Is uric acid a true antioxidant? Identification of uric acid oxidation products and their biological effects.

Uric acid (UA), the final product of purine metabolism in humans, exhibits a dual role as an anti or pro-oxidant, depending on the microenvironment. The two-electron oxidation of UA by biological oxidants can neutralize such harmful molecules. Additionally, UA chelates metals and can activate adaptive response against oxidation. However, some products of the reaction between UA and oxidants are not inert and, therefore, do not confer the anticipated antioxidant protection. A direct pro-oxidant effect is favoured in the one-electron oxidation of UA by heme-peroxidases yielding free radical intermediates that can initiate or propagate a radical-chain reaction. Additionally, an indirect pro-oxidant effect has been proposed by eliciting the expression or activation of enzymes that catalyse oxidant production, e.g. NADPH oxidase (NOX). This review brings together fundamental concepts and the molecular mechanisms of the redox reactions involving UA. The signature metabolites from these reactions are discussed to give valuable insights on whether these intermediates are being formed and what role they may play in disease pathogenesis. It proposes that, through identifying specific products, it may be possible to elucidate whether a harmful or protective action is linked to downstream bioactivities.