Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P47989 (xanthine oxidase)
 8,633 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Certain products of arachidonic acid have been demonstrated recently to possess chemotactic activity for human polymorphonuclear leukocytes (PMN). Enzymatic (lipoxygenase, cyclooxygenase) generation of these lipid chemotaxins proceeds through the formation of intermediate lipid peroxides. Since lipid peroxidation can be mediated by oxygen-derived free radicals, we have examined whether chemotactically active products of arachidonic acid could be produced by exposing this unsaturated fatty acid to a superoxide-generating system. A lipid with potent chemotactic activity for human PMN was produced by incubating arachidonic acid with xanthine oxidase and acetaldehyde. Generation of chemotactic activity was time-dependent and could be inhibited to the greatest extent by scavengers of singlet oxygen (i.e., histidine, uric acid, and 2,5-dimethylfuran). Inhibition was also observed with scavengers of superoxide anion radicals (i.e., superoxide dismutase), hydrogen peroxide (i.e., catalase), and hydroxyl radicals (i.e., mannitol). Silica gel thin-layer radiochromatography demonstrated a single peak with chemotactic activity (Rf = 0.33-0.38) distinct from unaltered arachidonic acid. The product of arachidonic acid was chemotactic at a concentration of 3.0 ng/ml and chemokinetic at concentrations of 0.75-1.5 ng/ml. Since PMN produce oxygen-derived free radicals and singlet oxygen upon stimulation of their plasma membrane, and since arachidonic acid is widely distributed in human tissues, free radical-mediated generations of chemotactic activity from arachidonic acid may play an important role in amplifying inflammatory responses.
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PMID:Generation of a chemotactic lipid from a arachidonic acid by exposure to a superoxide-generating system. 625 92

In previous studies, we noted that Candida hyphae and pseudohyphae could be damaged and probably killed by neutrophils, primarily by oxygen-dependent nonphagocytic mechanisms. In extending these studies, amount of damage to hyphae again was measured by inhibition of [(14)C]cytosine uptake. Neutrophils from only one of four patients with chronic granulomatous disease damaged hyphae at all, and neutrophils from this single patient damaged hyphae far less efficiently than simultaneously tested neutrophils from normal control subjects. Neutrophils from neither of two subjects with hereditary myeloperoxidase deficiency damaged the hyphae. This confirmed the importance of oxidative mechanisms in general and myeloperoxidase-mediated systems in particular in damaging Candida hyphae. Several potentially fungicidal oxidative intermediates are produced by metabolic pathways of normal neutrophils, but their relative toxicity for Candida hyphae was previously unknown. To help determine this, cell-free in vitro systems were used to generate these potentially microbicidal products. Myeloperoxidase with hydrogen peroxide, iodide, and chloride resulted in 91.2% damage to hyphal inocula in 11 experiments. There was less damage when either chloride or iodide was omitted, and no damage when myeloperoxidase was omitted or inactivated by heating. Azide, cyanide, and catalase (but not heated catalase) inhibited the damage. Systems for generation of hydrogen peroxide could replace reagent hydrogen peroxide in the myeloperoxidase system. These included glucose oxidase, in the presence of glucose, and xanthine oxidase, in the presence of either hypoxanthine or acetaldehyde. In the presence of myeloperoxidase and a halide, the toxicity of the xanthine oxidase system was not inhibited by superoxide dismutase and, under some conditions, was marginally increased by this enzyme. This suggested that superoxide radical did not damage hyphae directly but served primarily as an intermediate in the production of hydrogen peroxide. The possible damage to hyphae by singlet oxygen was examined using photoactivation of rose bengal. This dye damaged hyphae in the presence of light and oxygen. The effect was almost completely inhibited by putative quenchers of singlet oxygen: histidine, tryptophan, and 1,4-diazobicyclo[2.2.2]octane. These agents also inhibited damage to hyphae by myeloperoxidase, halide, and either hydrogen peroxide or a peroxide source (xanthine oxidase plus acetaldehyde). Myeloperoxidase-mediated damage to hyphae was also inhibited by dimethyl sulfoxide, an antioxidant and scavenger of the hydroxyl radical. These data support the involvement of oxidative mechanisms and the myeloperoxidase-H(2)O(2)-halide system, in particular in damaging hyphae in vitro and perhaps in vivo as well.
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PMID:Damage to Candida albicans hyphae and pseudohyphae by the myeloperoxidase system and oxidative products of neutrophil metabolism in vitro. 625 27

Our previous studies established that human neutrophils could damage and probably kill hyphae of Aspergillus fumigatus and Rhizopus oryzae in vitro, primarily by oxygen-dependent mechanisms active at the cell surface. These studies were extended, again quantitating hyphal damage by reduction in uptake of (14)C-labeled uracil or glutamine. Neither A. fumigatus nor R. oryzae hyphae were damaged by neutrophils from patients with chronic granulomatous disease, confirming the importance of oxidative mechanisms in damage to hyphae. In contrast, neutrophils from one patient with hereditary myeloperoxidase deficiency damaged R. oryzae but not A. fumigatus hyphae. Cell-free, in vitro systems were then used to help determine the relative importance of several potentially fungicidal products of neutrophils. Both A. fumigatus and R. oryzae hyphae were damaged by the myeloperoxidase-hydrogen peroxide-halide system either with reagent hydrogen peroxide or enzymatic systems for generating hydrogen peroxide (glucose oxidase with glucose, or xanthine oxidase with either hypoxanthine or acetaldehyde). Iodide with or without chloride supported the reaction, but damage was less with chloride alone as the halide cofactor. Hydrogen peroxide alone damaged hyphae only in concentrations >/=1 mM, but 0.01 mM hypochlorous acid, a potential product of the myeloperoxidase system, significantly damaged R. oryzae hyphae (a 1 mM concentration was required for significant damage to A. fumigatus hyphae). Damage to hyphae by the myeloperoxidase system was inhibited by azide, cyanide, catalase, histidine, and tryptophan, but not by superoxide dismutase, dimethyl sulfoxide, or mannitol. Photoactivation of the dye rose bengal resulted in hyphal damage which was inhibited by histidine, tryptophan, and 1,4-diazobicyclo(2,2,2)octane. Lysates of neutrophils or separated neutrophil granules did not affect A. fumigatus hyphae, but did damage R. oryzae hyphae. Similarly, three preparations of cationic proteins purified from human neutrophil granules were more active in damaging R. oryzae than A. fumigatus hyphae. This damage, as with the separated granules and whole cell lysates, was inhibited by the polyanion heparin. Damage to R. oryzae hyphae by neutrophil cationic proteins was enhanced by activity of the complete myeloperoxidase system or by hydrogen peroxide alone in subinhibitory concentrations. These data support the importance of oxidative products in general and the myeloperoxidase system in particular in damage to hyphae by neutrophils. Cationic proteins may also contribute significantly to neutrophil-mediated damage to R. oryzae hyphae.
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PMID:Damage to Aspergillus fumigatus and Rhizopus oryzae hyphae by oxidative and nonoxidative microbicidal products of human neutrophils in vitro. 629 3

Copper (Cu2+) ions at physiological concentrations can promote the formation of hydroxyl radical (OH) or a species of equivalent reactivity. The reaction requires H2O2 and a reducing agent. Reduction of Cu2+ can be achieved by superoxide ion generated by a mixture of hypoxanthine and xanthine oxidase or added directly as its potassium salt. Reduction of Cu2+ can also be achieved by ascorbic acid. Hence both O2- -dependent and ascorbate-dependent formation of OH from H2O2 in the presence of Cu2+ can be observed. Only the former reaction is significantly inhibited by superoxide dismutase. The binding of Cu2+ to histidine or albumin at physiological concentrations decreases the formation of OH radicals in free solution in the presence of either ascorbate or an (O2- -generating system. It is suggested that OH is still formed but reacts immediately with the binding molecule.
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PMID:Superoxide-dependent and ascorbate-dependent formation of hydroxyl radicals in the presence of copper salts: a physiologically significant reaction? 631 Nov 5

The polycyclic nitroaromatic hydrocarbon 1-nitropyrene is an environmental pollutant, a potent bacterial mutagen, and a carcinogen. Xanthine oxidase, a mammalian nitroreductase, catalyzed the in vitro metabolic activation of this compound to DNA-bound adducts. Maximum adduct formation occurred at pH 5.5 to 6.0 and was increased by the addition of catalase to the incubation medium. DNA binding from 1-nitropyrene was inhibited by hydrogen peroxide, L-ascorbate, and glutathione. Enzymatic hydrolysis of the modified DNA and subsequent analysis by high-pressure liquid chromatography indicated the presence of one major and two minor adducts. The major adduct was characterized by mass spectrometry and nuclear magnetic resonance spectroscopy as N-(deoxyguanosin-8-yl)-1-aminopyrene. The minor adducts appear to be decomposition products of the major adduct. When Salmonella typhimurium TA1538 was incubated with 1-nitropyrene, a strong correlation was found between the extent of DNA binding and the frequency of induced histidine reversions. Analysis of the bacterial DNA indicated one major adduct which had chromatographic properties and pKaS identical to those of N-(deoxyguanosin-8-yl)-1-aminopyrene. These data indicate that N-hydroxy-1-aminopyrene is probably the mutagenic and DNA-binding species formed during the metabolic reduction of 1-nitropyrene.
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PMID:Formation of DNA adducts in vitro and in Salmonella typhimurium upon metabolic reduction of the environmental mutagen 1-nitropyrene. 633 47

We examined the sensitivity of Treponema pallidum (Nichols strain) to toxic products of oxygen reduction. T pallidum was sensitive to hydrogen peroxide at concentrations similar to those to which obligate anaerobes are sensitive. Accelerated death of T pallidum occurred at hydrogen peroxide concentrations below 50 mumol/l. Agents protective against hydrogen peroxide and the hydroxyl free radical (catalase, peroxidase, and mannitol) significantly enhanced treponemal survival in vitro under all three conditions of aerobiosis tested--that is, air, 3% oxygen, and 3% oxygen in conjunction with a reduced medium. Superoxide dismutase (which provides protection against superoxide radicals) did not enhance treponemal survival in normal media. When superoxide radicals were generated in the medium by means of a xanthine and xanthine oxidase system, however, the enzyme did protect T pallidum. A possible toxic involvement of singlet oxygen was also indicated by enhanced treponemal survival in air in the presence of histidine. Extracts of T pallidum from infected rabbit testes showed catalase activity which, on polyacrylamide gel electrophoresis, had the same relative mobility as purified rabbit catalase. The treponemal catalase activity was neutralised by anti rabbit catalase antiserum (raised in guinea pigs). This confirmed that the catalase was of rabbit origin and not an endogenous enzyme of T pallidum. We discuss the relation of these results to the obligate parasitism of T pallidum.
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PMID:Susceptibility of Treponema pallidum to the toxic products of oxygen reduction and the non-treponemal nature of its catalase. 642 49

The effect of histidine on damage induced by oxygen radicals was studied in peripheral blood lymphocytes treated with free oxygen radical-inducing agents: hydrogen peroxide, xanthine oxidase plus hypoxanthine, bleomycin and gamma-rays. L-Histidine, at a concentration of 1 mM, was found to potentiate both cell killing and inhibition of PHA-stimulated cell division brought about by hydrogen peroxide or xanthine oxidase plus hypoxanthine. In contrast, L-histidine did not affect gamma-ray- or bleomycin-induced cell killing and inhibition of PHA-stimulated cell division. We suggest that L-histidine potentiation of cell damage is mainly mediated by interaction of the amino acid with hydrogen peroxide and/or iron rather than with other reactive oxygen species. In addition, these results also indicate that hydrogen peroxide produced by gamma-radiation- or bleomycin-treated cells plays no role in the toxic effects elicited by these agents.
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PMID:Differential effect of L-histidine in human lymphocytes damaged by different oxygen radical producing systems. 768 Jul 58

APRT deficiency is an enzyme disorder which is inherited as an autosomal recessive trait. The use of adenine in purine metabolism is disturbed and it accumulates in the body, where it is oxidised by xanthine oxidase to poorly insoluble 2, 8-dihydroxyadenine (DHA). The dihydroxyadenine forms stones which cause recurrent urolithiasis, frequent episodes of urinary tract infection or interstitial nephritis, and finally renal insufficiency in some cases. We report a case of APRT deficiency discovered by urine examination. The patient was a 33-year-old man who had never had any episodes of urolithiasis. He was admitted to our hospital because of pseudoarthrosis of his left arm caused by a traffic accident. His urinalysis revealed no proteinuria nor hematuria, but disclosed numerous round brown crystals in the sediment. These crystals had the characteristics of 2, 8-DHA. The enzyme activity of APRT in his blood was completely deficient. He was diagnosed as an APRT* QO homozygote. In addition, diagnostic imaging revealed that his right kidney was poorly hypoplastic and the pelvis of his left kidney was extra-renal. The renal function was slightly disturbed. In Japan 6 cases of 2, 8-DHA urolithiasis associated with hypoplastic kidney had been reported by 1989. Theoretically, the incidence of hypoplastic kidney is around 20% of all 2, 8-DHA urolithiasis cases. We suspect a genetic correlation between hypoplastic kidney and APRT deficiency. This patient was treated with Allopurinol, which inhibits the process of xanthine oxidation, after which crystals were no longer detected in his urine.
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PMID:[A case of adenine phosphoribosyltransferase (APRT) deficiency discovered by urine examination]. 781 52

Platelet-induced relaxation of endothelium-intact vascular tissues, mediated via release of endothelium-derived relaxing factor (EDRF), is diminished or lost after ischemia and reperfusion. Release of oxygen free radicals during ischemia-reperfusion may degrade EDRF and influence response of vascular tissues to platelets. To determine platelet modulation of tone of blood vessels treated with oxygen free radicals, rat aortic rings with intact endothelium were exposed to xanthine (X) plus xanthine oxidase (XO) 5 min before contraction with norepinephrine followed by exposure of rings to platelets. Treatment of aortic rings with X+XO caused a modest contraction, potentiated norepinephrine-mediated contraction, and inhibited platelet-mediated vasorelaxation. Exposure of aortic rings to X+XO also decreased ADP- as well as acetylcholine-mediated relaxation. Pretreatment of rings with superoxide dismutase or catalase did not change X+XO-induced inhibition of platelet-mediated relaxation, but it abolished the X+XO-induced contraction of rings as well as subsequent potentiation of norepinephrine-mediated contraction. Pretreatment of rings with hydroxyl radical scavengers dimethyl-2-thiourea, dimethyl sulfoxide, mannitol, or histidine attenuated the X+XO-induced inhibition of platelet-mediated relaxation, although these agents did not affect X+XO-induced contraction of rings. This study indicates that the vasoconstriction on exposure of aortic rings to X+XO is due to generation of superoxide anions, whereas inhibition of platelet-mediated relaxation after exposure of vessels to X+XO is due, at least in part, to release of hydroxyl radicals. Release of superoxide anions and hydroxyl radicals after temporary arterial occlusion may be the basis of subsequent modulation of vascular tone.
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PMID:Blockade of platelet-mediated relaxation in rat aortic rings exposed to xanthine-xanthine oxidase. 802 84

One of the current theories of cardiovascular disease is that it may begin with oxygen radical-induced damages. Extensive studies have been made in different laboratories to elucidate the mechanism of oxidative damages in the presence of added iron salts. However, those in vitro studies are unlikely to be relevant to the in vivo situation, where in the normal physiological condition most of the iron remains bound with proteins. In the present study we have demonstrated that an in vitro system containing desferrioxamine, a strong iron chelator, superoxide generated by the action of xanthine oxidase on acetaldehyde initiates lipid peroxidation and protein changes in the guinea pig cardiac microsomes. We have further demonstrated that superoxide-initiated lipid peroxidation and protein changes are completely prevented by ascorbic acid. SOD also prevents but catalase, alpha-tocopherol, glutathione, uric acid, thiourea, mannitol and histidine are without effect. When NADPH is used instead of generated superoxide, the lipid peroxidation and protein changes are exclusively inhibited by ascorbic acid. SOD, catalase and other antioxidants are ineffective. The results obtained with guinea pigs may be extrapolated to humans, because like guinea pigs humans are also incapable of synthesizing ascorbic acid.
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PMID:Protective effect of ascorbic acid against lipid peroxidation and oxidative damage in cardiac microsomes. 810 91


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