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)

Maintenance of an acidic intralysosomal compartment may be relevant to multiple aspects of neutrophil function. The effect of lysosomal alkalinization on the neutrophil respiratory burst was studied by measuring cytochrome c reduction in response to soluble stimuli in the presence of lysosomotropic weak bases. The weak bases chloroquine, ammonium chloride, methylamine, and clindamycin all raised the intralysosomal pH and inhibited neutrophil oxidative metabolism at concentrations ranging from 0.1 to 100 mmol/L. Inhibition was dose dependent for each base and correlated significantly with the degree of lysosomal alkalinization. Concentrations that did not alkalinize the lysosome did not inhibit the respiratory burst. Inhibition by weak bases was seen when oxidative metabolism was stimulated by phorbol myristate acetate, calcium ionophore A23187, formyl-methionyl-leucyl-phenylalanine, opsonized zymosan, or sodium fluoride. Increasing the stimulus concentration (from 5 ng/mL to 5 micrograms/mL phorbol myristate acetate and from 0.5 to 1 mumol/L A23187) diminished or abolished inhibition by weak bases. Washing the cells after incubation with bases and before stimulation substantially reversed the inhibition. None of the bases impaired detection of superoxide in a cell-free xanthine-xanthine oxidase assay. Other indexes of oxidative metabolism, including oxygen consumption and hydrogen peroxide release, were also inhibited by weak bases. Analysis of particulate NADPH oxidase activity from neutrophils stimulated in the presence of bases suggested that these cells assemble a subnormal amount of an enzyme complex with normal kinetic characteristics. Lysosomotropic weak bases alkalinized the neutrophil lysosome and produced inhibition of oxidative metabolism that was dose related, was not stimulus specific, and was largely reversed by washing the cells before stimulation. A possible explanation would be altered assembly of the enzyme complex involved in respiratory burst activation as a consequence of impaired granule/plasma membrane fusion in the presence of diminished transmembrane pH gradients.
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PMID:Inhibition of neutrophil oxidative metabolism by lysosomotropic weak bases. 300 23

Na-Ca exchange activity in bovine cardiac sarcolemmal vesicles was stimulated up to 10-fold by preincubating the vesicles with 1 microM FeSO4 plus 1 mM dithiothreitol (DTT) in a NaCl medium. The increase in activity was not reversed upon removing the Fe and DTT. Stimulation of exchange activity under these conditions was completely blocked by 0.1 mM EDTA or o-phenanthroline; this suggests that the production of reduced oxygen species (H2O2, O2-.,.OH) during Fecatalyzed DTT oxidation might be involved in stimulating exchange activity. In agreement with this hypothesis, the increase in exchange activity in the presence of Fe-DTT was inhibited 80% by anaerobiosis and 60% by catalase. H2O2 (0.1 mM) potentiated the stimulation of Na-Ca exchange by Fe-DTT under both aerobic and anaerobic conditions; H2O2 also produced an increase in activity in the presence of either FeSO4 (1 microM) or DTT (1 mM), but it had no effect on activity by itself. Superoxide dismutase did not block the effects of Fe-DTT on exchange activity; however, the generation of O2-. by xanthine oxidase in the presence of an oxidizable substrate stimulated activity more than 2-fold. Hydroxyl radical scavenging agents (mannitol, sodium formate, sodium benzoate) did not attenuate the stimulation of activity observed with Fe-H2O2. Exchange activity was also stimulated by the simultaneous presence of glutathione (GSH; 1-2 mM) and glutathione disulfide (GSSG; 1-2 mM). Neither GSH nor GSSG was effective by itself and either 0.1 mM EDTA or o-phenanthroline blocked the effects on transport activity of the combination of GSH + GSSG. Treatment of the GSH and GSSG solutions with Chelex ion-exchange resin to remove contaminating transition metal ions reduced (by 40%) the degree of stimulation observed with GSH + GSSG. Full stimulating activity was restored to the Chelex-treated GSH and GSSG solutions by the addition of 1 microM Fe2+; Cu2+ was less effective than Fe2+ whereas Co2+ and Mn2+ were without effect. In the presence of 1 microM Fe2+, GSH alone produced a slight increase in transport activity, but this was markedly enhanced by the addition of Chelex-treated GSSG. The results indicate that stimulation of exchange activity requires the presence of both a reducing agent (DTT, GSH, O-.2, or Fe2+) and an oxidizing agent (H2O2, GSSG, and perhaps O2) and that the effects of these agents are mediated by metal ions (e.g. Fe2+).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Redox modification of sodium-calcium exchange activity in cardiac sarcolemmal vesicles. 300 82

Spin-trapping of superoxide ion, O2-, which is produced from two different sources (OH(-)-DMSO and xanthine-xanthine oxidase systems), was investigated by use of a water-soluble, notroso-aromatic spin trap, sodium 3,5-dibromo-4-nitrosobenzene-sulfonate (DBNBS). It was found that O2- from all sources was easily trapped by DBNBS to yield the stable O2- adduct showing the ESR spectrum consisting of a triplet of a triplet [aN (1) = 12.63 G and aH (2) = 0.71 G]. Hydroperoxy radical (HO2.), which can be generated from the oxidation of hydrogen peroxide with Ce4+ ion, was not trapped by DBNBS. These results indicate that the trapped radical is O2-, but not HO2..
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PMID:Spin-trapping of superoxide ion by a water-soluble, nitroso-aromatic spin-trap. 301 Sep 90

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

Mouse cortical synaptosomal structure and function are altered when exposed to hypoxanthine/xanthine oxidase (HPX/XOD)-generated active oxygen/free radical species. The structure of both the synaptic vesicle and plasma membrane systems are altered by HPX/XOD treatment. The alteration of synaptic vesicle structure is exhibited by a significant increase in the cumulative length of nonsynaptic vesicle membrane per nerve terminal. With respect to the nerve terminal plasma membrane, the length of the perimeter of the synaptosome is increased as the membrane pulls away from portions of the terminal in blebs. The functional lesion generated by HPX/XOD treatment results in a reduction in selective high-affinity gamma-[14C]aminobutyric acid (GABA) uptake. Kinetic analysis of the reduction in high-affinity uptake reveals that the Vmax is significantly altered whereas the Km is not. Preincubation with specific active oxygen/free radical scavengers indicates that the super-oxide radical is directly involved. This radical, most probably in the protonated perhydroxyl form, initiates lipid peroxidative damage of the synaptosomal membrane systems. Low-affinity [14C]GABA transport is unaltered by the HPX/XOD treatment. The apparent ineffectiveness of free radical exposure on low-affinity [14C]GABA transport coupled with its effectiveness in reducing high-affinity transport supports the idea that two separate and different amino acid uptake systems exist in CNS tissue, with the high-affinity being more sensitive (lipid-dependent) and/or more energy-dependent (Na+,K+-ATPase) than the low-affinity system.
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PMID:Superoxide radical-mediated alteration of synaptosome membrane structure and high-affinity gamma-[14C]aminobutyric acid uptake. 302 6

Phosphate was reported to be an inhibitor of copper- and zinc-containing superoxide dismutase (SOD) [de Freitas, D.M., & Valentine, J.S. (1984) Biochemistry 23, 2079-2082]. Thus SOD activity, in 50 mM 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) (pH 7.4), was decreased by approximately 50% when the assay was made 10 mM in phosphate, and the ionic strength was adjusted with sodium fluoride. The inhibitory effect of phosphate was attributed to the neutralization of the positive charge on the guanidino residue of Arg-141. We have reexamined the effects of phosphate inhibition of SOD and found that the enzyme has identical activity in phosphate or HEPES buffer when the ionic strength is adjusted with NaBr. The putative inhibitory effect of phosphate appears to have been due to fluoride inhibition of the superoxide generating system of xanthine/xanthine oxidase. We have confirmed this result by using a photochemical generation of O2- in addition to the enzymatic generation of O2-. Chemical modification of the lysine residues to homoarginines does not affect the activity of the enzyme and does not impart a phosphate sensitivity. Chemical modification with phenylglyoxal caused approximately 80% inactivation of the native enzyme and 90% inactivation of the O-methylisourea-modified enzyme. Our results suggest that phosphate does not inhibit the copper- and zinc-containing superoxide dismutase (Cu,Zn-SOD) beyond the expectations of its effect on ionic strength.
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PMID:Phosphate inhibition of the copper- and zinc-containing superoxide dismutase: a reexamination. 302

In spontaneously hypertensive rats, we studied the participation of xanthine oxidase-linked free radical in ischemia and reperfusion-induced cerebral injury, using allopurinol, a xanthine oxidase inhibitor. The loss of righting reflex was noted in some animals after a 4 hour occlusion of bilateral common carotid arteries and 19 of 25 animals died within 72 hours after reperfusion. One hour after reperfusion, the cerebral water content increased significantly, with an increase in sodium content and a decrease in potassium content. In 7 animals treated with oral administrations of allopurinol (200 mg/kg) 24 hours and 1 hour before occlusion, no death was found either during occlusion or after reperfusion, and the loss of righting reflex was noted in only one animal 24-72 hours following reperfusion. The increase in cerebral water content and accompanied changes in electrolyte contents were clearly prevented by allopurinol. These results suggest the possibility that the production of xanthine oxidase-linked free radical participates in cerebral injury due to ischemia and reperfusion in spontaneously hypertensive rats.
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PMID:Effect of allopurinol on ischemia and reperfusion-induced cerebral injury in spontaneously hypertensive rats. 302 24

The role of O2 free radicals in the reduction of sarcolemmal Na+-K+-ATPase, which occurs during reperfusion of ischemic heart, was examined in isolated guinea pig heart using exogenous scavengers of O2 radicals and an inhibitor of xanthine oxidase. Ischemia and reperfusion reduced Na+-K+-ATPase activity and specific [3H]ouabain binding to the enzyme in ventricular muscle homogenates and also markedly lowered sodium pump activity estimated from ouabain-sensitive 86Rb+ uptake by ventricular muscle slices. These effects of ischemia and reperfusion were prevented to various degrees by O2-radical scavengers, such as superoxide dismutase, catalase, dimethyl-sulfoxide, histidine, or vitamin E or by the xanthine oxidase inhibitor, allopurinol. The degree of protection afforded by these agents paralleled that of reduction in enhanced lipid peroxidation of myocardial tissue as estimated from malondialdehyde production. These results strongly suggest that O2 radicals play a crucial role in the injury to sarcolemmal Na+-K+-ATPase during reperfusion of ischemic heart.
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PMID:O2 free radicals: cause of ischemia-reperfusion injury to cardiac Na+-K+-ATPase. 302 76

The anti-oxidant efficacy, in vitro, of the gold compounds auranofin (AF) and gold sodium thiomalate (GST) was examined by studying their effects on the generation of reactive oxygen species (ROS) using zymosan-stimulated polymorphonuclear leukocytes (PMNs) and a cell-free, xanthine-xanthine oxidase system. The oxygen species investigated were the superoxide radical anion (O2-), hydrogen peroxide (H2O2) and the hydroxyl radical (OH.). AF had an inhibitory effect on ROS production by PMNs. In particular, OH. generation was significantly suppressed in a dose-dependent fashion. AF did not inhibit ROS production in the cell-free system. GST produced only a small degree of inhibition at higher concentrations. These findings suggest that AF may play an important role in the inhibition of respiratory bursts and the generation of inflammatory reaction products. Since the products of the respiratory burst, especially potent oxidants such as OH. and H2O2, are thought to be important inflammatory mediators, it is postulated that the blockade of toxic ROS generation by AF affects rheumatoid as well as dermatological inflammation and tissue damage.
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PMID:Anti-oxidant effects of gold compounds. 302 64

The effects of allopurinol pretreatment (1 mg/ml in the drinking water for 7 days at an estimated daily dose of 75 mg/kg) on biochemical and chemical changes occurring following left circumflex coronary artery ligation (40 min) and reperfusion (60 min) were examined in pentobarbital-anesthetized rabbits. During the ischemic phase, allopurinol pretreatment provided significant preservation of cellular ATP levels and of mitochondrial ATP generation as compared with untreated animals (P less than 0.05). During the reperfusion phase, allopurinol pretreatment significantly prevented the decrease in left ventricular pressure, sodium and calcium accumulation and decreases in sarcolemmal Na+,K+-stimulated and sarcoplasmic reticulum K+,Ca2+-stimulated ATPase activities as compared with untreated animals (P less than 0.05). In contrast, the decrease in mitochondrial (azide-sensitive) ATPase during ischemia and the partial recovery during reperfusion were unaffected by allopurinol pretreatment. Our results indicate that the myocardial protective effects of allopurinol may differ mechanistically in the ischemic and reperfusion phases of injury. The fact that rabbit hearts do not contain detectable xanthine oxidase activity would seem to preclude an obligatory role of this enzyme both in the generation of myocardial ischemic/reperfusion injury and in the protective actions of allopurinol.
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PMID:Effects of allopurinol on myocardial ischemic injury induced by coronary artery ligation and reperfusion. 303 15


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