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

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)-N-center dot formation. To garner a more clear understanding of conditions necessary for in vivo XOR-catalyzed (NO)-N-center dot production, this review critically analyzes the impact of O-2 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)-N-center dot. (C) 2013 Elsevier Inc. All rights reserved.