Uric Acid: The Oxidant-Antioxidant Paradox

Abstract

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 ...

U‐Shaped Association Between Serum Uric Acid Levels With Cardiovascular and All‐Cause Mortality in the Elderly: The Role of Malnourishment

“…Cardiovascular disease (CVD) is the leading cause of death in the older population, and the prevalence and incidence of CVD increases exponentially with advancing age 2. Uric acid, the final product of purine degradation in humans, mediates proinflammatory endothelial dysfunction and is associated with greater risks for CVD events 3, 4. Although a wealth of research has reported that an elevated serum uric acid (SUA) level >7 mg/dL independently predicts all‐cause and CVD‐related mortality in middle‐aged adults,5, 6, 7 studies linking hyperuricemia to mortality risks in the elderly population are conflicting and inconclusive 8, 9, 10, 11, 12, 13, 14.…”

Levels of two oxidative stress indicators of human sickle erythrocytes incubated in aqueous extracts of Anacardium occidentale, Psidium guajava and Terminalia catappa.

“…Erythrocytes-reduced glutathione is one of the major non-enzymatic endogenous antioxidants protecting tissue against ROS. [9,22] Other antioxidants are alphatocopherol [23,24] , uric acid [25][26][27] , ascorbic acid [28] , carotenoids [29,30] and varieties of plant secondary metabolites such as flavonoid and related polyphenolic compounds. [31,32] Notable erythrocyte enzymatic ROS scavenging systems include glutathione reductase, [17,19] glutathione peroxidase, [33] glucose-6-phosphate dehydrogenase, [18,34] superoxide dismutase, [5,35] catalases, [36][37][38] peroxiredoxins, [39,40] and NADHmethaemoglobin reductase.…”

Behavior of the total antioxidant status in a group of subjects with metabolic syndrome

“…In the last years a paradoxal role of uric acid has been hypothesized as it could act as an antioxidant in plasma and extracellular environment and as a pro-oxidant within the cells [40,42]; it is not possible to exclude that MS subjects with type 2 diabetes mellitus were hyperuricemic but we know the serum uric acid levels of a small group of MS subjects (data not shown).…”