Febuxostat inhibition of endothelial-bound XO: implications for targeting vascular ROS production.

Xanthine oxidase (XO) is a critical source of reactive oxygen species (ROS) that contribute to vascular inflammation. Binding of XO to vascular endothelial cell glycosaminoglycans (GAGs) results in significant resistance to inhibition by traditional pyrazolopyrimidine-based inhibitors such as allopurinol. Therefore, we compared the extent of XO inhibition (free and GAG-bound) by allopurinol to that by febuxostat, a newly approved nonpurine XO-specific inhibitor.

Hydrogen peroxide is the major oxidant product of xanthine oxidase.

Xanthine oxidase (XO) is a critical source of reactive oxygen species (ROS) in inflammatory disease. Focus, however, has centered almost exclusively on XO-derived superoxide (O(2)(*-)), whereas direct H(2)O(2) production from XO has been less well investigated. Therefore, we examined the relative quantities of O(2)(*-) and H(2)O(2) produced by XO under a range (1-21%) of O(2) tensions.

Nitro-oleic acid, a novel and irreversible inhibitor of xanthine oxidoreductase.

Xanthine oxidoreductase (XOR) generates proinflammatory oxidants and secondary nitrating species, with inhibition of XOR proving beneficial in a variety of disorders. Electrophilic nitrated fatty acid derivatives, such as nitro-oleic acid (OA-NO2), display anti-inflammatory effects with pleiotropic properties. Nitro-oleic acid inhibits XOR activity in a concentration-dependent manner with an IC50 of 0.