Plasma and blood assay of xanthine and hypoxanthine by gas chromatography-mass spectrometry: physiological variations in humans

Lartigue-Mattei, C.; Chabard, J. L.; Bargnoux, H.; Petit, J.; Berger, J.A.; Ristori, J. M.; Bussière, J. L.; Catilina, P.; Catilina, M.J.

doi:10.1016/s0378-4347(00)83810-4

Cited by 19 publications

(8 citation statements)

References 11 publications

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“…In addition, binding of XO to GAGs reduces O 2 •− production by 34% thus favoring divalent electron transfer to O 2 (H 2 O 2 formation) (56). These observations were similar to those obtained when XO was bound to the milk fat globule membrane where immobilization of the enzyme in this setting induced a 2-fold increase in the K m for xanthine while enhancing affinity for NADH by decreasing the K m 3-fold at the FAD (41). Combined, immobilization-induced diminution of affinity for xanthine, enhanced affinity for NADH and substantive reduction in the amount of O 2 •− being produced would be favorable for NO 2 − reduction to bioavailable • NO.…”

Section: Introductionsupporting

confidence: 84%

“…The suggested mechanism for this inhibition is competition where xanthine binding to the oxidized Mo-co blocks access to NO 2 − . This observation becomes critically important when considering inflammatory/ischemic conditions can result in combined plasma concentrations of hypoxanthine + xanthine ranging from 50-100 μM, levels that would exceed the K i of 55 μM (41-44). Therefore, one could speculate that a clinical approach based on XOR-mediated • NO generation by enhancement of circulating NO 2 − and/or NO 3 − would most likely be buttressed with an adjuvant to reduce ischemia/hypoxia-mediated elevation of hypoxanthine.…”

Section: Introductionmentioning

confidence: 99%

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

2013

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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.

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Section: Introductionsupporting

confidence: 84%

Section: Introductionmentioning

confidence: 99%

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

2013

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“…Although ROS/RNS can be generated from many places, we are particularly interested in XOD, because in our previous study, ROS derived from XOD occupied 30% in total ROS products (32). Circulating XOD is still active in using serum hypoxanthine or xanthine to produce superoxide (33,34), Moreover, considering that increased circulating XOD levels are regarded as a marker of endothelial damage (35), the data also implied damage or dysfunction to ECs during aging.…”

Section: Discussionmentioning

confidence: 99%

Alteration of soluble adhesion molecules during aging and their modulation by calorie restriction

et al. 2003

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To investigate the status of soluble adhesion molecules (sAMs) during aging, the present study determined protein levels of several major sAMs in serum samples obtained from rats at different ages. These sAMs include E-selectin, P-selectin, vascular cell adhesion molecule 1 (VCAM-1), and intercellular adhesion molecule 1 (ICAM-1). Fischer 344 rats, ages 6, 12, 18, and 24 months, fed ad libitum (AL) and calorie restricted (CR) diets were used in this study. Analysis by Western blotting showed that the levels of all sAMs studied increased during aging in AL rats, but were effectively blunted in the CR rats. Total reactive oxygen species/reactive nitrogen species (ROS/RNS) levels were measured by fluorescent probe 2',7'-dichlorofluorescin diacetate. Increased ROS/RNS levels were found to coincide with increased levels of superoxide-generating xanthine oxidase in serum during aging, but were found suppressed by CR. Increases in sAMs levels were duplicated in another experiment in which young (13-month-old) and old (31-month-old) rats were injected with proinflammatory lipopolysaccharide. These findings suggest that the altered expressions of sAMs may be due to increased oxidative stress with advanced age and that these increases were prevented by CR through its antioxidative action.

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“…This is especially true when considering: (1) normal tissue NO 2 − concentration (~0.3 µM) while hypoxia results in diminution of NO 2 − levels and (2) the K m for xanthine is 6.5 μM while levels of xanthine above 20 μM, commonly seen under pathologic conditions, are reported to induce substrate-dependent inhibition of NO 2 − reduction (K i = 55 µM; Li et al 2001;Kleinbongard et al 2003;Lartigue-Mattei et al 1990;Pesonen et al 1998;Quinlan et al 1997;Himmel et al 1991). However, it must be noted that hypoxia enhances NO 3 − levels from 30-40 to 120-150 µM depending upon the tissue (Kleinbongard et al 2003).…”

Section: Xor As a Source Of Nitric Oxidementioning

confidence: 99%

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

Kelley

2015

Arch Toxicol

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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.

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Plasma and blood assay of xanthine and hypoxanthine by gas chromatography-mass spectrometry: physiological variations in humans

Cited by 19 publications

References 11 publications

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

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

Alteration of soluble adhesion molecules during aging and their modulation by calorie restriction

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

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