Febuxostat inhibition of endothelial-bound XO: Implications for targeting vascular ROS production
Document Type
Article
Department
Biological and Biomedical Sciences
Abstract
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. In solution, febuxostat was 1000-fold more potent than allopurinol at inhibiting XO-dependent uric acid formation (IC(50) = 1.8 nM vs 2.9 mu M). Association of XO with heparin-Sepharose 6B (HS6B-XO) had minimal effect on the inhibition of uric acid formation by febuxostat (IC(50) = 4.4 nM) while further limiting the effect of allopurinol (IC(50) = 64 mu M). Kinetic analysis of febuxostat inhibition revealed K(i) values of 0.96 (free) and 0.92 nM (HS6B-XO), confirming equivalent inhibition for both free and GAG-immobilized enzyme. When XO was bound to endothelial cell GAGs, complete enzyme inhibition was observed with 25 nM febuxostat, whereas no more than 80% inhibition was seen with either allopurinol or oxypurinol, even at concentrations above those tolerated clinically. The superior potency for inhibition of endothelium-associated XO is predictive of a significant role for febuxostat in investigating pathological states in which XO-derived ROS are contributive and traditional XO inhibitors are only slightly effective.
Publication (Name of Journal)
Free Radical Biology and Medicine
Recommended Citation
Malik, U.,
Hundley, N.,
Romero, G.,
Radi, R.,
Freeman, B.,
Tarpey, M.,
Kelley, E.
(2011). Febuxostat inhibition of endothelial-bound XO: Implications for targeting vascular ROS production. Free Radical Biology and Medicine, 51(1), 179-184.
Available at:
https://ecommons.aku.edu/pakistan_fhs_mc_bbs/150