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.