Sabán-Ruiz José, Alonso-Pacho Ana, Fabregate-Fuente Martín, de la Puerta González-Quevedo Cristina
Endothelium, CV Risk and Cardiometabolic Heath Unit. Internal Medicine Service. Ramon y Cajal Hospital, Carretera de Colmenar km. 9,100, 28034, Madrid, Spain.
Antiinflamm Antiallergy Agents Med Chem. 2013;12(1):94-9. doi: 10.2174/1871523011312010011.
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.
黄嘌呤氧化还原酶（XOR）催化导致尿酸形成的最后两个反应。XOR是一种复杂的钼黄素酶，以两种不同的功能形式存在：脱氢酶和黄嘌呤氧化酶（XO）。XO是活性氧（ROS）的关键来源，会导致血管炎症。在正常生理条件下，它主要以脱氢酶形式存在，而在炎症情况下，翻译后修饰会将脱氢酶形式转化为XO。这些炎症状态会导致XO水平升高，从而通过酶促过程增加ROS的产生，最终导致血管功能改变。研究还表明，XO继而会导致过氧亚硝酸盐的形成。过氧亚硝酸盐是一氧化氮和超氧自由基反应产生的最强大的ROS之一，被认为是活性氮物质的标志物，同时伴有氧化应激。非布司他是一种用于治疗高尿酸血症的新型非嘌呤XO特异性抑制剂。由于非布司他能抑制该酶的氧化型和还原型，因此它能抑制ROS的形成以及氧化应激所促进的炎症。非布司他的给药也降低了硝基氧化应激。在各种病理状态如炎症、缺血再灌注或衰老中，XO血清水平会显著升高，且XO衍生的ROS形成与氧化损伤有关。因此，非布司他抑制这一酶促途径可能对血管炎症有益。在动物模型中，非布司他治疗已显示出抗炎作用，同时XO活性降低。然而，非布司他在人类中的作用还需要进一步研究。
