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      Xanthine oxidoreductase-catalyzed reactive species generation: A process in critical need of reevaluation

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          Abstract

          Nearly 30 years have passed since the discovery of xanthine oxidoreductase (XOR) as a critical source of reactive species in ischemia/reperfusion injury. Since then, numerous inflammatory disease processes have been associated with elevated XOR activity and allied reactive species formation solidifying the ideology that enhancement of XOR activity equates to negative clinical outcomes. However, recent evidence may shatter this paradigm by describing a nitrate/nitrite reductase capacity for XOR whereby XOR may be considered a crucial source of beneficial NO under ischemic/hypoxic/acidic conditions; settings similar to those that limit the functional capacity of nitric oxide synthase. Herein, we review XOR-catalyzed reactive species generation and identify key microenvironmental factors whose interplay impacts the identity of the reactive species (oxidants vs. NO) produced. In doing so, we redefine existing dogma and shed new light on an enzyme that has weathered the evolutionary process not as gadfly but a crucial component in the maintenance of homeostasis.

          Highlights

          • Inflammation-induced elevation of XO has long been associated with negative outcomes.

          • Yet, XO-derived reactive species generation is poorly understood leading to misconceptions.

          • For example, H 2O 2 and not O 2 •− is the major reactive product of XO.

          • And, recent reports demonstrate beneficial NO production by XO and nitrite.

          • As such, a detailed reevaluation of XO-catalyzed reactive species generation is crucial.

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          Most cited references 59

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          Reduction of nitrite to nitric oxide during ischemia protects against myocardial ischemia-reperfusion damage.

          Nitric oxide (NO.) is thought to protect against the damaging effects of myocardial ischemia-reperfusion injury, whereas xanthine oxidoreductase (XOR) normally causes damage through the generation of reactive oxygen species. In the heart, inorganic nitrite (NO(2)(-)) has the potential to act as an endogenous store of NO., liberated specifically during ischemia. Using a detection method that we developed, we report that under ischemic conditions both rat and human homogenized myocardium and the isolated perfused rat heart (Langendorff preparation) generate NO. from NO(2)(-) in a reaction that depends on XOR activity. Functional studies of rat hearts in the Langendorff apparatus showed that nitrite (10 and 100 microM) reduced infarct size from 47.3 +/- 2.8% (mean percent of control +/- SEM) to 17.9 +/- 4.2% and 17.4 +/- 1.0%, respectively (P < 0.001), and was associated with comparable improvements in recovery of left ventricular function. This protective effect was completely blocked by the NO. scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazole-1-oxyl 3-oxide (carboxy-PTIO). In summary, the generation of NO. from NO(2)(-), by XOR, protects the myocardium from ischemia-reperfusion injury. Hence, if XOR is presented with NO(2)(-) as an alternative substrate, the resultant effects of its activity may be protective, by means of its production of NO. , rather than damaging.
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            Structure and function of xanthine oxidoreductase: where are we now?

            Xanthine oxidoreductase (XOR) is a complex molybdoflavoenzyme, present in milk and many other tissues, which has been studied for over 100 years. While it is generally recognized as a key enzyme in purine catabolism, its structural complexity and specialized tissue distribution suggest other functions that have never been fully identified. The publication, just over 20 years ago, of a hypothesis implicating XOR in ischemia-reperfusion injury focused research attention on the enzyme and its ability to generate reactive oxygen species (ROS). Since that time a great deal more information has been obtained concerning the tissue distribution, structure, and enzymology of XOR, particularly the human enzyme. XOR is subject to both pre- and post-translational control by a range of mechanisms in response to hormones, cytokines, and oxygen tension. Of special interest has been the finding that XOR can catalyze the reduction of nitrates and nitrites to nitric oxide (NO), acting as a source of both NO and peroxynitrite. The concept of a widely distributed and highly regulated enzyme capable of generating both ROS and NO is intriguing in both physiological and pathological contexts. The details of these recent findings, their pathophysiological implications, and the requirements for future research are addressed in this review. Copyright 2002 Elsevier Science Inc.
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              Hydrogen peroxide is the major oxidant product of xanthine oxidase.

              Xanthine oxidase (XO) is a critical source of reactive oxygen species (ROS) in inflammatory disease. Focus, however, has centered almost exclusively on XO-derived superoxide (O(2)(*-)), whereas direct H(2)O(2) production from XO has been less well investigated. Therefore, we examined the relative quantities of O(2)(*-) and H(2)O(2) produced by XO under a range (1-21%) of O(2) tensions. At O(2) concentrations between 10 and 21%, H(2)O(2) accounted for approximately 75% of ROS production. As O(2) concentrations were lowered, there was a concentration-dependent increase in H(2)O(2) formation, accounting for 90% of ROS production at 1% O(2). Alterations in pH between 5.5 and 7.4 did not affect the relative proportions of H(2)O(2) and O(2)(*-) formation. Immobilization of XO, by binding to heparin-Sepharose, further enhanced relative H(2)O(2) production by approximately 30%, under both normoxic and hypoxic conditions. Furthermore, XO bound to glycosaminoglycans on the apical surface of bovine aortic endothelial cells demonstrated a similar ROS production profile. These data establish H(2)O(2) as the dominant (70-95%) reactive product produced by XO under clinically relevant conditions and emphasize the importance of H(2)O(2) as a critical factor when examining the contributory roles of XO-catalyzed ROS in inflammatory processes as well as cellular signaling. Published by Elsevier Inc.
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                Author and article information

                Contributors
                Journal
                Redox Biol
                Redox Biol
                Redox Biology
                Elsevier
                2213-2317
                10 June 2013
                10 June 2013
                2013
                : 1
                : 1
                : 353-358
                Affiliations
                [a ]Department of Anesthesiology, University of Pittsburgh, United States
                [b ]Vascular Medicine Institute, University of Pittsburgh, United States
                Author notes
                [* ]Correspondence to: Department of Anesthesiology, School of Medicine, University of Pittsburgh, W1357 BST, 200 Lothrop Street, Pittsburgh 15213, PA, United States. Tel.: +1 412 648 9683; fax: +1 412 648 9587. ekelley@ 123456pitt.edu
                Article
                REDOX45
                10.1016/j.redox.2013.05.002
                3757702
                24024171
                © 2013 The Authors

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution and reproduction in any medium, provided the original author and source are credited.

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                Graphical Review

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