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PubMed2001

Reduction of organic nitrates catalysed by xanthine oxidoreductase under anaerobic conditions.

Xanthine oxidoreductase catalyses the anaerobic reduction of glyceryl trinitrate (GTN), isosorbide dinitrate and isosorbide mononitrate to inorganic nitrite using xanthine or NADH as reducing substrates. Reduction rates are much faster with xanthine as reducing substrate than with NADH. In the presence of xanthine, urate is produced in essentially 1:1 stoichiometric ratio with inorganic nitrite, further reduction of which is relatively slow. Organic nitrates were shown to interact with the FAD site of the enzyme. In the course of reduction of GTN, xanthine oxidoreductase was progressively inactivated by conversion to its desulpho form. It is proposed that xanthine oxidoreductase is one of several flavoenzymes that catalyse the conversion of organic nitrate to inorganic nitrite in vivo. Evidence for its further involvement in reduction of the resulting nitrite to nitric oxide is discussed.

Anaerobiosis↗
PubMed1976

Studies by electron-paramagnetic-resonance spectroscopy and stopped-flow spectrophotometry on the mechanism of action of turkey liver xanthine dehydrogenase.

Studies by e.p.r. (electron-paramagnetic-resonance) spectroscopy and by stopped-flow spectrophotometry on turkey liver xanthine dehydrogenase revealed strong similarities to as well as important differences from the Veillonella alcalescens xanthine dehydrogenase and milk xanthine oxidase. The turkey enzyme is contaminated by up to three non-functional forms, giving molybdenum e.p.r. signals designated Resting I, Resting II and Slow. Slow and to a lesser extent Resting I signals are like those from the Veillonella enzyme, whereas Resting II is very like a resting signal described by K. V. Rajagopolan, P. Handler, G. Palmer & H. Beinert (1968) (J. Biol. Chem. 243, 3784-3796) for aldehyde oxidase. Another non-functional form that gives the Inhibited signal is produced on treatment of the enzyme with formaldehyde. Stopped-flow measurements at 450 nm show that, as for the milk enzyme, reduction by xanthine is rate-limiting in enzyme turnover. The active enzyme gives rise to Very Rapid and Rapid molybdenum(V) e.p.r. signals, as well as to an FADH signal. That these signals are almost indistinguishable from those of the milk enzyme, confirms the similarities between the active sites. There are two types of iron-sulphur centres that give signals like those in the milk enzyme, though with slightly different parameters. Quantitative reduction titration of the functional enzyme with xanthine revealed two important differences between the turkey and the milk enzymes. First, the turkey enzyme FADH/FADH2 system has a redox potential sufficiently low that xanthine is incapable of reducing the flavin completely. This finding presumably explains the very low oxidase activity. Secondly, whereas the Fe/S II chromophore in the milk enzyme has a relatively high redox potential, for the turkey enzyme the value of this potential is lower and similar to that of its Fe/S I chromophore.

Animals↗
PubMed1988

A kinetic study of hypoxanthine oxidation by milk xanthine oxidase.

The course of the reaction sequence hypoxanthine----xanthine----uric acid catalysed by xanthine:oxygen oxidoreductase from milk was investigated on the basis of u.v. spectra taken during the course of hypoxanthine and xanthine oxidations. It was found that xanthine accumulated in the reaction mixture when hypoxanthine was used as a substrate. The time course of the concentrations of hypoxanthine, xanthine intermediate and uric acid product was simulated numerically. The mathematical model takes into account the competition of substrate, intermediate and product and the accumulation of the intermediate at the enzyme. This type of analysis permits the kinetic parameters of the enzyme for hypoxanthine and xanthine to be obtained.

Animals↗
PubMed1988

[Effect of tranquilizers of the 1,4-benzodiazepine series on the xanthine oxidase activity of the rat brain].

Experiments in vivo and in vitro on 90 rats were made to study the influence of 1,4-benzodiazepine tranquilizers (phenazepam, nitrazepam and diazepam) on cerebral xanthine oxidase activity. Phenazepam, nitrazepam and diazepam in the dose of 5 mg per 200 g bw were shown to reduce xanthine oxidase activity by 80.4%, 64.3% and 55.8%, respectively 2 h after intraperitoneal injection. 6 h after the injection of benzodiazepines the enzyme activity grows, but control values are achieved only after nitrazepam injection. In vitro experiments revealed direct influence of the tranquilizers on xanthine oxidase. Phenazepam inhibits xanthine oxidase activity in concentration as long as 10(-10) M (to 36.6%), and practically completely in 10(-6) M concentration. Nitrazepam and diazepam inhibit xanthine oxidase activity within concentration range between 10(-8) M (to 51.5% and 33.2%, respectively), and 10(-4) M (practically completely). The inhibition of xanthine oxidase activity is shown to be caused by the competition between hypoxanthine, the reaction substrate, and tranquilizer, to bind with the active site of the enzyme.

Animals↗
PubMed1980

Catabolism of adenine derivatives in leaves: study of the role of light on the in vivo activity of xanthine dehydrogenase.

The in vivo activity of xanthine dehydrogenase (E.C. 1.2.1.37) was followed in leaf discs excised from illuminated or darkened plants. In cotyledons of Pharbitis nil, 24 hours of darkness enhanced the in vivo activity of xanthine dehydrogenase which increased between 2 to 5-fold depending on the concentration of hypoxanthine of the solution where cotyledon discs were incubated. The same effect occurred in leaves of several other species, in plants with both high and low ureide content. However, the effect of light was not observed in leaves of Zea mays, Pennisetum americanum and Atriplex spongiosa, whereas, it appeared very clearly in other C(4) plants such as Sorghum sudanense and Portulaca oleracea. This enzymic activity in chlorophyll-deficient tobacco leaves was the same both for illuminated and darkened plants. In addition, the in vivo activity of xanthine dehydrogenase in roots of Pharbitis nil was not dependent upon the light conditions applied to leaves. In cotyledons of Pharbitis nil, the level of the in vivo activity of xanthine dehydrogenase was influenced by the energy of light and the duration of illumination. The supply of carbohydrates to darkened cotyledons had the same effect as light on the in vivo activity of xanthine dehydrogenase. It is proposed that the effect of light on the in vivo activity of xanthine dehydrogenase in leaves is mainly due to the production of photosynthates which changes the osmotic state of leaf tissue and thus modifies the level of the in vivo activity of xanthine dehydrogenase.

Journal Article↗
PubMed1986

Production, characterization, and applications of monoclonal antibodies reactive with soybean nodule xanthine dehydrogenase.

Seven monoclonal antibodies were produced against soybean nodule xanthine dehydrogenase, an enzyme involved in ureide synthesis. Specificity of the seven monoclonal antibodies for xanthine dehydrogenase was demonstrated by immunopurifying the enzyme to homogeneity from a crude nodule extract using antibodies immobilized to Sepharose 4B beads. Each monoclonal antibody was covalently bound to Sepharose 4B beads for the preparation of immunoaffinity columns for each antibody. All seven antibodies were found to be of the IgG1,K subclass. A competitive, indirect enzyme-linked immunosorbent assay demonstrated that two of the seven antibodies shared a common epitope while the remaining five antibodies defined unique determinants on the protein. Rapid, large scale purification of active xanthine dehydrogenase to homogeneity was performed by immunoaffinity chromatography. The presence of xanthine dehydrogenase activity and protein in every organ of the soybean plant was determined. Crude extracts of nodules, roots, stems, and leaves cross-reacted with all seven monoclonal antibodies in an indirect enzyme-linked immunosorbent assay. A positive correlation was observed between the degree of cross-reactivity of a given organ and the level of enzyme activity in that organ. These data demonstrate that xanthine dehydrogenase is not nodule specific. Antigenic variability of xanthine dehydrogenase present in crude extracts from nodules of soybean, wild soybean, cowpea, lima bean, pea, and lupin were detected in the indirect enzyme-linked immunosorbent assay which corresponded to six binding patterns for xanthine dehydrogenase from these plant species. These results correspond well with the epitope determination data which showed that the seven antibodies bind to six different binding determinants on the enzyme.

Journal Article↗
PubMed1983

Purification and characterization of Escherichia coli guanine-xanthine phosphoribosyltransferase produced by a high efficiency expression plasmid utilizing a lambda PL promoter and CI857 temperature-sensitive repressor.

The gene for Escherichia coli guanine-xanthine phosphoribosyltransferase was placed after the high efficiency lambda phage leftward promoter in plasmid pHEGPT also containing the lambda CI857 temperature-sensitive repressor. Guanine-xanthine phosphoribosyltransferase increases 780-fold when cells containing pHEGPT are shifted from 30 to 42 degrees C. Guanine-xanthine phosphoribosyltransferase represents approximately 5% of the protein in a crude extract of induced cells. Guanine-xanthine phosphoribosyltransferase may be purified to apparent homogeneity by ammonium sulfate fractionation, Sephadex G-100, and DEAE-cellulose column chromatography. The enzyme has a subunit molecular weight of 18,600 determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and behaves as a trimer during Sephadex G-100 column chromatography. Guanine-xanthine phosphoribosyltransferase is active from pH 7.5 to 10.5 with maximum activity at pH 9.5. The enzyme is protected from heat inactivation by phosphoribosylpyrophosphate (PRPP). At 65 degrees C, the enzyme has a half-life of 2 min in the absence of PRPP and 90 min in the presence of PRPP. The enzyme displays Michaelis-Menten kinetics with apparent Michaelis constants for guanine, xanthine, hypoxanthine, and PRPP of 2.6, 39, 167, and 95 microM, respectively. The activity of the enzyme with guanine is 2-fold greater than that with xanthine and 3-fold greater than that with hypoxanthine.

DNA Restriction Enzymes↗
PubMed1991

The role of xanthine oxidase in paraquat intoxication.

The role of xanthine oxidase in the mechanism of paraquat toxicity was assessed by in vitro and in vivo experiments. Paraquat stimulated the reduction of cytochrome c by xanthine-xanthine oxidase system in vitro. Paraquat, when added in vitro, stimulated hypoxanthine-dependent superoxide production in the cytosol of rat lung. Tungsten-feeding inhibits xanthine oxidase activity in a variety of tissues in experimental animals. Its therapeutic effect on paraquat intoxication was studied in this paper. In rats fed a tungsten-enriched diet for 5 weeks prior to intraperitoneal injection of 50 mg/kg paraquat dichloride, the mortality decreased significantly compared with rats fed a standard diet. Pretreatment with oxypurinol (1000 mg/kg, s.c.) also ameliorated the paraquat toxicity in rats. We conclude that xanthine oxidase plays an important role in paraquat toxicity and that xanthine oxidase inhibitors may become antidotes for paraquat intoxication.

Animals↗
PubMed1992

Effects of hypoxia and ethanol on xanthine oxidase of isolated rat hepatocytes: conversion from D to O form and leakage from cells.

The combined effects of ethanol and hypoxia on the conversion of xanthine dehydrogenase (D form) to xanthine oxidase (O form) and on the leakage of the enzyme from isolated rat hepatocytes was studied. Time-dependent death of cells occurred during incubation in hypoxic conditions. Ethanol (40 mM) had only a moderate effect on viability in aerobiosis, but accelerated the loss of hypoxic cells, which was 96% after 3 h of incubation. In hypoxic conditions, the xanthine oxidase was gradually converted from D into O form. The conversion was complete in 3 h, and was accelerated by 1 mM xanthine or by ethanol, in a concentration-related manner. Hypoxia brought about a progressive leakage of xanthine oxidase from hepatocytes, which was accelerated by ethanol in a concentration-dependent manner. The enzyme found outside hepatocytes was mostly in its O form. The xanthine oxidase of hepatocytes cytosol was converted from D into O form by human plasma or serum. In all cases the conversion could be completely reverted by treatment of the extract with dithiothreitol.

Animals↗
PubMed1983

Myocardial xanthine oxidase/dehydrogenase.

High-energy phosphates in heart muscle deprived of oxygen are rapidly broken down to purine nucleosides and oxypurines. We studied the role of xanthine oxidase/dehydrogenase (EC 1.2.3.2/EC 1.2.1.37) in this process with novel high-pressure liquid chromatographic techniques. Under various conditions, including ischemia and anoxia, the isolated perfused rat heart released adenosine, inosine and hypoxanthine, and also substantial amounts of xanthine and urate. Allopurinol, an inhibitor of xanthine oxidase, greatly enhanced the release of hypoxanthine. From the purine release we calculated that the rat heart contained about 18 mU xanthine oxidase per g wet weight. Subsequently, we measured a xanthine oxidase activity of 9 mU/g wet wt. in rat-heart homogenate. When endogenous low molecular weight inhibitors were removed by gel-filtration, the activity increased to 31 mU/g wet wt. Rat myocardial xanthine oxidase seems to be present mainly in the dehydrogenase form, which upon storage at -20 degrees C is converted to the oxidase form.

Animals↗
PubMed1995

Effects of fatty acids and fatty acyl CoA esters on Cu(2+)-induced conversion of xanthine dehydrogenase to oxidase in rabbit liver.

Effects of various fatty acids and fatty acyl CoA esters on Cu(2+)-induced conversion of xanthine dehydrogenase to oxidase in rabbit liver were examined. Cu2+ (2-10 microM) brought about the conversion of xanthine dehydrogenase to oxidase in a dose-dependent manner. Oleic, arachidonic, eicosapentaenoic, and docosahexaenoic acids (50-200 microM) prevented the conversion of xanthine dehydrogenase to oxidase catalyzed by 6 microM-Cu2+. The effect of these four fatty acids was concentration-dependent, whereas palmitic, stearic, and linoleic acids had no effect on the conversion of xanthine dehydrogenase to oxidase at the same concentration range. On the other hand, palmitoyl, linoleoyl, and arachidonoyl CoAs elicited the inhibition of 6 microM-Cu(2+)-induced conversion of xanthine dehydrogenase to oxidase at concentrations of 50, 100, and 200 microM. These results suggest that oleic, arachidonic, eicosapentaenoic and docosahexaenoic acids, and fatty acyl CoAs have the potential to inhibit the conversion of xanthine dehydrogenase to oxidase in rabbit liver.

Acyl Coenzyme A↗
PubMed1988

Renal excretion of hypoxanthine and xanthine in primary gout.

PURPOSE: The renal excretion of uric acid is usually diminished in primary gout with respect to increased serum urate levels. To determine whether the renal excretion of uric acid precursors, hypoxanthine and xanthine, is also abnormal in primary gout, the concentrations of these purines were measured in plasma and 24-hour urine samples in normal subjects, in patients with primary gout and uric acid underexcretion, and in patients with enzyme deficiencies that are known to result in over-production of uric acid. SUBJECTS AND METHODS: Three groups of subjects were studied: Group I consisted of 10 ambulatory healthy normal men; Group II consisted of 15 patients in whom primary gout was diagnosed; and Group III consisted of 10 patients with various enzyme defects known to produce an excessive synthesis of uric acid. In each subject, plasma and 24-hour urinary uric acid, hypoxanthine, xanthine, and creatinine concentrations were measured and the mean of three consecutive determinations was used. The fractional excretion of purine compounds was calculated from a formula. Hypoxanthine phosphoribosyltransferase, adenine phosphoribosyltransferase, and hemoglobin were also measured in each subject. RESULTS: Plasma hypoxanthine and xanthine were increased in the two groups of patients compared with the control subjects. Urinary hypoxanthine and xanthine levels were reduced in gouty patients compared with control subjects, whereas levels were increased in patients with uric acid overproduction. A positive correlation was found between the renal clearances of uric acid, hypoxanthine, and xanthine. CONCLUSION: The results indicate that the renal excretion of hypoxanthine and xanthine is severely impaired in most patients with primary gout.

Adult↗
PubMed1998

Circulating xanthine oxidase and neutrophil activation during human liver transplantation.

BACKGROUND & AIMS: Oxygen free radicals, generated by xanthine oxidase (XO) and activated leukocytes, are involved in reperfusion injury in experimental liver transplantation. The roles of XO and neutrophil activation during reperfusion in clinical liver transplantation were studied. METHODS: In 10 patients undergoing liver transplantation, we assessed plasma concentrations of circulating XO by enzyme-linked immunosorbent assay (ELISA), the purine metabolites hypoxanthine, xanthine, and urate by high-performance liquid chromatography, lactoferrin by ELISA, and malondialdehyde fluorometrically up to 48 hours postoperatively. RESULTS: During reperfusion after portal vein declamping, elevated plasma concentrations of XO (52.1 ng/mL [range, 8.0-440.1]), hypoxanthine (81.62 micromol/L [48.2-108.7]), xanthine (21.01 micromol/L [8.7-22.3]), and lactoferrin (532.6 ng/mL [370.4-1326.6]) were observed compared with the preoperative levels (0 ng/mL [0-12], 1.88 micromol/L [0.62-3.15], 0.95 micromol/L [0-0.41], and 164.3 ng/mL [73.7-334.1], respectively; all P < 0.05). No changes occurred in urate or malondialdehyde. After portal vein declamping, XO, hypoxanthine, and xanthine levels were substantially greater in the hepatic than portal vein (all P < 0.05). Marginal transhepatic differences occurred in lactoferrin. CONCLUSIONS: Reperfusion during liver transplantation is associated with liberation of xanthine oxidase, hypoxanthine, and xanthine from the liver into the circulation. During reperfusion, intravascular neutrophil activation takes place in the hepatic circulation.

Adult↗
PubMed1998

Free radicals generated by xanthine oxidase mediate pancreatitis-associated organ failure.

In the present study we evaluate the possibility that xanthine oxidase released by damaged pancreas could act as a source of oxidative damage in systemic tissues during the early stages of acute pancreatitis. This was accomplished by evaluating the effects of xanthine oxidase inhibition with oxypurinol infused into the portal vein. Under these conditions, we inhibited the enzyme before it reached the liver and other distant organs, without inducing changes in the severity of pancreatic damage. Results indicate that pancreatitis parallels increases in xanthine oxidase activity in plasma. Superoxide radicals generated by this enzyme appears to be involved in the decrease of reduced glutathione levels in the plasma and liver. In addition, xanthine oxidase inhibition prevents the infiltration of neutrophils into the lungs. We conclude that oxygen free radicals generated by xanthine and xanthine oxidase released to the bloodstream are involved in the systemic organ failure associated with acute pancreatitis.

Acute Disease↗
PubMed2004

Administration of procyanidins from grape seeds reduces serum uric acid levels and decreases hepatic xanthine dehydrogenase/oxidase activities in oxonate-treated mice.

In this study we have investigated the effects of administration of procyanidins from grape seeds on serum uric acid levels in a model of hyperuricaemia in mice pretreated with oxonate, as well as the xanthine dehydrogenase and xanthine oxidase activities in mouse liver in vivo. The procyanidins, when orally administered to the oxonate-pretreated hyperuricaemic mice, were able to elicit a dose-dependent hypouricaemic effect. At a dose of 400 mg/kg for 3 days, the serum urate levels of the oxonate-pretreated mice were not different from the normal mice. In addition, the hepatic activities of xanthine dehydrogenase and xanthine oxidase in the procyanidins-treated mice were found to decrease significantly. However, the hypouricaemic effects observed in the experimental animals did not seem to parallel the changes in xanthine dehydrogenase and xanthine oxidase activities, implying that the procyanidins might be acting via other mechanisms apart from simple inhibition of enzyme activities. Furthermore, the procyanidin-treated animals exhibited normal growth while the allopurinol-treated animals exhibited some retarded growth. These results demonstrated for the first time that the procyanidins from grape seeds possess in vivo urate-lowering activities. The potential application of these natural compounds in the treatment of hyperuricaemia is discussed.

Allopurinol↗
PubMed1994

Induction of the conversion of xanthine dehydrogenase to oxidase in rabbit liver by Cu2+,Zn2+ and selenium ions.

Effects of Cu2+,Zn2+,Fe2+ and selenium ions on the conversion of xanthine dehydrogenase to oxidase in rabbit liver were examined. Under basal conditions, xanthine oxidase activity represented only 16% of the total xanthine oxidase plus dehydrogenase activity. Cu2+ (2-10 microM), Zn2+ (5-30 microM) and selenium ions (5-100 microM) brought about the conversion of xanthine dehydrogenase to oxidase in a dose-dependent manner. The concentrations of Cu2+,Zn2+ and selenium ions required for increasing xanthine oxidase activity by 50% was approximately 4, 10 and 20 microM, respectively. On the other hand, Fe2+ had no effect on the conversion of the enzyme up to 100 microM. These results suggest that Cu2+,Zn2+ and selenium ions have the potential to modulate the conversion of xanthine dehydrogenase to oxidase in rabbit liver.

Allopurinol↗
PubMed1991

Role of xanthine dehydrogenase and oxidase in focal cerebral ischemic injury to rat.

The role of xanthine dehydrogenase and oxidase as a source of free radicals contributing to focal cerebral ischemic injury was evaluated in Long-Evans rats after the middle cerebral artery was permanently occluded and both carotid arteries were clamped for 90 min. The fraction of xanthine dehydrogenase present as the free radical producing oxidase increased slightly from 22% in control cortex to 30% in the ischemic right cortex during the first 3 h of reperfusion and then remained relatively unchanged over the next 24 h. This increase may in part be due to entrapped plasma, which contained 4.5 +/- 0.8 nmol.min-1.ml-1 xanthine oxidase entirely in the free radical-producing form. Infarct volume was unaffected by pretreatment with 50 mg allopurinol/kg per day over 3 days before surgery but was decreased by 8% with 100 mg/kg and 24% with 150 mg/kg of allopurinol (P less than 0.05). However, inhibition of xanthine oxidase by dietary depletion of the essential molybdenum cofactor increased infarct volume by 19%, suggesting that protection by allopurinol at higher dosages was independent of xanthine oxidase inhibition. Neither xanthine oxidase present in rat brain nor circulating in plasma appears to be the primary source of oxygen radicals that contributes to infarction in focal cerebral ischemia.

Allopurinol↗
PubMed2003

Development of a new reporter gene system--dsRed/xanthine phosphoribosyltransferase-xanthine for molecular imaging of processes behind the intact blood-brain barrier.

We report the development of a novel dual-modality fusion reporter gene system consisting of Escherichia coli xanthine phosphoribosyltransferase (XPRT) for nuclear imaging with radiolabeled xanthine and Discosoma red fluorescent protein for optical fluorescent imaging applications. The dsRed/XPRT fusion gene was successfully created and stably transduced into RG2 glioma cells, and both reporters were shown to be functional. The level of dsRed fluorescence directly correlated with XPRT enzymatic activity as measured by ribophosphorylation of [14C]-xanthine was in vitro (Ki = 0.124 +/- 0.008 vs. 0.00031 +/- 0.00005 mL/min/g in parental cell line), and [*]-xanthine octanol/water partition coefficient was 0.20 at pH = 7.4 (logP = -0.69), meeting requirements for the blood-brain barrier (BBB) penetrating tracer. In the in vivo experiment, the concentration of [14C]-xanthine in the normal brain varied from 0.20 to 0.16 + 0.05% dose/g under 0.87 + 0.24% dose/g plasma radiotracer concentration. The accumulation in vivo in the transfected flank tumor was to 2.4 +/- 0.3% dose/g, compared to 0.78 +/- 0.02% dose/g and 0.64 +/- 0.05% dose/g in the control flank tumors and intact muscle, respectively. [14C]-Xanthine appeared to be capable of specific accumulation in the transfected infiltrative brain tumor (RG2-dsRed/XPRT), which corresponded to the 585 nm fluorescent signal obtained from the adjacent cryosections. The images of endogenous gene expression with the "sensory system" have to be normalized for the transfection efficiency based on the "beacon system" image data. Such an approach requires two different "reporter genes" and two different "reporter substrates." Therefore, the novel dsRed/XPRT fusion gene can be used as a multimodality reporter system in the biological applications requiring two independent reporter genes, including the cells located behind the BBB.

Amino Acid Sequence↗