Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.17.1.4 (xanthine dehydrogenase)
1,236 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of anoxic submergence (20 h at 5 degrees C) and subsequent 24 h aerobic recovery on the antioxidant systems of six organs were examined in freshwater turtles, Trachemys scripta elegans. Both xanthine oxidase and xanthine dehydrogenase were detected in turtle tissues with xanthine oxidase composing 36-75% of the total activity. Turtle organs displayed high constitutive activities of catalase (CAT), superoxide dismutase (SOD), and alkyl hydroperoxide reductase (AHR). Measurements of lipid peroxidation damage products (conjugated dienes, lipid hydroperoxides, thiobarbituric acid reactive substances) showed minimal changes during anoxia or recovery suggesting that natural anoxic-aerobic transitions occur without the free radical damage that is seen during ischemia-reperfusion in mammals. Anoxia exposure led to selected decreases in enzyme activities in organs, consistent with a reduced potential for oxidative damage during anoxia: SOD decreased in liver by 30%, CAT decreased in heart by 31%, CAT and total glutathione peroxidase (GPOX) decreased in kidney (by 68 and 41%), and CAT and SOD decreased in brain (by 80 and 15%). AHR, however, increased 2 and 3.5 fold during anoxia in heart and kidney respectively. Most anoxia-induced changes were reversed during aerobic recovery although brain enzyme activities remained suppressed. Some specific changes occurred during the recovery period: SOD increased from controls in heart by 45%, AHR increased to 200 and 168% of control values in red and white muscle respectively, and total GPOX decreased from controls in heart and white muscle by 75 and 77% respectively. The results show that biochemical adaptation for natural anoxia tolerance in turtles includes well-developed antioxidant defenses that minimize or prevent damage by reactive oxygen species during the reoxygenation of organs after anoxic submergence.
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PMID:Antioxidant systems and anoxia tolerance in a freshwater turtle Trachemys scripta elegans. 914 33

Measure of oxidative stress were studied in blood samples from 10 patients undergoing bloodless lower limb surgery. Ischaemia induced a significant increase in plasma hypoxanthine concentration and xanthine oxidase activity both in the operated leg and in the systemic circulation. Five minutes after reperfusion, ratio of xanthine oxidase/total xanthine oxidase and dehydrogenase activities rose moderately, whereas at 20 min xanthine oxidase accounted for all xanthine oxidoreductase activity in the systemic circulation. A significant increase in blood glutathione redox ratio, enhanced oxidation of haemoglobin to methaemoglobin and rise in plasma haemoglobin concentration were present only in the operated limb. Thus, although the level of the potential free radical generators rose significantly both locally and in the systemic circulation, oxidative stress, as indicated by blood glutathione and erythrocyte injuries, remained limited to the reperfused leg.
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PMID:Oxidative stress induced by bloodless limb surgery on humans. 946 25

Xanthine oxidoreductase is an important cytoplasmic source of reactive oxygen species, and has been implicated in the pathogenesis of ischemia-reperfusion damage. Because the cellular localization of this protein remains unclear, our aim was to study its distribution in fresh normal human tissue obtained at surgery. For immunohistochemical studies we purified the protein from human milk and raised a polyclonal antibody in rabbits. In the liver the protein was preferentially localized to the periportal hepatocytes and it was absent from the perivenous region. In the proximal intestine, the protein was expressed in epithelial cells and goblet cells. Lactating mammary gland acinar cells showed intense staining. Small vessel vascular endothelial cells of the intestine, mammary gland, and skeletal muscle showed immunoreactivity, but in the kidney, glomerular endothelial cells were negative. No cells in the heart, brain, or lung expressed the enzyme protein. The observed localization of the xanthine oxidoreductase protein is consistent with previously observed enzyme activities in the organs studied. The widely assumed exclusive localization to capillary endothelium obviously does not apply to humans.
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PMID:Cellular expression of xanthine oxidoreductase protein in normal human tissues. 1046 34

Previous studies have demonstrated that intestinal preconditioning protects the organ from ischemia reperfusion damage. Xanthine oxidase mediating free radical generation contributes to the development of injury associated to ischemia reperfusion. Thus, any process able to modulate the oxygen free radical generation system could attenuate the injury. Also, it is known that nitric oxide is implicated in the preconditioning response. The aim of this work is to determine: (1) the effect of intestinal preconditioning on the xanthine oxidase system, (2) the relevance of this system in the development of injury, and (3) its relationship with nitric oxide. For this purpose, we have determined the activity of the xanthine dehydrogenase/xanthine oxidase system, the levels of its substrate (xanthine), and end-product (uric acid) and oxidant stress status in rat small intestine subjected to ischemic pre-conditioning. The effects of nitric oxide inhibition have also been evaluated. Results show that the percentage of xanthine dehydrogenase to xanthine oxidase conversion, xanthine, uric acid concentration, lipoperoxides, and reduced glutathione were significantly reduced in preconditioned rats irrespectively of nitric oxide inhibition. In summary, this work shows that oxidative stress in intestinal preconditioning is reduced as consequence of the diminished conversion of xanthine dehydrogenase to xanthine oxidase, and also as a consequence of the reduced availability of xanthine.
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PMID:Modification of oxidative stress in response to intestinal preconditioning. 1075 24

Xanthine oxidoreductase (XD: xanthine dehydrogenase + xanthine oxidase) is a complex enzyme that catalyzes oxidation of hypoxathine to xanthine, subsequently producing uric acid. The enzyme complex exists in separate but interconvertible forms, xanthine dehydrogenase (XDH) and xanthine oxidase (XOD). XOD is one of the major cellular sources of superoxide production and is well known as a causative factor in ischemia/reperfusion damage. At present, almost no information on the conversion status is available with respect to aging. In the present study, we investigated the effect of age on the XOD/XDH status and gene expression in the kidney. In addition, we assessed XOD-induced reactive oxygen species (ROS) using the dichlorofluoroscein (DCF) method. Our results show that XD activity gradually up to 18 months of age and then a slight decrease at 24 months of age. XDH activity showed increases up to 18 months of age, then decreased at 24 months of age. The conversion of XDH to XOD, assessed by changes in the ratios of XOD/(XOD+XDH), showed an age-related increase, which peaked at 24 months. Levels of XD protein and its mRNA paralleled to overall XD activity. ROS generation has tendency to increase with age. Our results suggest that the increased conversion of XDH to XOD observed with age may be an important contributing factor to the increased renal oxidative stress during aging.
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PMID:Modulation of renal xanthine oxidoreductase in aging: gene expression and reactive oxygen species generation. 1088 79

We have shown previously that rats subjected to tourniquet shock develop an acute form of remote organ injury of the liver that is both Kupffer cell (KC) and polymorphonuclear (PMN) leukocyte dependent. Circulating plasma xanthine oxidase (XO) has been shown to be responsible for the development of endothelial dysfunction and for remote organ injury of the lung and intestine after ischemia-reperfusion protocols. We now hypothesize that XO is released from rat hind limbs upon reperfusion and that it is responsible for KC and PMN leukocyte activation in this shock model. Our results show that about 30% of rat gastrocnemius muscle xanthine dehydrogenase (XD) is converted to XO during the 5-h tourniquet period and that it is released into the femoral vein within 10 min of reperfusion. Total muscle xanthine oxidoreductase activity (XO + XD) decreases within 30 min of reperfusion and is paralleled by a corresponding increase in femoral vein lactic dehydrogenase. In addition, liver tissue XO increases significantly within 30 min of reperfusion without a corresponding conversion of endogenous XD. Conversion of hepatic XD becomes evident 60 min after reperfusion is initiated, as does XO, and alanine aminotransferase (ALT) release into the hepatic vein, presumably from damaged hepatocytes as a consequence of oxidative stress. Tissue myeloperoxidase activity also increases significantly after the 60-min reperfusion period. That XO mediates KC and PMN activation is supported by the following observations: a) the close relationships between plasma XO and the time courses of tumor necrosis factor-alpha TNFalpha release into the hepatic vein and colloidal carbon clearance by KCs; b) that colloidal carbon clearance, TNFalpha and ALT release, loss of tissue free thiols, lipid peroxidation (TBARS), and liver infiltration by PMN neutrophils can also be induced by the administration of exogenous XO to normal rats; and c) pretreatment of rats with allopurinol inhibits KC activation and liver leukocyte infiltration. These results suggest that XO, released from the ischemic limb on reperfusion, is taken up by the liver were it mediates KC and PMN neutrophil activation and thus contributes to the development of multiple system organ failure after hind limb reperfusion.
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PMID:Xanthine oxidase released from reperfused hind limbs mediate kupffer cell activation, neutrophil sequestration, and hepatic oxidative stress in rats subjected to tourniquet shock. 1109 91

Xanthine oxidase (EC 1.1.3.22) and xanthine dehydrogenase (EC 1.1.1. 204) are both members of the molybdenum hydroxylase flavoprotein family and represent different forms of the same gene product. The two enzyme forms and their reactions are often referred to as xanthine oxidoreductase (XOR) activity. Physiologically, XOR is known as the rate-limiting enzyme in purine catabolism but has also been shown to be able to metabolize a number of other physiological compounds. Recent studies have also demonstrated its ability to metabolize xenobiotics, including a number of anticancer compounds, to their active metabolites. During the past 10 years, evidence has mounted to support a role for XOR in the pathophysiology of inflammatory diseases and atherosclerosis as well as its previously determined role in ischemia-reperfusion injury. While significant progress has recently been made in our understanding of the physiological and biochemical nature of this enzyme system, considerable work still needs to be done. This paper will review some of the more recent work characterizing the interactions and the factors that influence the interactions of XOR with various physiological and xenobiotic compounds.
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PMID:Cellular distribution, metabolism and regulation of the xanthine oxidoreductase enzyme system. 1115 41

The enzyme xanthine oxidase (XO) has been implicated in the pathogenesis of several disease processes, such as ischemia-reperfusion injury, because of its ability to generate reactive oxygen species. The expression of XO and its precursor xanthine dehydrogenase (XDH) is regulated at pre- and posttranslational levels by agents such as lipopolysaccharide and hypoxia. Posttranslational modification of the protein, for example through thiol oxidation or proteolysis, has been shown to be important in converting XDH to XO. The possibility of posttranslational modification of XDH/XO through phosphorylation has not been adequately investigated in mammalian cells, and studies have reported conflicting results. The present report demonstrates that XDH/XO is phosphorylated in rat pulmonary microvascular endothelial cells (RPMEC) and that phosphorylation is greatly increased ( approximately 50-fold) in response to acute hypoxia (4 h). XDH/XO phosphorylation appears to be mediated, at least in part, by casein kinase II and p38 kinase as inhibitors of these kinases partially prevent XDH/XO phosphorylation. In addition, the results indicate that p38 kinase, a stress-activated kinase, becomes activated in response to hypoxia (an approximately 4-fold increase after 1 h of exposure of RPMEC to hypoxia) further supporting a role for this kinase in hypoxia-stimulated XDH/XO phosphorylation. Finally, hypoxia-induced XDH/XO phosphorylation is accompanied by a 2-fold increase in XDH/XO activity, which is prevented by inhibitors of phosphorylation. In summary, this study shows that XDH/XO is phosphorylated in hypoxic RPMEC through a mechanism involving p38 kinase and casein kinase II and that phosphorylation is necessary for hypoxia-induced enzymatic activation.
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PMID:Phosphorylation of xanthine dehydrogenase/oxidase in hypoxia. 1127 16

It is well known that biomembranes and subcellular organelles are susceptible to lipid peroxidation. There is a steadily increasing body of evidence indicating that lipid peroxidation is involved in basic deteriorative mechanisms, e.g., membrane damage, enzyme damage, and nucleic acid mutagenicity. The formation of lipid peroxides can be induced by enzymatic or nonenzymatic peroxidation in the presence of oxygen. The mechanisms of formation and removal of reactive oxygen species, lipid peroxides, and free radicals in biological systems are briefly reviewed. In recent years, there has been renewed interest in the role played by lipid peroxidation in many disease states. Xanthine oxidase has been shown to generate reactive oxygen species, superoxide (O2-.), and hydrogen peroxide (H2O2) that are involved in the peroxidative damage to cells that occurs in ischemia-reperfusion injury. During ischemia, this enzyme is induced from xanthine dehydrogenase. We have shown that peroxynitrite (a reactive nitrogen species) has the potential to convert xanthine dehydrogenase to oxidase. The following biological effects of lipid peroxidation were found: a) the lipid peroxidation induced by ascorbic acid and Fe2+ affects the membrane transport in the kidney cortex and the cyclooxygenase activity in the kidney medulla, and b) the hydroperoxy adducts of linoleic acid and eicosapentaenoic acid inhibit the cyclooxygenase activity in platelets. The balance between the formation and removal of lipid peroxides determines the peroxide level in cells. This balance can be disturbed if cellular defenses are decreased or if there is a significant increase in peroxidative reactions. Once lipid peroxidation is initiated, the reactive intermediate formed induces cell damage.
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PMID:[Formation and removal of reactive oxygen species, lipid peroxides and free radicals, and their biological effects]. 1190 46

Xanthine oxidoreductase (XOR) is a ubiquitous metalloflavoprotein that appears in two interconvertible yet functionally distinct forms: xanthine dehydrogenase (XD), which is constitutively expressed in vivo; and xanthine oxidase (XO), which is generated by the posttranslational modification of XD, either through the reversible, incremental thiol oxidation of sulfhydryl residues on XD or the irreversible proteolytic cleavage of a segment of XD, which occurs at low oxygen tension and in the presence of several proinflammatory mediators. Functionally, both XD and XO catalyze the oxidation of purines to urate. However, whereas XD requires NAD+ as an electron acceptor for these redox reactions, thereby generating the stable product NADH, XO is unable to use NAD+ as an electron acceptor, requiring instead the reduction of molecular oxygen for this purine oxidation and generating the highly reactive superoxide free radical. Nearly 100 years of study has documented the physiologic role of XD in urate catabolism. However, the rapid, posttranslational conversion of XD to the oxidant-generating form XO provides a possible physiologic mechanism for rapid, posttranslational, oxidant-mediated signaling. XO-generated reactive oxygen species (ROS) have been implicated in various clinicopathologic entities, including ischemia/reperfusion injury and multisystem organ failure. More recently, the concept of physiologic signal transduction mediated by ROS has been proposed, and the possibility of XD to XO conversion, with subsequent ROS generation, serving as the trigger of the microvascular inflammatory response in vivo has been hypothesized. This review presents the evidence and basis for this hypothesis.
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PMID:The physiology of endothelial xanthine oxidase: from urate catabolism to reperfusion injury to inflammatory signal transduction. 1208 Apr 14


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