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)

Hydroxyl radicals have been generated from hydrogen peroxide and superoxide (produced with xanthine oxidase), and an iron (EDTA) catalyst, and detected with deoxyribose, or in some cases with benzoate or alpha-keto-gamma-methiolbutyric acid. Purified myeloperoxidase, and neutrophils stimulated with fMet-Leu-Phe and cytochalasin B, strongly inhibited this hydroxyl radical production in a concentration-dependent manner. Supernatants from stimulated cells also inhibited, and inhibition by cells or supernatant was prevented by azide. There was much less inhibition by myeloperoxidase-deficient neutrophils. Inhibition thus was due to myeloperoxidase released by the cells. With neutrophils stimulated with phorbol myristate acetate, which release very little myeloperoxidase, hydroxyl radical production was enhanced due to the additional superoxide produced by the cells. It is concluded that under conditions where neutrophils release myeloperoxidase as well as superoxide and hydrogen peroxide, breakdown of hydrogen peroxide by myeloperoxidase would make conditions unfavorable for hydroxyl radical production.
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PMID:Myeloperoxidase as an effective inhibitor of hydroxyl radical production. Implications for the oxidative reactions of neutrophils. 301 31

The effects of antirheumatic drugs on superoxide anion (O2-.) production by human polymorphonuclear leukocytes (PMNL) activated in vitro with phorbol myristate acetate (PMA) or N-formyl-methionyl-leucyl-phenylalanine (fMLP) were investigated. Chloroquine (CLQ), auranofin (AF) and chlorotriethylphosphine gold (CTEP-G) at 10(-6) to 10(-4) M inhibited PMA and fMLP induced O2-. production in a dose dependent fashion. These drugs had no effect on O2-. production by the hypoxanthine/xanthine oxidase system, indicating that their inhibitory effects were directed at the O2-. generating mechanism and that they were not scavengers of the O2-. formed. AF and CTEP-G inhibited the specific binding of 3H fMPL to PMNL membrane receptors, whereas CLQ had no effect. Colchicine (COL) and gold sodium thiomalate (GSTM) on the other hand did not significantly affect PMA and fMLP induced O2-. production or the specific binding of the ligands to PMNL. The antirheumatic drugs had no effect on isolated neutrophil membrane protease, a chymotrypsin-like enzyme that has been implicated in the activation of NAD(P)H oxidase. However, several of the drugs inhibited the enzymatic activity of a subcellular preparation of PMNL NAD(P)H oxidase, the order of potency being GSTM greater than CLQ greater than penicillamine greater than COL greater than AF approximately equal to CTEP-G. The isolated NAD(P)H oxidase was also inhibited by the thiol compounds--thiomalic acid and dithiothreitol, suggesting that the mechanism of inhibition may involve sulfhydryl-disulfide interchange reactions.
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PMID:Interactions of antirheumatic drugs with the superoxide generation system of activated human polymorphonuclear leukocytes. 301 58

We have found that pretreatment of human neutrophils with ibuprofen (0.10-1.0 mg/ml) results in an irreversible, concentration-dependent inhibition of superoxide anion generation and release of lysosomal enzymes (myeloperoxidase, lysozyme) stimulated by the synthetic peptide, N-formyl-methionyl-leucyl-phenylalanine (FMLP), the complement fragment C5a, and to a lesser extent by serum opsonized zymosan. Inhibition of granule exocytosis and oxygen radical generation at ibuprofen concentrations less than 5 mg/ml was not due to drug cytotoxicity since release of the cytoplasmic enzyme lactate dehydrogenase was not affected by ibuprofen. In contrast to neutrophil responses mediated by C5a or FMLP, ibuprofen did not inhibit either enzyme release or superoxide anion generation by neutrophils stimulated with phorbol myristate acetate. Ibuprofen did not function as an oxygen radical scavenger in a cell-free system in which superoxide anion was generated by the aerobic action of xanthine oxidase on hypoxanthine. Ibuprofen also inhibited in a concentration-dependent fashion both directed migration (chemotaxis) and stimulated random migration (chemokinesis) of neutrophils exposed to either FMLP or C5a. Inhibition of neutrophil adherence to plastic surfaces and bovine pulmonary artery endothelial cells was equally effective when the neutrophils were treated with ibuprofen before stimulation with FMLP or phorbol myristate acetate. The inhibitory effects of ibuprofen pretreatment of neutrophils could not be overcome by addition of prostaglandins E1 or E2 (0.3-300 nM). These results demonstrate that ibuprofen is capable of suppressing many functions thought to be important in neutrophil-mediated acute pulmonary inflammatory processes. Results of these experiments further suggest that ibuprofen may inhibit neutrophil functions by acting on cellular components separate from membrane receptors or by blockade of cyclo-oxygenase products which may be involved in these neutrophil functions.
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PMID:Inhibition of human polymorphonuclear leukocyte functions by ibuprofen. 303 52

The polyamines putrescine, spermidine and spermine, at concentrations of 10 microM, stimulated superoxide generation by human polymorphonuclear leukocytes induced by fMet-Leu-Phe in the presence of Ca2+. This positive effect was not evident in the absence of Ca2+ or when the polymorphonuclear leukocytes were stimulated by phorbol myristate acetate. Spermidine in the range of 10-100 microM showed a dose-dependent stimulatory effect on the superoxide generation induced by fMet-Leu-Phe, whilst at doses above 25 mM it produced an inhibitory effect. At this concentration, spermidine did not reduce the phorbol myristate acetate-neutrophil-induced O2-. generation, while an inhibitory effect by the polyamine was evident at concentrations above 50 mM. In addition, 100 microM spermidine increased the amount of superoxide generated and enhanced the ability of the chemotactic peptide to stimulate superoxide generation. The polyamines in the range of 10 microM-25 mM did not modify the activity of purified NADPH oxidase, nor the rate of reduction of cytochrome c as supported by the xanthine/xanthine oxidase reaction. These results indicate that physiological concentrations of polyamines can stimulate superoxide formation by polymorphonuclear leukocyte cells produced by the chemotactic peptide fMet-Leu-Phe, probably by increasing the availability of external calcium.
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PMID:Polyamines stimulate superoxide production in human neutrophils activated by N-fMet-Leu-Phe but not by phorbol myristate acetate. 304 Jan 18

Brief treatment (3 min at 37 degrees C) of human neutrophils with triphenyltin chloride (TPTC1) resulted in a dose-dependent inhibition of superoxide (O2-.) production stimulated by concanavalin A+ cytochalasin D. It was considered from the following findings that the inhibition may be caused by some functional disorders of neutrophils: 1) O2-. generated by xanthine oxidase-acetaldehyde system was not inhibited by TPTC1. 2) There was no change in cell viability after treatment with TPTC1. When the other phenyltin compounds were examined, the relative potencies of inhibitory effect were shown to be in the order of TPTC1 greater than diphenyltin dichloride greater than phenyltin trichloride greater than tetraphenyltin on a molar basis. Lysosomal enzyme release caused by neutrophils stimulated by N-formyl-methionyl-leucyl-phenylalanine (FMLP) was also inhibited by TPTC1. These results suggest that TPTC1 inhibits the common pathway(s) of the two stimulus responses.
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PMID:[Effect of triphenyltin chloride on superoxide (O2-.) production in human neutrophils]. 609 90

Chemotactic factors, which are important in attracting neutrophils to inflammatory sites, have also been shown to stimulate oxidative metabolism, resulting in increased chemiluminescence and release of superoxide anion (O2-). We observed a unique bimodal chemiluminescence pattern upon stimulation with either the complement-derived factor C5a or formyl-methionyl-leucyl-phenylalanine. A sharp peak of activity occurred within 1 to 2 min, and a second more extended peak was seen between 3 and 6 min. Enhancement of both peaks occurred when the cells were pretreated with cytochalasin B. Expression of both peaks was found to be related to cell density, and expression of the second peak was not dependent upon extracellular metabolites released during the first peak. Cells preincubated in luminol and then thoroughly washed responded with only a single peak coincident with the second peak. Together these findings indicate that the first peak is extracellular in origin, whereas the second peak is cell associated. Studies with scavengers of oxygen intermediates and inhibitors of myeloperoxidase for the oxidation of luminol, which may occur in part through the formation of HOCl as well as through a non-HOCl-mediated mechanism. Evidence for a non-HOCl-mediated mechanism comes from experiments in which luminol, myeloperoxidase, and O2- generated by xanthine-xanthine oxidase produce luminescence in the absence of chloride ion. These studies provide further insight into the sequence of events which occur during the stimulation of neutrophils with chemotactic factors and the nature of neutrophil chemiluminescence.
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PMID:Analysis of the bimodal chemiluminescence pattern stimulated in human neutrophils by chemotactic factors. 630 58

Using mouse small intestine brush-border membrane vesicles virtually free of xanthine oxidase (EC 1.2.3.2) and free of uricase (EC 1.7.3.3) the uptake of the purines uric acid, xanthine and hypoxanthine have been studied. The sodium-dependent overshoot phenomenon shown to exist for the uptake into the vesicles for D-glucose and L-phenylalanine was not observed with the purines. However, the uptake of the three purines in the presence of NaCl or KCl was greater than the uptake in the presence of either NaSCN or mannitol. Although 12.9% of the xanthine uptake and 17.6% of the hypoxanthine uptake was attributed to binding to the membranes, almost all the uric acid uptake was due to transport into an osmotically active space. The apparent intravesicular volume, calculated after 60 min incubation, for the three purines was consistently greater than the values obtained with D-glucose, L-glucose and L-phenylalanine equilibration, suggesting slow continuing penetration of purines associated with swelling or an apparent accumulation of purines within the vesicles associated with normal vesicle volume.
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PMID:Uptake of uric acid, xanthine and hypoxanthine by brush-border membrane vesicles from mouse small intestine. 650 51

A 4-year-old patient is described with hyperphenylalaninemia, severe retardation in development, severe muscular hypotonia of the trunk and hypertonia of the extremities, convulsions, and frequent episodes of hyperthermia without infections. Urinary excretion of neopterin, biopterin, pterin, isoxanthopterin, dopamine, and serotonin was very low, although the relative proportions of pterins were normal. In lumbar cerebrospinal fluid, homovanillic acid, 5-hydroxyindoleacetic acid, neopterin and biopterin were low. Oral administration of L-erythro tetrahydrobiopterin normalized the elevated serum phenylalanine within 4 h, serum tyrosine was increased briefly and serum alanine and glutamic acid for a longer time. Urinary dopamine and serotonin excretion were also increased. Administration of an equivalent dose of D-erythro tetrahydroneopterin was ineffective and demonstrated that this compound is not a cofactor in vivo and cannot be transformed into an active cofactor. GTP cyclohydrolase I activity was not detectable in liver biopsies from the patient. The presence of an endogenous inhibitor in the patient's liver was excluded. This is the first case of a new variant of hyperphenylalaninemia in which the formation of dihydroneopterin triphosphate and its pterin metabolites in liver is markedly diminished. Normal activities of xanthine oxidase and sulfite oxidase were apparent since uric acid levels were normal and no increase in hypoxanthine, xanthine, and S-sulfocysteine concentrations could be observed in urine. It is concluded that the molybdenum cofactor of these enzymes may not be derived from dihydroneopterin triphosphate in man. Also, since no gross abnormalities in the patient's immune system could be found, it seems unlikely that dihydroneopterin triphosphate metabolites, such as neopterin, participate actively in immunological processes, as postulated by others. See Note added in proof.
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PMID:GTP cyclohydrolase I deficiency, a new enzyme defect causing hyperphenylalaninemia with neopterin, biopterin, dopamine, and serotonin deficiencies and muscular hypotonia. 673 69

We evaluated the effect of 4-(2-benzylphenoxy)-N-methylbutylamine hydrochloride (bifemelane hydrochloride) on superoxide production by human neutrophils using an MCLA-dependent chemiluminescence assay. Bifemelane hydrochloride dose-dependently inhibited superoxide production by neutrophils stimulated with phorbol myristate acetate, opsonized zymosan, or N-formyl-methionyl-leucyl-phenylalanine, while it had no effect on superoxide production by a hypoxanthine-xanthine oxidase system. These results indicate that bifemelane hydrochloride does not have a scavenging effect, but has an inhibitory effect on superoxide generation by neutrophils. Although this drug is commonly used for treating chronic cerebral infarction, it may also have a protective effect on acute ischemia/reperfusion injury.
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PMID:Inhibitory effect of bifemelane on superoxide generation by activated neutrophils measured using a simple chemiluminescence method. 783 51

1. The possible mechanisms of action of the inhibitory effect of gomisin C on the respiratory burst of rat neutrophils in vitro was investigated. 2. The peptide formyl-Met-Leu-Phe (FMLP) induced superoxide anion (O2-) formation and O2 consumption, which was inhibited by gomisin C in a concentration-dependent manner (IC50 21.5 +/- 4.2 micrograms ml-1 for O2- formation). Gomisin C also suppressed O2- formation and consumption at low concentrations of phorbol myristate acetate (PMA) with an IC50 value of 26.9 +/- 2.1 micrograms ml-1 for O2- formation. However, gomisin C did not affect the responses induced by a high concentration of PMA. 3. Gomisin C had no effect on O2- generation and uric acid formation in the xanthine-xanthine oxidase system, and failed to alter O2- generation during dihydroxyfumaric acid (DHF) autoxidation, indicating that it does not scavenge superoxide. 4. Like trifluoperazine (TFP), gomisin C attenuated the activity of PMA-activated neutrophil particulate NADPH oxidase in a concentration-dependent manner. 5. Gomisin C reduced the elevations of cytosolic free Ca2+ in neutrophils stimulated by FMLP in the presence or absence of EDTA. Cyclopiazonic acid (CPA) induced the release of Ca2+ from intracellular stores and this was also reduced by gomisin C. However, the Ca2+ influx pathway activated by CPA was not affected by gomisin C. 6. The cellular cyclic AMP level was markedly increased by forskolin, but not by gomisin C. Moreover, the inositol phosphate levels in FMLP-activated neutrophils were not affected by gomisin C. 7. These results show that the inhibitory action of gomisin C on the respiratory burst is not mediated by changes in cellular cyclic AMP or in inositol phosphates, or by scavenging O2- released from neutrophils, but may be mediated partly by the suppression of NADPH oxidase and partly by the decrease of cytosolic Ca2+ released from an agonist-sensitive intracellular store.
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PMID:Inhibition by gomisin C (a lignan from Schizandra chinensis) of the respiratory burst of rat neutrophils. 785 90


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