep mutation process. [1,2] In other mammals, the last enzymatic product of purine degradation chain is allantoin, which is excreted in the urine. Lower vertebrates (e.g., fish) have enzymes that further degrade allantoin to allantoic acid and glyoxylic acid and finally to urea. As a consequence, humans have to cope with relatively higher levels of uric acid in the blood (200-400 μM) and are prone to hyperuricemia and gout. [3] According to a hypothesis championed in the early eighties by Ames et al.,[4] the silencing of the uricase gene with an increase in the blood level of uric acid provided an evolutionary advantage for ancestors of Homo sapiens. This hypothesis was based on in vitro experiments which showed that uric acid is a powerful scavenger of singlet oxygen, peroxyl radicals (RO · 2 ) and hydroxyl radicals ( · OH). Urate circulating in elevated concentrations was proposed to be one of the major antioxidants of the plasma that protects cells from oxidative damage, thereby contributing to an increase in life span of our species and decreasing the risk for cancer.On the other hand, a vast literature on the epidemiology of cardiovascular disease, hypertension, and metabolic syndrome overwhelmingly shows that, at least among modern Homo sapiens, a high level of uric acid is strongly associated and in many cases predicts development of hypertension, [5][6][7] visceral obesity, [8][9][10] insulin resistance, [8,11,12] dyslipidemia, [8,[11][12][13] ANTIOXIDANT FUNCTION OF URIC ACID AND ITS LIMITATIONSThe ability of urate to scavenge oxygen radicals and protect the erythrocyte membrane from lipid oxidation was originally described by Kellogg and Fridovich,[21] and was characterized further by Ames et al.[4] Although these experiments defined a paradigm, they addressed effects of uric acid under specific conditions in which exogenously added uric acid protected cells from oxidants, which were also added exogenously to ...

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“…Urate thus accounts for approximately half of the antioxidant capacity of human plasma, and its antioxidant properties are as powerful as those of ascorbic acid (27,28). As illustrated in Figure 2A, uric acid can prevent peroxynitrite-induced protein nitrosation (29), lipid and protein peroxidation (30), and inactivation of tetrahydrobiopterin (31), a cofactor necessary for NOS. Uric acid also protects LDL from Cu 2+ -mediated oxidation ( Figure 2B).…”

Section: Uric Acid: Antioxidant or Pro-oxidant?mentioning

confidence: 99%

Uric acid transport and disease

Thorens²

2010

J. Clin. Invest.

669

496

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Uric acid is the metabolic end product of purine metabolism in humans. It has antioxidant properties that may be protective but can also be pro-oxidant, depending on its chemical microenvironment. Hyperuricemia predisposes to disease through the formation of urate crystals that cause gout, but hyperuricemia, independent of crystal formation, has also been linked with hypertension, atherosclerosis, insulin resistance, and diabetes. We discuss here the biology of urate metabolism and its role in disease. We also cover the genetics of urate transport, including URAT1, and recent studies identifying SLC2A9, which encodes the glucose transporter family isoform Glut9, as a major determinant of plasma uric acid levels and of gout development.Conflict of interest: Alexander So has acted as a consultant and advisor for Novartis.Citation for this article:

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Inhibition by Uric Acid of Free Radicals that Damage Biological Molecules

Cited by 115 publications

References 31 publications

Uric acid protects against secondary damage after spinal cord injury

Uric acid protects against secondary damage after spinal cord injury

Uric Acid: The Oxidant-Antioxidant Paradox

Uric acid transport and disease

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