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)

1. The effects of inhibiting endogenous Cu/Zn superoxide dismutase (SOD) with diethyldithiocarbamate (DETCA) were examined on the ability of hydroquinone, hydroxocobalamin and carboxy-PTIO to block nitrergic relaxation in the bovine retractor penis (BRP) muscle. 2. Incubation of strips of BRP with DETCA (3 mM) for 2 h reduced SOD activity from 73.1 +/- 15.7 to 8.2 +/- 1.9 units mg-1 protein. 3. Hydroquinone (10 microM--1 mM) produced weak inhibition of nitrergic (4 Hz, 10 s) relaxation in control strips of BRP, but powerful inhibition in strips treated with DETCA (3 mM, 2 h). Exogenous SOD (250 units ml--1) produced a partial blockade of the ability of hydroquinone to inhibit nitrergic relaxation in DETCA-treated strips. 4. In an assay of SOD-inhibitable reduction of cytochrome C, hypoxanthine (0.1 mM)/xanthine oxidase (16 munits ml-1) and pyrogallol (10 microM), led to the rapid generation of superoxide anion. Hydroquinone (10 microM) also led to the generation of the free radical, although the rate of generation was slower. 5. Two NO-scavenging agents, hydroxocobalamin (0.1 microM--1 mM) and carboxy-PTIO (0.1-1 mM), produced concentration-dependent blockade of nitrergic relaxation of the BRP. The magnitude of the blockade induced by these agents was unaffected following treatment with DETCA or SOD. 6. The findings with hydroquinone support our previous proposal that endogenous Cu/Zn SOD plays a vital role in protecting nitrergic neurotransmission from inactivation by superoxide anion. Results with hydroxocobalamin and carboxy-PTIO are consistent with the known ability of these agents to scavenge NO. The nitrergic neurotransmitter in the BRP thus appears to have the properties of NO.
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PMID:Blockade of nitrergic transmission by hydroquinone, hydroxocobalamin and carboxy-PTIO in bovine retractor penis: role of superoxide anion. 873 70

This study was designed to test the hypothesis that nitric oxide (NO) is the relaxant metabolite produced by metabolic activation of glyceryl trinitrate (GTN) in rabbit aortic strip (RAS). Superoxide anion, an inactivator of NO, was included in a two-tissue bioassay in which rabbit Taenia coli strip (RTCS) relaxed to GTN in the presence of RAS. Superoxide as generated by xanthine (10 microM)/ xanthine oxidase (20 mU/ml) failed to attenuate relaxations of RTCS to GTN (0.1 nM-10 microM) and RAS, compared with the untreated control. In contrast, superoxide attenuated the relaxation of RTCS to both authentic NO gas and to SIN-1 (0.1 nM-10 microM), a known spontaneous releaser of NO; the attenuation of RTCS relaxation to NO gas was reversed by superoxide dismutase (100 units/ml). In addition, another drug that has been reported to scavenge NO, hydroquinone, did not attenuate the RTCS relaxation to GTN. These results suggest that biotransformation of GTN in vascular smooth muscle that leads to relaxation is caused by a NO-containing species (i.e. a S-nitrosothiol). Such a molecule would be less susceptible to inactivation by superoxide anion and hydroquinone.
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PMID:Superoxide does not inhibit glyceryl trinitrate-rabbit aortic strip-mediated relaxation of rabbit Taenia coli. Evidence against a role for nitric oxide itself as the smooth muscle active drug metabolite? 881 76

1. The influence of diethyldithiocarbamate (DETCA), that irreversibly inhibits Cu/Zn-containing superoxide dismutase, on the inability of 6-anilino-5,8-quinolinedione (LY83583), hypoxanthine/xanthine oxidase, hydroquinone and hydroxocobalamin to reduce electrically-induced NANC relaxations in the rat gastric fundus was investigated. 2. Longitudinal muscle strips of the rat gastric fundus were mounted for auxotonic recording in the presence of atropine and guanethidine and tone was raised by administration of prostaglandin F2 alpha DETCA (3 x 10(-3) M) slightly reduced the short-lasting relaxations induced by 10(-5) M exogenous nitric oxide (NO) and transmural electrical stimulation for 10 s at 4 Hz but this effect was not influenced by 1000 u ml-1 superoxide dismutase (SOD). 3. DETCA (3 x 10(-5) -3 x 10(-3) M) concentration-dependently potentiated the inhibitory effect of LY83583 upon the electrically-induced relaxations, although this was less pronounced than the inhibition of the NO-induced relaxations. The inhibition of the electrically-induced non-adrenergic non-cholinergic (NANC) relaxations was not reversed by SOD while that of the NO-induced relaxations was partially reversed. 4. The inhibitory effect of hypoxanthine/xanthine oxidase, hydroquinone and hydroxocobalamin on the electrically-induced NANC relaxations in the presence of DETCA (3 x 10(-3) M) was not different from the inhibitory effect of DETCA alone. 5. It was concluded that the differentiating effect of LY83583 between exogenous NO and the endogenous nitrergic neurotransmitter is partially related to protection of the endogenous nitrergic neurotransmitter by high levels of intracellular superoxide dismutase. This mechanism does not hold for hydroquinone and hydroxocobalamin, as they still discriminate between exogenous NO and the endogenous nitrergic neurotransmitter in the presence of DETCA. The possibility that the endogenous nitrergic neurotransmitter is not free NO in the rat gastric fundus therefore remains open.
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PMID:Influence of superoxide dismutase inhibition on the discrimination between NO and the nitrergic neurotransmitter in the rat gastric fundus. 886 58

The properties of the semiquinone radical from [3-hydroxy-5-aziridinyl-1-methyl-2-(1H-indole-4,7-indi one)-prop-beta-en-alpha-ol], EO9, have been studied using pulse-radiolysis techniques. The reduction potential of the semiquinone of EO9 at pH7.4, E(EO9/EO9-), is -253 +/- 6 mV and hence this quinone can be readily reduced by one-electron reducing enzymes such as cytochrome P450 reductase and xanthine oxidase. However, the radical is unstable in the presence of oxygen (k = 1.3 +/- 0.15 x 10(8) M-1 s-1). The semiquinone radicals and the hydroquinone are in equilibrium although the formation of the hydroquinone is favoured t physiologically relevant pH. The hydroquinone of EO9 is also unstable in the presence of oxygen and it is predicted that in fully aerated solutions, its half life is 1.5 +/- 0.3 seconds. These results are discussed in view of the selective cytotoxicity of EO9 and its ability to undergo bioreductive activation by one-electron reducing enzymes and DT-diaphorase.
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PMID:The autoxidation of the reduced forms of EO9. 888 32

1. The potential protective effect of several antioxidants [Cu/Zn superoxide dismutase (Cu/Zn SOD), ascorbate, reduced glutathione (GSH), and alpha-tocopherol (alpha-TOC)] on relaxations of the mouse anococcygeus muscle to nitric oxide (NO; 15 microM) and, where appropriate, nitrergic field stimulation (10 Hz; 10 s trains) was investigated. 2. The superoxide anion generating drug duroquinone (100 microM) reduced relaxations to exogenous NO by 54 +/- 6%; this inhibition was partially reversed by Cu/Zn SOD (250 u ml-1), and by ascorbate (500 microM). Following inhibition of endogenous Cu/Zn SOD activity with diethyldithiocarbamate (DETCA), duroquinone (50 microM) also reduced relaxations to nitrergic field stimulation (by 53 +/- 6%) and this effect was again reversed by Cu/Zn SOD and by ascorbate. Neither GSH (500 microM) nor alpha-TOC (400 microM) afforded any protection against duroquinone. 3. Xanthine (20 mu ml-1); xanthine oxidase (100 microM) inhibited NO-induced relaxations by 73 +/- 14%, but had no effect on those to nitrergic field stimulation, even after DETCA treatment. The inhibition of exogenous NO was reduced by Cu/Zn SOD (250 u ml-1) and ascorbate (400 microM), but was unaffected by GSH or alpha-TOC (both 400 microM). 4. Hydroquinone (100 microM) also inhibited relaxations to NO (by 52 +/- 10%), but not nitrergic stimulation. In this case, however, the inhibition was reversed by GSH (5-100 microM) and ascorbate (100-400 microM), although Cu/Zn SOD and alpha-TOC were ineffective. 5. 2-(4-Carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (carboxy-PTIO, 50 microM) inhibited NO-induced relaxations by 50 +/- 4%, but had no effect on nitrergic responses; the inhibition was reduced by ascorbate (2-200 microM) and alpha-TOC (10-200 microM), but not by Cu/Zn SOD or GSH. 6. Hydroxocobalamin (5-100 microM) inhibited, equally, relaxations to both NO (-logIC40 3.14 +/- 0.33) and nitrergic stimulation (-logIC40 3.17 +/- 0.22). 7. Thus, a number of physiological antioxidants protected NO from superoxide anions, and from direct NO-scavengers. The possibility that the presence of these antioxidants within nitrergically-innervated tissues might explain the lack of effect of the NO inhibitors on nerve-induced relaxation, without the need to invoke a transmitter other than free radical NO, is discussed.
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PMID:Antioxidant protection of NO-induced relaxations of the mouse anococcygeus against inhibition by superoxide anions, hydroquinone and carboxy-PTIO. 888 31

Xanthine dehydrogenase (XDH) from bovine milk contains significant activity in xanthine/oxygen turnover assays. The oxidative half-reaction of XDH with molecular oxygen has been studied in detail, at 25 degrees C, pH 7.5, to determine the basis of the preference of XDH for NAD over oxygen as oxidizing substrate. Spectral changes of XDH accompanying oxidation were followed by stopped-flow spectrophotometry. The amount of superoxide radicals formed during oxidation was investigated to assess the ability of XDH to catalyze production of oxygen radicals. Reduced XDH reacts with oxygen in at least 4 bi-molecular steps, with 1.7-1.9 mol of superoxide per mol of XDH formed from the last 2 electrons oxidized. A model is discussed in which the flavin hydroquinone transfers electrons to oxygen to produce hydrogen peroxide at a rate constant of at least 72,000 M-1 s-1, whereas flavin semiquinone reduces oxygen to form superoxide as slow as 16 M-1 s-1. Steady-state kinetics of xanthine/oxygen and NADH/oxygen turnover of XDH were determined to have kcat values of 2.1 +/- 0.1 and 2.5 +/- 0.9 s-1, respectively, at 25 degrees C, pH 7.5. XDH is therefore capable of catalyzing the formation of reduced oxygen species at one-third the rate of xanthine/NAD turnover, 6.3 s-1 (Hunt, J., and Massey, V. (1992) J. Biol. Chem. 267, 21479-21485), in the absence of NAD. As XDH contains a significant and intrinsic xanthine oxidase activity, estimates of relative amounts of XO and XDH based solely upon turnover assays must be made with caution. Initial-rate assays containing varying amounts of xanthine, NAD, and oxygen indicate that at 100% oxygen saturation, NADH formation is only inhibited at concentrations of xanthine and NAD below Km for each substrate.
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PMID:The reaction of reduced xanthine dehydrogenase with molecular oxygen. Reaction kinetics and measurement of superoxide radical. 907 61

In low concentrations, benzene and its metabolite hydroquinone are known to have diverse biological effects on cells, including the synergistic stimulation with GM-CSF of hematopoietic colony formation in vitro, stimulation of granulocytic differentiation in vitro and in vivo, and general suppression of hematopoiesis in vivo. These chemicals are also known to be active in the induction of active oxygen species. We used several assays to determine the effects of benzene metabolites (hydroquinone, benzenetriol, benzoquinone) and active oxygen species (xanthine/xanthine oxidase) on cell growth and cell cycle kinetics of the human myeloid cell line HL-60. HL-60 cells treated with these chemicals for 2 h in PBS showed increased growth over untreated controls in a subsequent 18h growth period in complete media. Incorporation of 3H-thymidine was also increased proportionately by these treatments. Catalase treatment abrogated the increased cell growth of all chemicals, suggesting an oxidative mechanism for the effect of all treatments alike. Cell cycle kinetics assays showed that the growth increase was caused by an increased recruitment of cells from G0/G1 to S-phase for both hydroquinone and active oxygen, rather than a decrease in the length of the cell cycle. Benzene metabolite's enhancement of growth of myeloid cells through an active oxygen mechanism may be involved in a number of aspects of benzene toxicity, including enhanced granulocytic growth and differentiation, stimulation of GM-CSF-induced colony formation, apoptosis inhibition, and stimulation of progenitor cell mitogenesis in the bone marrow. These effects in sum may be involved in the benzene-induced "promotion" of a clonal cell population to the fully leukemic state.
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PMID:Enhancement of myeloid cell growth by benzene metabolites via the production of active oxygen species. 1019 77

Strain IC203, deficient in OxyR, and its oxyR(+) parent WP2 uvrA/pKM101 (denoted IC188) are the basis of a new bacterial reversion assay, the WP2 Mutoxitest, which has been used in the evaluation of 80 chemicals for oxidative mutagenicity. The following 31 oxidative mutagens were recognized by their greater mutagenic response in IC203 than in IC188: (1) peroxides: hydrogen peroxide (HP), t-butyl hydroperoxide (BOOH) and cumene hydroperoxide (COOH); (2) benzoquinones (BQ): 2-methyl-1,4-BQ, 2,6-dimethyl-1,4-BQ and 2,3, 5,6-tetramethyl-1,4-BQ; (3) naphthoquinones (NQ): 1,4-NQ, 2-methyl-1, 4-NQ and 2-hydroxy-1,4-NQ; (4) phenol derivatives: catechol, hydroquinone, pyrogallol, 1,2,4-benzenetriol, t-butylhydroquinone, gallic acid and 4-aminophenol; (5) catecholamines: DL- and L-dopa, DL- and L-epinephrine, dopamine and L-norepinephrine; (6) thiols: L-cysteine methyl ester, L-cysteine ethyl ester, L-penicillamine and dithiothreitol; (7) diverse: 3,4-dihydroxyphenylacetic acid, hypoxanthine and xanthine, both in the presence of xanthine oxidase, L-ascorbic acid plus copper (II) and phenazine methosulfate. Among these oxidative mutagens, 25 were found to be uniquely positive in IC203. With the exception of BOOH and COOH, mutagenesis by all oxidative mutagens was inhibited by catalase present in rat liver S9, indicating that it is mediated by HP generation, probably in autoxidation reactions. These catalase-sensitive oxidative mutagens were poor inducers of mutations derived from 8-oxoguanine lesions, whereas such mutations were efficiently induced by organic hydroperoxides. The results support the usefulness of incorporating IC203 in the bacterial battery for testing of chemicals. The well-characterized oxidative mutagens available with the use of the WP2 Mutoxitest may serve as a reference in studies on the genotoxicity of oxidative stress.
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PMID:Mutagenicity of 80 chemicals in Escherichia coli tester strains IC203, deficient in OxyR, and its oxyR(+) parent WP2 uvrA/pKM101: detection of 31 oxidative mutagens. 1077 Dec 70

Under physiological conditions, small amounts of free arachidonic acid (AA) are released from membrane phospholipids, and cyclooxygenase (COX) and acyl-CoA synthetase (ACS) competitively act on this fatty acid to form prostaglandins (PGs) and arachidonoyl-CoA (AA-CoA). To clarify factors deciding the metabolic fate of free AA into these two pathways, we investigated the effects of a nitric oxide (NO) donor 1-hydroxyl-2-oxo-3-(N-methyl-3-aminopropyl)-3-methyl-1-triazene (NOC7), and peroxynitrite (ONOO(-)) on the formation of PG and AA-CoA from high and low concentrations of AA (60 and 5 micro M) in rabbit kidney medulla microsomes. The kidney medulla microsomes were incubated with 60 or 5 micro M [14C]-AA in 0.1M Tris/HCl buffer (pH 8.0) containing cofactors of COX (reduced GSH and hydroquinone) and cofactors of ACS (ATP, MgCl(2) and CoA). After incubation, PG (as total PGs) and AA-CoA were separated by selective extraction using petroleum ether and ethyl acetate. When 60 micro M AA was used as the substrate concentration, NOC7 stimulated the PG formation at 0.5 micro M, and inhibited it at 50 and 100 micro M, without affecting the AA-CoA formation. When 5 micro M AA was used as the substrate concentration, NOC7 showed no effect on the PG and AA-CoA formation up to 10 micro M or below, but enhanced the AA-CoA formation with a coincident decrease in the PG formation at 50 micro M or over. Experiments utilizing a NO antidote, carboxy-2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide, revealed that the observed effects of NOC7 using 60 and 5 micro M AA are caused by NO. On the other hand, ONOO(-) stimulated the PG formation from 60 micro M AA, with no alteration in the AA-CoA formation at a concentration of 100 micro M, but when 5 micro M AA was used as the substrate concentration, it was without effect on the PG and AA-CoA formation. These findings indicate that actions of NO and ONOO(-) on the PG and AA-CoA formation by the kidney medulla microsomes may change depending on the substrate concentration. The effects of NO using 5 micro M AA were reversed by the addition of the superoxide generating system (xanthine-xanthine oxidase plus catalase), indicating that superoxide is a vital modulator of the action of NO. These results suggest that NO, but not ONOO(-), can be a regulator of the PG and AA-CoA formation at low substrate concentrations (close to the physiological concentration of AA), and that superoxide may play an important role in the action of NO.
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PMID:The effects of nitric oxide and peroxynitrite on the formation of prostaglandin and arachidonoyl-CoA formed from arachidonic acid in rabbit kidney medulla microsomes. 1271 Dec 52

Experiments using purified recombinant human NAD(P)H:quinone oxidoreductase 1 (NQO1) revealed that the auto-oxidation of fully reduced protein resulted in a 1:1 stoichiometry of oxygen consumption to NADH oxidation with the production of hydrogen peroxide. The rate of auto-oxidation of fully reduced NQO1 was markedly accelerated in the presence of superoxide (O(2)(*)(-)), whereas the addition of superoxide dismutase greatly inhibited the rate of auto-oxidation. The ability of reduced NQO1 to react with O(2)(*)(-) suggested a role for NQO1 in scavenging O(2)(*)(-), and this hypothesis was tested using established methods for O(2)(*)(-) production and detection. The addition of NQO1 in combination with NAD(P)H resulted in inhibition of dihydroethidium oxidation, pyrogallol auto-oxidation, and elimination of a potassium superoxide-generated ethoxycarbonyl-2-methyl-3,4-dihydro-2H-pyrrole-1-oxide:O(2)(*)(-) adduct signal (electron spin resonance). Kinetic parameters for the reduction of O(2)(*)(-) by NQO1 were estimated using xanthine/xanthine oxidase as the source of O(2)(*)(-) and after NQO1-dependent NADH oxidation at 340 nm. The ability of NQO1 to scavenge O(2)(*)(-) was also examined using cell sonicates prepared from isogenic cell lines containing no NQO1 activity (NQO1(-)) or very high levels of NQO1 activity (NQO1(+)). We demonstrated that addition of NAD(P)H and cell sonicate from NQO1(+) but not NQO1(-) cells resulted in an increased level of O(2)(*)(-) scavenging could be inhibited by 5-methoxy-1,2-dimethyl-3-[(4-nitrophenoxy)methyl]indole-4,7-dione (ES936), a mechanism-based inhibitor of NQO1. NQO1 can generate hydroquinones that are redox active, and the O(2)(*)(-) scavenging activity of NQO1 may allow protection against O(2)(*)(-) at the site of hydroquinone generation. In addition, the O(2)(*)(-) scavenging activity of NQO1 may provide an additional level of protection against O(2)(*)(-) induced toxicity.
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PMID:NAD(P)H:quinone oxidoreductase 1: role as a superoxide scavenger. 1510 52


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