Uric Acid as an Antioxidant

Also see:
Hypothyroidism, Gout, and Uric Acid
Coffee Inhibits Iron Absorption

Quotes by Ray Peat, PhD:
“Lipid peroxidation is involved in the degenerative diseases, and many publications argue that fructose increases it, despite the fact that it can increase the production of uric acid, which is a major component of our endogenous antioxidant system (e.g., Waring, et al., 2003).”

“The antioxidants in our body have to fit together with uric acid which is naturally there, and enzymes which naturally break down free radicals. And if you put things in that don’t fit, apparent antioxidants in a test tube can become a pro-oxidant in a body. Things have to fit together, so that vitamin A and vitamin E are locked together and vitamin E and vit. C locked together, Uric acid and vit.C locked together and the glucose and other sugars have to be streaming through the systems of enzymes turning into carbon dioxide. Carbon dioxide has to be flowing out of the cells properly. The whole antioxidant system is really one piece and if you try to staff in any super-antioxidants like they’re selling as health products, you’re likely to create more oxidation than you had without it. Recent publication saw that cataracts are twice as common in men over the age of 65, who took big supplements of vit. E and vit. C. Almost doubled their rate of cataracts.”

“One of the ways in which uric acid functions as an “antioxidant” is by modifying the activity of the enzyme xanthine oxidase, which in stress can become a dangerous source of free radicals. Caffeine also restrains this enzyme. There are several other ways in which uric acid and caffeine (and a variety of intermediate xanthines) protect against oxidative damage. Coffee drinkers, for example, have been found to have lower levels of cadmium in their kidneys than people who don’t use coffee, and coffee is known to inhibit the absorption of iron by the intestine, helping to prevent iron overload.”

“To talk about caffeine, it’s necessary to talk about uric acid. Uric acid, synthesized in the body, is both a stimulant and a very important antioxidant, and its structure is very similar to that of caffeine. A deficiency of uric acid is a serious problem. Caffeine and uric acid are in the group of chemicals called purines.”

“Antioxidants: Vitamin E and vitamin C are known as antioxidants, because they stop the harmful free· radical chain reactions which often involve oxygen, but they do not inhibit normal oxidation processes in cells. “Chain breaker” would be a more suitable term. It is often the deficiency of oxygen which unleashes the dangerous free-radical processes. Many substances can function as antioxidants/chain breakers: thyroxine, uric acid, biliverdin, selenium, iodine, vitamin A, sodium, magnesium, and lithium, and a variety of enzymes. Saturated fats work with antioxidanrs to block the spread of free-radical chain reactions.”

Clin Sci (Lond). 2003 Oct;105(4):425-30.
Uric acid reduces exercise-induced oxidative stress in healthy adults.
Waring WS, Convery A, Mishra V, Shenkin A, Webb DJ, Maxwell SR.
Uric acid (UA) possesses free-radical-scavenging properties, and systemic administration is known to increase serum antioxidant capacity. However, it is not known whether this protects against oxidative stress. The effects of raising UA concentration were studied during acute aerobic physical exercise in healthy subjects, as a model of oxidative stress characterized by increased circulating 8-iso-prostaglandin F2alpha (8-iso-PGF2alpha) concentrations. Twenty healthy subjects were recruited to a randomized double-blind placebo-controlled crossover study, and underwent systemic administration of 0.5 g of UA in 250 ml of 0.1% lithium carbonate/4% dextrose vehicle or vehicle alone as control. Subjects performed high-intensity aerobic exercise for 20 min to induce oxidative stress. Plasma 8-iso-PGF2alpha concentrations were determined at baseline, after exercise and after recovery for 20 min. A single bout of high-intensity exercise caused a significant increase in plasma 8-iso-PGF2alpha concentrations from 35.0 +/- 4.7 pg/ml to 45.6 +/- 6.7 pg/ml (P<0.01). UA administration raised serum urate concentration from 293 +/- 16 to 487 +/- 16 micromol/l (P<0.001), accompanied by increased serum antioxidant capacity from 1786+/-39 to 1899 +/- 45 micromol/l (P<0.01). UA administration abolished the exercise-induced elevation of plasma 8-iso-PGF2alpha concentrations. High UA concentrations are associated with increased serum antioxidant capacity and reduced oxidative stress during acute physical exercise in healthy subjects. These findings indicate that the antioxidant properties of UA are of biological importance in vivo.

J Cardiovasc Pharmacol. 2001 Sep;38(3):365-71.
Systemic uric acid administration increases serum antioxidant capacity in healthy volunteers.
Waring WS, Webb DJ, Maxwell SR.
Oxidative stress plays an important role in the development of atherosclerosis and contributes to tissue damage that occurs as a consequence, particularly in myocardial infarction and acute stroke. Antioxidant properties of uric acid have long been recognized and, as a result of its comparatively high serum concentrations, it is the most abundant scavenger of free radicals in humans. Elevation of serum uric acid concentration occurs as a physiologic response to increased oxidative stress-for example, during acute exercise-thus providing a counter-regulatory increase in antioxidant defenses. In view of its antioxidant properties, uric acid may have potentially important and beneficial effects within the cardiovascular system. We wished to investigate whether administration of uric acid was feasible and if it could have an impact on antioxidant function in vivo. We have, therefore, performed a randomized, placebo-controlled double-blind study of the effects of systemic administration of uric acid, 1,000 mg, in healthy volunteers, compared with vitamin C, 1,000 mg. We observed a significant increase in serum free-radical scavenging capacity from baseline during uric acid and vitamin C infusion, using two methodologically distinct antioxidant assays. The effect of uric acid was substantially greater than that of vitamin C.

Diabetes. 2006 Nov;55(11):3127-32.
Uric acid restores endothelial function in patients with type 1 diabetes and regular smokers.
Waring WS, McKnight JA, Webb DJ, Maxwell SR.
Endothelial dysfunction is a characteristic finding in both patients with type 1 diabetes and in regular smokers and is an important precursor to atherosclerosis. The urate molecule has antioxidant properties, which could influence endothelial function. The impact of acutely raising uric acid concentrations on endothelial function was studied in eight men with type 1 diabetes, eight healthy regular smokers, and eight age-matched healthy control subjects in a randomized, four-way, double-blind, placebo-controlled study. Subjects received 1,000 mg uric acid i.v. in vehicle, 1,000 mg vitamin C as a control antioxidant, vehicle alone, or 0.9% saline on separate occasions over 1 h. Forearm blood flow responses to intrabrachial acetylcholine and sodium nitroprusside were assessed using venous occlusion plethysmography. Responses to acetylcholine, but not sodium nitroprusside, were impaired in patients with diabetes (P < 0.001) and in smokers (P < 0.005) compared with control subjects. Administration of uric acid and vitamin C selectively improved acetylcholine responses in patients with type 1 diabetes (P < 0.01) and in regular smokers (P < 0.05). Uric acid administration improved endothelial function in the forearm vascular bed of patients with type 1 diabetes and smokers, suggesting that high uric acid concentrations in vivo might serve a protective role in these and other conditions associated with increased cardiovascular risk.

Diabetologia. 2007 Dec;50(12):2572-9. Epub 2007 Oct 10.
Lowering serum urate does not improve endothelial function in patients with type 2 diabetes.
Waring WS, McKnight JA, Webb DJ, Maxwell SR.
Endothelial dysfunction contributes to excess cardiovascular risk in patients with type 2 diabetes. There is strong evidence of an association between high serum uric acid concentrations and endothelial dysfunction, and uric acid has been proposed as an independent cardiovascular risk factor in type 2 diabetes. We hypothesised that lowering of uric acid concentrations might allow restoration of endothelial function in this high-risk group.
Intravenous urate oxidase (1.5 mg) was administered to ten patients with type 2 diabetes and ten healthy participants in a two-way, randomised, placebo-controlled, crossover study. Forearm blood flow responses to intra-brachial acetylcholine, sodium nitroprusside and N(G)-monomethyl-L-arginine (L-NMMA) were measured using venous occlusion plethysmography. The augmentation index (AIx) was determined by pulse wave analysis as a measure of large arterial stiffness.
Acetylcholine and L-NMMA evoked lesser responses in patients with type 2 diabetes than in healthy participants. Baseline AIx was higher in patients with type 2 diabetes (mean +/- SD: 13.1 +/- 6.9%) than in healthy participants (2.0 +/- 5.1%; p = 0.006). Urate oxidase lowered serum uric acid concentrations by 64 +/- 11% (p < 0.001), but this had no effect on forearm blood flow responses or AIx in either group.
Substantial short-term lowering of uric acid did not have a direct vascular effect, suggesting that, on its own, this might not be an effective strategy for restoring endothelial function in patients with type 2 diabetes.

Curr Pharm Des. 2005;11(32):4145-51.
Uric acid and oxidative stress.
Glantzounis GK, Tsimoyiannis EC, Kappas AM, Galaris DA.
Uric acid is the final product of purine metabolism in humans. The final two reactions of its production catalyzing the conversion of hypoxanthine to xanthine and the latter to uric acid are catalysed by the enzyme xanthine oxidoreductase, which may attain two inter-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 oxidative stress is not entirely clear. Evidence mainly based on epidemiological 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 effects in situations associated with oxidative stress (e.g. ischaemia-reperfusion injury, cardiovascular disease). However, there is increasing experimental and clinical evidence showing that uric acid has an important role in vivo as an antioxidant. This review presents the current evidence regarding the antioxidant role of uric acid and suggests that it has an important role as an oxidative stress marker and a potential therapeutic role as an antioxidant. Further well designed clinical studies are needed to clarify the potential use of uric acid (or uric acid precursors) in diseases associated with oxidative stress.

J. W. Davis, et al., 1996, found that high uric acid levels seem to protectagainst the development of Parkinson’s disease. They ascribed this effect to uric acid’s antioxidant function. -Ray Peat, PhD

Am. J. Epidemiol. (1996) 144 (5): 480-484
Observations on Serum Uric Acid Levels and the Risk of Idiopathic Parkinson’s Disease
J. W. Davis, A. Grandinetti, C. J. Waslien, G. W. Ross, L. R. White and D. M. Morens
Uric acid, an antioxidant found in high concentrations in serum and in the brain, has been hypothesized to protect against oxidative damage and cell death in Parkinson’s disease. The authors tested this hypothesis among men participating in a 30-year prospective study known as the Honolulu Heart Program. Serum uric acid was measured in 7,968 men at the baseline examination held from 1965 to 1968. Of these men, 92 subsequently developed idiopathic Parkinson’s disease (IPD). In analyses adjusted for age and smoking, men with uric acid concentrations above the median at enrollment had a 40% reduction in IPD incidence (rate ratio (RR) = 0.6; 95% confidence interval (CI) 0.4–1.0). Reduced IPD incidence rates persisted in analyses restricted to nonsmokers (RR = 0.5; 95% Cl 0.3–1.0) and cases younger than age 75 years (RR = 0.5; 95% Cl 0.3–0.9). Incidence rates were not notably affected when analyses were restricted to cases that occurred more than 5 years after uric acid measurement (RR = 0.6; 95% Cl 0.4–1.0). Inclusion of known or computed correlates of uric acid in regression models did not substantially change risk of IPD. This study provides prospective evidence of an association between uric acid and reduced occurrence of IPD and indicates that further investigations of this association are warranted.

“Antioxidants, including uric acid, are deficient in schizophrenics.” -Ray Peat, PhD

Psychiatry Res. 1998 Jul 27;80(1):29-39.
Reduced level of plasma antioxidant uric acid in schizophrenia.
Yao JK, Reddy R, van Kammen DP.
There is evidence of dysregulation of the antioxidant defense system in schizophrenia. The purpose of the present study was to examine whether uric acid, a potent antioxidant, is reduced in the plasma of patients with schizophrenia. To this end, a within-subject, repeated measures, on-off-on haloperidol treatment design was utilized. Male schizophrenic patients with either a haloperidol treatment (n=47) or a drug-free condition (n=35) had significantly lower levels of plasma uric acid than the age- and sex-matched normal control subjects (n=34). Following haloperidol withdrawal, plasma uric acid levels were further reduced in schizophrenic patients (P=0.018; paired t-test, n=35). However, no relationship was found between uric acid levels and the length of the drug-free period (< 5 or > 5 weeks) or days drug free. In addition, the plasma levels of uric acid in patient groups were significantly and inversely correlated with psychosis. There was a trend for lower uric acid levels in relapsed patients relative to clinically stable patients. Smoking, which can modify plasma antioxidant capacity, was not found to have prominent effects on uric acid levels. The present finding of a significant decrease of a selective antioxidant provides additional support to the hypothesis that oxidative stress in schizophrenia may be due to a defect in the antioxidant defense system.

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