Xanthine Oxidase Inhibitor Febuxostat as a Novel Agent Postulated to Act Against Vascular Inflammation
Cristina de la Puerta Gonzalez-Quevedo.
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.
Keywords: Endothelium, febuxostat, hyperuricemia, inflammation, oxidative stress, xanthine oxidase
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