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)

Appropriately stimulated neutrophils release peroxidase and undergo a respiratory burst to form hydrogen peroxide (H2O2) and hydroxyl radicals (OH). We report here that both the myeloperoxidase-H2O2-halide system and OH released in this way can degrade the leukotrienes (LT) formed by neutrophils. More LTB4 and LTC4 were recovered from the supernatants of chronic granulomatous disease neutrophils (which are unable to respond to stimulation with a respiratory burst) than from normal or myeloperoxidase-deficient neutrophils when stimulated with the calcium ionophore A23187. When radiolabeled LTC4 was added, 72% of the LTC4 was recovered from the chronic granulomatous disease cells in contrast to 0% from the myeloperoxidase-deficient and normal cells. Inhibitor studies using catalase, superoxide dismutase, azide, mannitol, or ethanol suggested that LTC4 degradation was mediated primarily by the myeloperoxidase system in normal cells and by OH in myeloperoxidase-deficient cells. LTC4 degradation by the cell-free myeloperoxidase-H2O2-halide system and the OH -generating acetaldehyde-xanthine oxidase-Fe2+ system had inhibitor profiles comparable to normal and myeloperoxidase-deficient neutrophils, respectively. LTC4 degradation products formed by the stimulated neutrophils and model systems included the 5-(S), 12-(R)- and 5-(S), 12-(S)-6-trans-isomers of LTB4. Thus phagocytes may modulate LT activity in inflammatory sites by the inactivation of these potent biologic mediators by at least two oxidative mechanisms.
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PMID:Leukotriene production and inactivation by normal, chronic granulomatous disease and myeloperoxidase-deficient neutrophils. 631

BAY X1005, (R)-2-[4-(quinolin-2-yl-methoxy)phenyl]-2-cyclopentyl acetic acid, is an enantioselective inhibitor of leukotriene biosynthesis. It effectively inhibits the synthesis of LTB4 in A23187-stimulated leukocytes from rats, mice and humans (IC50 0.026, 0.039 and 0.22 mumol/l, respectively) as well as the formation of LTC4 (IC50 0.021 mumol/l) in mouse peritoneal macrophages stimulated with opsonized zymosan. The compound is, however, less active in inhibiting LTB4 synthesis in human whole blood (IC50 17.0 and 11.6 mumol/l, as measured by RIA or HPLC, respectively). BAY X1005 exhibits a high enantioselectivity in human whole blood (31 times over the (S)-enantiomer). BAY X1005 is shown to be a selective inhibitor of the formation of 5-lipoxygenase-derived metabolites in vitro, without effects on other routes of arachidonic acid metabolism such as 12-lipoxygenase in human whole blood and cyclooxygenase in both mouse macrophages and human whole blood. BAY X1005 is devoid of any antioxidant activity (methemoglobin induction and xanthine-xanthine oxidase assay), without effects on granule release and with only weak effects on reactive oxygen species generation in human PMNL.
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PMID:In vitro pharmacology of BAY X1005, a new inhibitor of leukotriene synthesis. 821 45

Oxygen radicals produced by the hypoxanthine-xanthine oxidase (Hyp-XO) system potently constrict the pulmonary circulation of pigs. D-penicillamine (DPA) is thought to be a free radical scavenger. In the present work we have studied if DPA may influence the vasoactive action of Hyp-XO in pig lungs. Further, we have measured how this drug influences the output of cyclooxygenase and lipoxygenase products from the left atrium in pigs infused with XO into the pulmonary circulation. Twelve young pigs were divided into two groups. Group 1, the XO group, was infused 1 U/kg XO into right atrium. Group 2, the DPA group, was pretreated with DPA, 100 mg/kg intravenously before XO infusion as in group 1. Pulmonary artery pressure, left atrial pressure, pulmonary artery blood flow and systemic blood flow and pressure were recorded continuously. Plasma tromboxane B2 and prostaglandin (6-keto-PGF1 alpha) were determined with a radioimmunoassay method. Cysteinyl containing leukotrienes LTC4, LTD4, and LTE4, were measured together by RIA analyses of plasma samples, using a monoclonal antibody. There was a significant parallel decrease in paO2 and saO2 during the 130 minutes duration of the experiments in both groups without differences between the groups. Pulmonary vascular pressure and resistance increased sharply with a peak found after 25 minutes in the XO group. DPA attenuated the hemodynamic response. DPA inhibited the XO induced pulmonary blood pressure changes with 80% and inhibited the increase in pulmonary vascular resistance 68%. Plasma TXB2 increased two folds in the XO group reaching a maximum after 40 minutes, this effect was completely inhibited by DPA (92% inhibition). DPA also inhibited the XO induced increase in 6-keto-PGF1 alpha, however, not as efficient as with TXB2 (40% inhibition). Plasma cysteinyl leukotrienes increased after XO infusion reaching a peak at 20 minutes. DPA completely abolished this effect (100% inhibition). The study demonstrates that DPA attenuates or even abolishes the hemodynamic effects of XO on the pulmonary circulation in pigs. It seems that DPA inhibits the production of both lipoxygenase and cyclooxygenase products per se, and it is tempting to speculate that the observed DPA effect is caused by its action as an oxygen radical scavenger. It is further speculated that the vasoconstricting effect of XO is due to the fact that oxygen radicals may inactivate nitric oxide (NO), and that DPA stabilizes NO so it more efficiently possess its vasorelaxant activity. We conclude that DPA is an extremely potent inhibitor of XO induced pulmonary vascular effects. The mechanism of action is not fully understood, although its action as an oxygen radical scavenger may explain part of it.
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PMID:D-penicillamine inhibits the action of reactive oxygen species in the pig pulmonary circulation. 860 45

The disturbance of endothelium-dependent and endothelium-independent vascular reactions of relaxation was registered in the preparations of aorta of radiosensitive BALB/c mice, exposed to chronic external gamma-irradiation (cumulative dose of 0.43 Sv). Low doses of radiation induced an intensive hydrolysis of membrane phospholipids by phospholipase A2, displayed by an increase in the level of eukosanoisds--LTC4 and TxB2, formed under effects of lipid oxidases (lipoxygenase and cyclooxygenase) at the same time with O2 generation. High doses of O2- can also be formed under the effect of low doses of radiation along xanthine oxidase pathway simultaneously with uric acid. In these conditions *OH-radical is formed not only at the expense of water radiolysis, which is observed under the effect of high doses, as well as along the two--NO-dependent and NO-independent--pathways. Significant increase in the content of lipid peroxidation products--dienic conjugates and valonic dialdehyde--in the organs of cardiovascular system is a confirmation of active generation of *OH and *NO2 under the effect of low doses of radiation. The latter induce significant changes in the pools of NO stable metabolites, which can cause disturbance of NO-dependent physiological functions of both heart and aorta. Significant decrease in the levels of nitrite and nitrozothiols in these conditions may result in an oxidative stress. In increased simultaneous generation of *O2- and NO they may bind and thus form a toxic substance peroxynitrite. This notion can be confirmed by the low doses of nitrite, which are formed spontaneously in the presence of molecular oxygen against the background of increased or control levels of nitrate, which is formed mainly at the degradation of peroxynitrite, i.e. at high levels of superoxide anion.
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PMID:[Vascular reactivity and metabolism of the reactive oxygen species and nitrogen in effects of low doses of radiation]. 1979 69

In experiments on the anaesthetized dogs with modeling of experimental ischemia (90 min) and reperfusion (180 min) of myocardium it was investigated changes of biochemical processes in arterial blood at intragastric introduction of medicinal form (tablets) of flocalin (the fluorine-containing opener of ATP-sensitive potassium channels) in a dose 2,2 mg/kg. The data analysis allowed to define a few possible mechanisms of cardioprotective action offlocalin, which prevented the opening of a mitochondrial permeability transition pore (MPTP) and inhibition of apoptosis induced by it. They consist, from one side, in activating of the constitutive de novo biosynthesis of nitric oxide by cNOS, from other side, in suppression of inducible nitric oxide de novo synthesis by iNOS in such way to prevent the formation of toxic peroxynitrite by co-operation of surplus nitric oxide with superoxide anion, thereby limits the generation of toxic active forms of nitrogen (*NO2) and oxygen (*OH). The first effect of flocalin takes place due to limitation the degradation of L-arginine by arginase which keeps substrat for cNOS, second--due to the inhibition of superoxide generation, in particular, by xanthine oxidase (marker uric acid), lipoxigenase (marker LTC4) and cyclooxygenase (marker TxB2). Because LTC4 have coronaroconstrictory, arrhythmogenic and chemoattractory properties in the conditions of myocardial ischemia, inhibition of its production both with superoxide generation (markers H2O2 and diene conjugates) may be the another mechanisms of flocalin's cardioprotection. Powerful antiischemic action of flocalin (marker nitrite anion) as the mechanisms of cardioprotection is possible as well as inhibition of ATP and GTP degradation (marker hypoxanthine+xanthine+inosine levels in the blood) and, possibly, stimulation ofhaem degradation by haem oxygenase (markers total bilirubin and Fe in the blood). Diminishing content of free arachidonic acid in arterial blood can testify inhibition of cellular membranes phospholipides degradation by phospholipase A2 as a result of flocalin cardioprotection.
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PMID:[Biochemical mechanisms of the cardioprotective effect of the K(ATP) channels opener flocalin (medicinal form) in ischemia-reperfusion of myocardium]. 2417 72