Comment on Fabbrini et al. Effect of Plasma Uric Acid on Antioxidant Capacity, Oxidative Stress, and Insulin Sensitivity in Obese Subjects. Diabetes 2014;63:976−981

The article by Fabbrini et al. (1) addressed the potential impact of obesity-mediated enhancement of plasma uric acid (UA) levels on oxidative stress and resultant effects on impaired glucose tolerance/insulin resistance. By lowering UA levels in obese patients with elevated UA via administration of uricase (rasburicase), the authors demonstrate substantive diminution of circulating small molecule antioxidants as well as enhanced abundance of secondary indicators of oxidative stress (8-isoprostane and protein carbonylation). They conclude that these observations validate UA’s role as an antioxidant. However, the authors fail to appreciate that every molecule of UA consumed by uricase generates one molecule of H₂O₂ (UA + O₂ → allantoin + H₂O₂) (2). Considering the average concentration of UA in these patients (7.1 mg/dL or 4.22 μmol/L), the reported achievement of 0.0 μmol/L plasma UA with rasburicase treatment would have concomitantly produced 4.22 μmol/L of H₂O₂. Generation of µmol/L levels of this oxidant may explain both the observed diminution of antioxidants as well as elevation in secondary indicators of oxidative stress. It also eliminates the capacity to critically evaluate the “antioxidant” characteristics of UA. This is an important point especially when considering that manipulation of UA concentration at the level of production via inhibition of xanthine oxidase (XO) also directly alters reactive oxygen species (ROS) levels. For example, XO uses electrons derived from the oxidation of hypoxanthine to xanthine and the oxidation of xanthine to UA for univalent and divalent reduction of O₂ to O₂˙ˉ and H₂O₂, respectively. As such, lowering UA by inhibiting XO would confer a fourfold decrease in electron flux to O₂; two electrons for hypoxanthine oxidation to xanthine and two electrons for xanthine oxidation to one molecule of UA. When taken together, it is apparent that manipulation of UA levels via modulation of enzymatic production/catabolism is inextricably linked to modulation of ROS levels. It is therefore crucial that this unappreciated concept be considered when formulating conclusions from studies designed to define contributory roles for UA and ROS as well as the relative impact of one versus the other.