Dispelling dogma and misconceptions regarding the most pharmacologically targetable source of reactive species in inflammatory disease, xanthine oxidoreductase

Abstract

Xanthine oxidoreductase (XOR), the molybdoflavin enzyme responsible for the terminal steps of purine degradation in humans, is also recognized as a significant source of reactive species contributory to inflammatory disease. In animal models and clinical studies, inhibition of XOR has resulted in diminution of symptoms and enhancement of function in a number of pathologies including heart failure, diabetes, sickle cell anemia, hypertension and ischemia-reperfusion injury. For decades, XOR involvement in pathologic processes has been established by salutary outcomes attained from treatment with the XOR inhibitor allopurinol. This has served to frame a working dogma that elevation of XOR-specific activity is associated with enhanced rates of reactive species generation that mediate negative outcomes. While adherence to this narrowly focused practice of designating elevated XOR activity to be "bad" has produced some benefit, it has also led to significant underdevelopment of the processes mediating XOR regulation, identification of alternative reactants and products as well as micro-environmental factors that alter enzymatic activity. This is exemplified by recent reports: (1) identifying XOR as a nitrite reductase and thus a source of beneficial nitric oxide ((•)NO) under in vivo conditions similar to those where XOR inhibition has been assumed an optimal treatment choice, (2) describing XOR-derived uric acid (UA) as a critical pro-inflammatory mediator in vascular and metabolic disease and (3) ascribing an antioxidant/protective role for XOR-derived UA. When taken together, these proposed and countervailing functions of XOR affirm the need for a more comprehensive evaluation of product formation as well as the factors that govern product identity. As such, this review will critically evaluate XOR-catalyzed oxidant, (•)NO and UA formation as well as identify factors that mediate their production, inhibition and the resultant impact on inflammatory disease.

Characteristics of Patients with an Abnormally Decreased Plasma Xanthine Oxidoreductase Activity in Acute Heart Failure Who Visited the Emergency Department

“…One hypothesis is that patients with a severely reduced renal function develop marked atherosclerosis, which leads to vascular endothelial dysfunction. A previous study showed that a certain level of XOR was expressed on the vascular endothelium, wherein XO binds to glycosaminoglycan residues as a consequence of tissue damage, such as ischemia and inflammation [27]. Therefore, a too-low XOR activity in AHF patients might reflect an impaired endothelial viability due to renal dysfunction.…”

Activity of xanthine oxidase in plasma correlates with indices of insulin resistance and liver dysfunction in patients with type 2 diabetes mellitus and metabolic syndrome: A pilot exploratory study

“…The gene for XOR is initially transcribed as xanthine dehydrogenase (XDH), which controls purine metabolism mainly in the liver and intestine in humans. Previous studies showed that the majority of XOR protein is derived from the liver throughout the body in humans, and noticeably, when the liver is suffers from hypoxia or inflammation, XDH is released into the circulation and is subsequently converted into xanthine oxidase (XO) by proteases in the peripheral vasculature. Importantly, XO locally produces a considerable amount of reactive oxygen species (ROS), such as H 2 O 2 and O 2 − .…”

Plasma xanthine oxidoreductase activity in patients with decompensated acute heart failure requiring intensive care

“…8,17 A previous study showed that a certain level of XOR was expressed on the vascular endothelium, wherein XO binds to glycosaminoglycan residues as a consequence of tissue damage such as ischaemia and inflammation. 18 It is believed that the enhancement of XOR activity produces ROS and ultimately induces oxidative stress. These mechanisms adversely affect various types of disease conditions.…”