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:1.17.3.2 (xanthine oxidase)
8,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Both distal (canine lung strips) and proximal (bovine trachealis strips) airway smooth muscle contract in isolated organ baths as the percentage of environmental oxygen is increased from 12% to 95%. This effect is blocked by prostaglandin synthetase inhibitors (indomethacin, 10(-4)M; meclofenamate, 10(-4)M). To determine whether this contractile response is due to molecular oxygen, or to other products of oxidative metabolism, we examined the effects of ozone, hydrogen peroxide, and superoxide radical generating systems (paraquat and xanthine-xanthine oxidase) on the smooth muscle preparations. Ozone (3 ppm), paraquat (2 mM), and xanthine (10(-3)M)-xanthine oxidase (1 unit) were without effect. Hydrogen peroxide (10(-5)-10(-3)M) produce consistent contractions in both preparations, an effect which was appreciably greater in an hypoxic environment and which was blocked by both indomethacin and meclofenamate. Contraction from both hyperoxia and hydrogen peroxide was partially reversed by various oxygen radical scavengers, including methional (10 mM), ascorbic acid (10 mM), nitroblue tetrazolium (0.3 mM), butylated hydroxyanisole (1 mM), and 2',7' naphthalonediol (1 mM). These results suggest that hyperoxic contraction in airway smooth muscle is mediated by active oxygen species, perhaps by their effects on prostaglandin metabolism.
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PMID:Hydrogen peroxide contracts airway smooth muscle: a possible endogenous mechanism. 733 Apr 88

Aconitase is a member of a family of iron-sulfur-containing (de)hydratases whose activities are modulated in bacteria by superoxide radical (O2-.)-mediated inactivation and iron-dependent reactivation. The inactivation-reactivation of aconitase(s) in cultured mammalian cells was explored since these reactions may impact important and diverse aconitase functions in the cytoplasm and mitochondria. Conditions which increase O2-. production including exposure to the redox-cycling agent phenazine methosulfate (PMS), inhibitors of mitochondrial ubiquinol-cytochrome c oxidoreductase, or hyperoxia inactivated aconitase in mammalian cells. Overproduction of mitochondrial Mn-superoxide dismutase protected aconitase from inactivation by PMS or inhibitors of ubiquinol-cytochrome c oxidoreductase, but not from normobaric hyperoxia. Aconitase activity was reactivated (t1/2 of 12 +/- 3 min) upon removal of PMS. The iron chelator deferoxamine impaired reactivation and increased net inactivation of aconitase by O2-.. The ability of ubiquinol-cytochrome c oxidoreductase-generated O2-. to inactivate aconitase in several cell types correlated with the fraction of the aconitase activity localized in mitochondria. Extracellular O2-. generated with xanthine oxidase did not affect aconitase activity nor did exogenous superoxide dismutase decrease aconitase inactivation by PMS. The results demonstrate a dynamic and cyclical O2-.-mediated inactivation and iron-dependent reactivation of the mammalian [4Fe-4S] aconitases under normal and stress conditions and provide further evidence for the membrane compartmentalization of O2-..
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PMID:Superoxide radical and iron modulate aconitase activity in mammalian cells. 776 42

Recent studies have demonstrated that xanthine dehydrogenase/xanthine oxidase (XD/XO) activities of bovine endothelial cells (EC) are inversely regulated by O2 tensions to which the cells are exposed. We have confirmed these reports and extended the observation to a variety of cells from other sources. All EC that had detectable XD/XO activity demonstrated the greatest activity at the lowest O2 level. Bovine pulmonary artery smooth muscle cells showed XD/XO activity only under hypoxic conditions. The ratio of XO to XO+XD did not change significantly under various O2 concentrations for all cell types tested. Treatment of bovine pulmonary artery and rat epididymal fat pad EC with actinomycin D (1 microgram/ml), an inhibitor of transcription, suppressed XO and XO+XD activities in cells exposed both to 20 and 3% O2. High-dose cycloheximide (5 micrograms/ml), an inhibitor of translation, also reduced XO and XO+XD activities in these cells, whereas low-dose cycloheximide (0.5 microgram/ml) enhanced the stimulatory effect of hypoxia on XO+XD activity. We developed a digoxigenin-labeled probe that recognizes and hybridizes to rat XD cDNA and used it to examine the effect of O2 concentration on XD/XO mRNA expression of rat epididymal fat pad EC. XD/XO mRNA concentration was increased in cells exposed to hypoxia and decreased in cells exposed to hyperoxia compared with normoxic cells. The increase in mRNA concentration resulting from exposure to hypoxia was enhanced by cycloheximide. There was no change in XD/XO mRNA stability in cells exposed to hypoxia compared with normoxia. We conclude that the regulation of XD/XO by oxygen tension most likely occurs at the transcriptional level.
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PMID:Regulation of endothelial cell xanthine dehydrogenase xanthine oxidase gene expression by oxygen tension. 814 12

Neutrophil accumulation in alveolar spaces is a conspicuous finding in hyperoxia-exposed lungs. We hypothesized that xanthine oxidase (XO)-derived oxidants contribute to retention of neutrophils in hyperoxic lungs. Rats were subjected to normobaric hyperoxia (100% O2) for 48 h, and lungs were assessed for neutrophil sequestration (morphometry and lavage cell counts) and injury (lavage albumin levels and lung weights). In rats exposed to hyperoxia, we found increased (P < 0.05) lung neutrophil retention, lavage albumin levels, and lung weights compared with normoxia-exposed control rats. Suppression of XO activity by pretreatment with allopurinol decreased (P < 0.05) lung neutrophil retention but increased (P < 0.05) lavage albumin concentrations and lung weights in hyperoxic rats. Allopurinol treatment had no effect (P > 0.05) on the numbers of macrophages or lymphocytes recoverable by lung lavage. Depletion of XO activity by an independent method, tungsten feeding, also decreased (P < 0.05) lung lavage neutrophil counts and increased (P < 0.05) lavage albumin concentrations. We conclude that XO may be involved in lung neutrophil retention but not lung injury during exposure to hyperoxia.
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PMID:Xanthine oxidase promotes neutrophil sequestration but not injury in hyperoxic lungs. 817 9

Exposure to hyperbaric oxygen [3 atmospheres absolute (ATA) for 45 min] inhibited carbon monoxide (CO)-mediated lipid peroxidation in the brains of rats by preventing the conversion of xanthine dehydrogenase to oxidase, a conversion process known to be due to the action of leukocytes. The effect was the same whether treatment was given 24 hr before or up to 45 min after poisoning. Hyperbaric oxygen did not inhibit the initial interaction of leukocytes with brain microvasculature, based on measurements of myeloperoxidase (MPO) in microvessel segments, but persistent adherence, which is due to B2 integrins, did not occur. Exposing rats to 3 ATA pressure (0.21 ATA O2) after CO poisoning had no significant effects. A progressive reduction in brain microvessel MPO titers occurred with exposure to O2 at 1, 2, or 3 ATA after CO poisoning, but 1 ATA O2 treatment did not significantly inhibit xanthine oxidase formation or lipid peroxidation. In vitro studies with polymorphonuclear leukocytes (PMN) from rats exposed to hyperbaric oxygen corroborated the absence of PMN B2 integrin function, but when these cells were stimulated they exhibited normal B2 integrin expression on their surface and also normal elastase release and superoxide radical production. Adherence functions of PMN that do not require B2 integrins appeared to remain intact after exposure to hyperbaric oxygen, as peritoneal neutrophilia in response to a glycogen challenge was not inhibited. B2 integrin function could be restored by incubating cells with 8 bromo cGMP, and incubation with phorbol ester stimulated the adherence function of both control and hyperbaric oxygen-exposed PMN. These results provide a clear mechanism for the inhibition of CO-mediated brain lipid peroxidation by hyperbaric oxygen and indicate that hyperoxia causes a discrete disturbance of PMN adherence function.
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PMID:Functional inhibition of leukocyte B2 integrins by hyperbaric oxygen in carbon monoxide-mediated brain injury in rats. 824 32

This multifaceted study involved a combined biochemical and cellular analysis of oxidant metabolism by a lung cell at risk from injury by endogenous and environmental oxidants, the pulmonary alveolar type II epithelial cell. Within the framework of this study, a method was developed for effectively delivering antioxidant enzymes and alpha-tocopherol to the intracellular compartment of alveolar epithelial cells. Alveolar type II cells are key sources of pulmonary surfactant phospholipids and apoproteins and serve as progenitors of type I alveolar epithelium, thus playing an important role in the re-epithelialization of the lung alveolus after exposure to pulmonary oxidants. The type I and II pulmonary epithelium also play an essential collaborative role in maintaining the integrity of the air-blood barrier of the lung. Because of these critical properties of the alveolar epithelium and their recognized sensitivity to oxidant stress derived from diverse sources, such as activated inflammatory cells, hyperoxia, the environmental oxidants and nitrogen dioxide, and surgical procedures, such as cardiopulmonary bypass and lung transplantation, we endeavored to understand more about the oxidant metabolism and antioxidant pharmacology of these cells. In our experiments, we made the observation that loss of differentiated oxidant generation and antioxidant properties of type II cells occurs very rapidly in vitro. For example, we observed a 50% to 75% reduction in the specific activities of type II cell superoxide dismutase, catalase, and glutathione peroxidase, all critical scavengers of cell superoxide and hydrogen peroxide and key enzymes in the attenuation of hydroxyl radical formation. Although the differentiated characteristics of the type II cell antioxidant defenses changed in vitro, they may have become more reflective of type I alveolar epithelial cells. The type I cell is the most vulnerable for oxidant damage in the alveolus because of its large surface area and the possibility of a reduced antioxidant capacity compared to type II alveolar epithelium. In spite of this limitation, we were able to culture type II cells and study their adaptive and toxic responses to exogenously administered oxidant stress. We also observed that a significant source of self-generated oxidants in type II cells was the enzyme xanthine oxidase. Normal rates of oxidant production by this enzyme had an inhibitory effect on incorporation of biosynthetic precursors into surfactant phospholipids; these effects were eliminated by the xanthine oxidase inhibitor, allopurinol.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Oxidant injury to the alveolar epithelium: biochemical and pharmacologic studies. 843 7

We have investigated the relationship between intracellular glutathione levels and the inducibility of the mRNAs encoding the major antioxidant enzymes Cu,Zn superoxide dismutase (Cu,Zn SOD), catalase (CAT), glutathione peroxidase (GP), and the stress protein heme oxygenase (HO) following exposure of human umbilical vein endothelial cells (HUVEC) to either hypoxanthine-xanthine oxidase or 95% O2. Treatment of HUVEC with 2 and 200 microM buthionine sulfoximine (BSO) for 16 h reduced total glutathione (GSH) levels by 51 and 95%, respectively, whereas treatment with 100 microM diethylmaleate (DEM) for 24 h increased the cellular GSH content by 58%. None of these treatments affected the responsiveness of HUVEC to a subsequent oxidant challenge, in terms of antioxidant enzymes activities and mRNA levels. On the contrary, HO mRNA was significantly induced by both BSO and DEM, as well as by hyperoxia, albeit to a different extent. We conclude that intracellular redox changes do not appear to regulate the expression of the mRNAs encoding Cu,Zn SOD, CAT, and GP. Furthermore, factors other than endogenous thiols may play a role in the control of HO mRNA expression.
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PMID:Variable glutathione levels and expression of antioxidant enzymes in human endothelial cells. 849 25

Since the description of bronchopulmonary dysplasia (BPD) in premature infants, the supplemental oxygen administered has been suspect in the etiology of BPD. This has prompted studies on the effect of hyperoxia on lung growth in neonatal animals. So far, these have not led to a treatment which either prevents or mitigates BPD. Another approach to investigate the effect of hyperoxia on the immature lung is to use lung explants from 12-d gestation mouse fetuses. Exposing explants to different concentrations of oxygen for 48 h, we found that exposures to oxygen both below (10%) and above (35% or greater) normoxia adversely affected branching morphogenesis and growth. The effect was irreversible at exposures of 50% oxygen and greater. To determine the role of reactive oxygen species (ROS) in the effect of hyperoxia, antioxidants and inhibitors of ROS formation were added to the incubating explants, and their influence on reducing the adverse effect of 50% oxygen was assessed. The combination of CuZn superoxide dismutase (SOD) and catalase, manganese SOD, manganese-3-tetrakis(1-methyl-4-pyridyl)porphorin, a low molecular weight SOD mimetic, and to a lesser extent, deferoximine, an antioxidant and inhibitor of hydroxyl radical formation, were successful in reducing the effect of 50% oxygen on morphogenesis. Not successful were N-nitro-L-arginine methyl ester (an inhibitor of nitric oxide synthase); allopurinol (an inhibitor of xanthine oxidase); N-acetylcysteine and ebselen (a glutathione peroxidase mimetic); Trolox (a synthetic tocopherol); catalase, and CuZnSOD used alone. These results provide evidence that superoxide anion and possibly hydroxyl radical are the ROS most likely responsible for the growth effects of hyperoxia on mouse fetal lung morphogenesis.
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PMID:Oxygen toxicity to the developing lung of the mouse: role of reactive oxygen species. 882 70

Hypoxia increases the activity of xanthine oxidase (XO) and its precursor, xanthine dehydrogenase (XDH), but the mechanism of regulation is unclear. In hypoxic Swiss 3T3 cells, an early (0-24 h) cycloheximide-insensitive increase in XO-XDH activity, coupled with a lack of increase in de novo XO-XDH synthesis (immunoprecipitation) or mRNA levels (quantitative RT-PCR), demonstrated a posttranslational effect of hypoxia. Similarly, hyperoxia decreased XO-XDH activity faster than could be accounted for by cessation of XO-XDH protein synthesis. In further support of a posttranslational effect, cells transfected with a constitutively driven XDH construct displayed an exaggerated increase in activity in hypoxia but no increase in activity in hyperoxia. However, more prolonged exposure to hypoxia (24-48 h) induced an increase in XO-XDH mRNA levels and de novo XO-XDH protein synthesis, suggesting an additional pretranslational effect. Finally, hypoxic induction of XO-XDH activity was found to be cell-type-restricted. We conclude that control of XO-XDH levels by oxygen tension is a complex process which involves several points of regulation.
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PMID:Hypoxia regulates xanthine dehydrogenase activity at pre- and posttranslational levels. 939 Jan 87

The effects of respiratory hyperoxia (RH) and xanthine oxidase (XO) during localized hyperthermia (HT) were investigated by determining markers of oxidative damage to lipids and proteins and tumor growth. Anesthetized rats with s.c. DS-sarcomas underwent one of the following treatments: (a) localized saline-bath HT (60 min, 44 degrees C); (b) HT + RH (100% O2); and (c) HT + RH + XO (15 units/kg i.v.). Sham-treated animals served as controls. Tumors were investigated for: (a) thiobarbituric acid-reactive substance formation and protein-bound 4-hydroxynonenal, as indicators of lipid peroxidation; (b) reactive oxygen-mediated protein modifications; (c) apoptosis; and (d) tumor volume growth. Upon treatment, increases in thiobarbituric acid-reactive substances, protein-bound 4-hydroxynonenal, protein-associated carbonyl functions, and number of cells undergoing apoptosis were found in tumor tissue, together with an inhibition of tumor growth. When treatment groups were compared, effects in the group HT + RH + XO were generally most pronounced. These findings indicate that the antitumor effect of HT is at least partially mediated through the selective induction of lipid peroxidation and oxidative injury in tumor cells, leading to apoptosis. This effect was enhanced by adding RH or RH + XO, presumably due to enhanced tissue damage following an increased formation of reactive oxygen species, with higher levels of lipid peroxidation and protein oxidation.
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PMID:Enhancement of oxidative cell injury and antitumor effects of localized 44 degrees C hyperthermia upon combination with respiratory hyperoxia and xanthine oxidase. 966 74


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