Xanthine oxidoreductase-catalyzed reduction of nitrite to nitric oxide: Insights regarding where, when and how

Abstract

Numerous inflammatory disorders are associated with elevated levels of xanthine oxidoreductase (XOR) and allied enhancement of reactive species formation contributory to systemic pathology. Despite a long standing association between increased XOR activity and negative clinical outcomes, recent reports describe a paradigm shift where XOR mediates beneficial actions by catalyzing the reduction of NO2− to •NO. While provocative, these observations contradict reports of improved outcomes in similar models upon XOR inhibition as well as reports revealing strict anoxia as a requisite for XOR-mediated •NO formation. To garner a more clear understanding of conditions necessary for in vivo XOR-catalyzed •NO production, this review critically analyzes the impact of O2 tension, pH, substrate concentrations, glycoaminoglycan docking and inhibition strategies on the nitrite reductase activity of XOR and reveals a hypoxic milieu where this process may be operative. As such, information herein serves to link recent reports in which XOR activity has been identified as mediating the beneficial outcomes resulting from nitrite supplementation to a microenviromental setting where XOR can serve as substantial source of •NO.

Nitrite Reductase Activity of Rat and Human Xanthine Oxidase, Xanthine Dehydrogenase, and Aldehyde Oxidase: Evaluation of Their Contribution to NO Formation in Vivo

“…19,25,29 Together, all these studies provide consistent support for the participation of XO/XD and AO in NO generation pathways. Nevertheless, this is a controversial subject, and conflicting results have being described.…”

Oxygen Metabolism in the Lung

“…In this mechanism, NO 2 À can substitute for the O 2 at the molybdenumepterin complex and be reduced to NO. This provides for an O 2 tension regulated NO generation mechanism (Cantu-Medellin and Kelley, 2013). This may have important implications for the control of blood flow and ventilation/perfusion matching within the lung (Bueno et al, 2013).…”

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

“…However, this assessment countervails in vivo reports demonstrating XOR-dependence of NO 2 − -mediated protective effects upon co-treatment with allopurinol, febuxostat or by dietary supplementation with NaW and affirms the need for a more detailed analysis of the factors that affect this catalytic process. These microenvironmental factors have been reviewed in detail and are summarized below (Cantu-Medellin and Kelley 2013).…”