Xanthine Oxidase Inhibitor Febuxostat as a Novel Agent Postulated to Act Against Vascular Inflammation

Abstract

Xanthine oxidoreductase (XOR) catalyzes the final two reactions that lead to uric acid formation. XOR is a complex molibdoflavoenzyme present in two different functional forms: dehydrogenase and xantine oxidase (XO). XO is a critical source of reactive oxygen species (ROS) that contribute to vascular inflammation. Under normal physiological conditions, it is mainly found in the dehydrogenase form, while in inflammatory situations, posttranslational modification converts the dehydrogenase form into XO. These inflammatory conditions lead to an increase in XO levels and thus an increased ROS generation by the enzymatic process, finally resulting in alterations in vascular function. It has also been shown that XO secondarily leads to peroxynitrite formation. Peroxynitrite is one of the most powerful ROS that is produced by the reaction of nitric oxide and superoxide radicals, and is considered to be a marker for reactive nitrogen species, accompanied by oxidative stress. Febuxostat is a novel nonpurine XO-specific inhibitor for treating hyperuricemia. As febuxostat inhibits both oxidized and reduced forms of the enzyme, it inhibits the ROS formation and the inflammation promoted by oxidative stress. The administration of febuxostat has also reduced nitro-oxidative stress. XO serum levels are significantly increased in various pathological states such as inflammation, ischemia-reperfusion or aging and that XO-derived ROS formation is involved in oxidative damage. Thus, it may be possible that the inhibition of this enzymatic pathway by febuxostat would be beneficial for the vascular inflammation. In animal models, febuxostat treatment has already demonstrated anti-inflammatory effects, together with the reduction in XO activity. However, the role of febuxostat in humans requires further investigation.

Effect of Allopurinol on Myocardial Energy Metabolism in Chronic Heart Failure Rats After Myocardial Infarct

“…XO is a prominent source of ROS in the setting of CHF. [23][24][25][26][27] We therefore hypothesized that ALLO, an XO inhibitor, attenuated lipid oxidation by mitigating cardiomyocyte injury. Therefore, the MDA content of the myocardium was measured to examine the protective effects of ALLO in CHF.…”

Xanthine oxidoreductase in atherosclerosis pathogenesis: Not only oxidative stress

“…[13]]. In a mouse model, febuxostat provided protection by attenuating systolic overload-induced left ventricular hypertrophy and dysfunction [14].…”

Febuxostat Ameliorates Diabetic Renal Injury in a Streptozotocin-Induced Diabetic Rat Model

“…A recent study showed that febuxostat inhibited the activity of XO simply by obstructing substrate binding, and that this inhibition was not influenced by changes in the redox status of the co-factor [11]. Therefore, because febuxostat inhibits both oxidized and reduced forms of XO, it can also inhibit ROS formation and inflammation induced by oxidative stress [12]. The renoprotective effects of XO inhibitors have been demonstrated in experimental animal models, including 5/6 nephrectomized rats [13], renal ischemic-reperfusion injury rats [14], unilateral-ureteral obstruction rats [15], and fructose-induced metabolic syndrome rats [16,17].…”