Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer: a hypothesis.

Abstract

During primate evolution, a major factor in lengthening life-span and decreasing age-specific cancer rates may have been improved protective mechanisms against oxygen radicals. We propose that one ofthese protective systems is plasma uric acid, the level of which increased markedly during primate evolution as a consequence of a series of mutations. Uric acid is a powerful antioxidant and is a scavenger of singlet oxygen and radicals. We show that, at physiological concentrations, urate reduces the oxo-heme oxidant formed by peroxide reaction with hemoglobin, protects erythrocyte ghosts against lipid peroxidation, and protects erythrocytes from peroxidative damage leading to lysis. Urate is about as effective an antioxidant as ascorbate in these experiments. Urate is much more easily oxidized than deoxynucleosides by singlet oxygen and is destroyed by hydroxyl radicals at a comparable rate. The plasma urate level in humans (about 300 ILM) is considerably higher than the ascorbate level, making it one of the major antioxidants in humans. Previous work on urate reported in the literature supports our experiments and interpretations, although the findings were not discussed in a physiological context.Toxicity by oxygen radicals has been suggested as a major cause of cancer, heart disease, and aging (1-13). Oxygen radicals and other oxidants appear to be toxic in large part because they initiate the chain reaction of lipid peroxidation (rancidity). Lipid peroxidation generates various reactive species-such as radicals, hydroperoxides, aldehydes, and epoxides-with the capability of causing damage to DNA, RNA, proteins, cellular membranes, and cellular organization. Aerobic organisms have an array of protective mechanisms both for preventing the formation of oxidants and lipid peroxidation and for repairing oxidative damage. The protective systems include enzymes, such as superoxide dismutase (12) and the selenium-containing glutathione peroxidase (9, 10), and antioxidants and radical scavengers, such as a-tocopherol (vitamin E) and a-carotene in the lipid portion ofthe cell and glutathione and ascorbic acid in the aqueous phase (9, 10). These protective mechanisms are now being recognized as anticarcinogenic and, in some cases, even as life-span extending (5-7).A marked increase in life-span has occurred in human evolution during the descent from prosimians over the past 60 million years (4). At the same time an enormous decrease in the age-specific cancer rate has occurred in humans compared to short-lived mammals (14, 15). It seems likely that a major factor in lengthening life-span and decreasing age-specific cancer rates may have been the evolution ofeffective protective mechanisms against oxygen radicals (2-7, 10). We propose that one such mechanism is high plasma uric acid. MATERIALS AND METHODS'y-Ray Irradiation. Solutions of substrate (0.3 mM) in potassium phosphate buffer (20 mM, pH 7.4) were purged with 2, N2, or N20, sealed, and irradiated at room temperature with a 60Co y-ray source [12.7 krads/mi...

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