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PubMed1995

Release of xanthine oxidase to the systemic circulation during resuscitation from severe hypoxemia in newborn pigs.

Xanthine oxidase may contribute to oxygen free radical formation during reoxygenation after hypoxia, but in humans the enzyme is present in substantial amounts only in the liver and intestine. We developed a sensitive assay for xanthine oxidase using 14C-xanthine as substrate and investigated whether xanthine oxidase was released into the systemic circulation when 19 newborn pigs were resuscitated after severe hypoxemia. In five piglets plasma xanthine oxidase concentrations increased from undetectable levels to a median value of 8 (range 4-18) microU/ml after 30 min of reoxygenation. In these pigs serum aspartate aminotransferase increased from 45 to 148 U/l, while alanine aminotransferase was unchanged (28-31 U/l). The release of xanthine oxidase did not seem to correlate with the severity of the histological brain damage after 4 days. We conclude that only low levels of xanthine oxidase are released to the systemic circulation after severe hypoxemia in newborn pigs.

Alanine Transaminase↗
PubMed1978

Bacterial xanthine oxidase from Arthrobacter S-2.

Arthrobacter S-2, originally isolated by enrichment on xanthine, produced high levels of xanthine oxidase activity, requiring as little as a 20-fold purification to approach homogeneity with some preparations. Molecular oxygen, ferricyanide, and 2,6-dichlorophenol-indophenol served as electron acceptors, but nicotinamide adenine dinucleotide did not. The enzyme was relatively specific when compared with previously studied xanthine-oxidizing enzymes, but at least one purine was observed to be oxidized at each of the three positions of the purine ring that have been subject to oxidation by this type of enzyme. The enzyme had a relatively high Km for xanthine (1.3 X 10(-4) M), and substrate inhibition was not observed with this compound, in contrast to the enzyme from cow's milk. In fact, an opposite effect was observed, and double-reciprocal plots with xanthine as the variable substrate showed a concave downward deviation at high concentrations. At 2.5 mM xanthine the enzyme had a specific activity approximately 50 times that of the most active preparations of the milk enzyme. The spectrum of the Arthrobacter enzyme resembled that of milk xanthine oxidase, suggesting a similarity of the prosthetic centers of the two enzymes. The bacterial enzyme was relatively small and may be dimeric, with approximate native and subunit molecular weights of 146,000 and 79,000, respectively.

2,6-Dichloroindophenol↗
PubMed1991

A role for xanthine oxidase in the loss of cytochrome P-450 evoked by interferon.

It has been suggested that the loss of cytochrome P-450, which is mediated by interferon and its inducers, can result from the generation of free radical species by the enzyme xanthine oxidase. Cytochrome P-450, aminopyrine N-demethylase, and ethoxyresorufin deethylase were depressed by 35, 36, 38%, respectively, in the livers of hamsters 24 h following the administration of a synthetic interferon (IFN-alpha-Con1) which contains the most frequent amino acid sequences of the human subtypes. Interferon increased the activities of the D and O forms of xanthine oxidase by 65 and 74%, respectively, in the same animals. The induction of the D form of xanthine oxidase, which is the precursor of the O form, preceded the loss in cytochrome P-450. The protein synthesis inhibitor, actinomycin D, prevented the interferon-induced loss of drug biotransformation and the increase in xanthine oxidase. The free radical scavenger, alpha-tocopherol, and the xanthine oxidase inhibitor, allopurinol, also prevented the loss of cytochrome P-450 mediated by the interferon inducer poly rI.rC. In chickens in which xanthine oxidase cannot be formed, poly rI.rC had no effect on cytochrome P-450 levels. These results suggest that xanthine oxidase induction may play some role in the interferon-mediated loss of cytochrome P-450.

Allopurinol↗
PubMed2002

Iron regulates xanthine oxidase activity in the lung.

The iron chelator deferoxamine has been reported to inhibit both xanthine oxidase (XO) and xanthine dehydrogenase activity, but the relationship of this effect to the availability of iron in the cellular and tissue environment remains unexplored. XO and total xanthine oxidoreductase activity in cultured V79 cells was increased with exposure to ferric ammonium sulfate and inhibited by deferoxamine. Lung XO and total xanthine oxidoreductase activities were reduced in rats fed an iron-depleted diet and increased in rats supplemented with iron, without change in the ratio of XO to total oxidoreductase. Intratracheal injection of an iron salt or silica-iron, but not aluminum salts or silica-zinc, significantly increased rat lung XO and total xanthine oxidoreductase activities, immunoreactive xanthine oxidoreductase, and the concentration of urate in bronchoalveolar fluid. These results suggest the possibility that the production of uric acid, a major chelator of iron in extracellular fluid, is directly influenced by iron-mediated regulation of the expression and/or activity of its enzymatic source, xanthine oxidase.

Animals↗
PubMed1990

Role of xanthine oxidase in ischemia/reperfusion injury.

Oxygen metabolites formed during reperfusion of ischemic kidneys prevent recovery of renal function after short periods of renal ischemia. Xanthine oxidase has been proposed as a source of toxic oxygen metabolites during reperfusion of ischemic kidneys. To determine whether the enzyme is converted from the non-oxygen metabolite-producing dehydrogenase (type D) to the oxygen metabolite-producing oxidase (type O), we measured type D and type O (total, reversible, and irreversible) xanthine oxidase in renal cortical homogenates after 30 min of ischemia in vivo and 60 min of reperfusion by the isolated perfused kidney technique. Total enzyme activity (type D plus type O) was not altered by ischemia or reperfusion. Compared with nonischemic conditions, ischemia increased total type O (53 +/- 5 vs. 21 +/- 3%, P less than 0.01) and reversible type O (15.4 +/- 1.5 vs. 2.1 +/- 1.4 U/g) xanthine oxidase activities. Reperfusion further increased total type O (82 +/- 3%) and reversible type O (27.7 +/- 3.3 U/g, both P less than 0.01 vs. nonischemic perfusions) xanthine oxidase activities. To determine the physiological role of xanthine oxidase in renal ischemia, we depleted rats of xanthine oxidase by feeding tungsten. After 4 wk of tungsten, renal xanthine oxidase levels were reduced by greater than 90% and renal function was markedly improved during reperfusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Failure of the xanthine oxidase inhibitor allopurinol to limit infarct size after ischemia and reperfusion in dogs.

During the acute phase of myocardial ischemia, adenine nucleotides are degraded to nucleosides and bases, especially inosine and hypoxanthine. Simultaneously, xanthine dehydrogenase is converted to xanthine oxidase, an enzyme that converts hypoxanthine to xanthine, and xanthine to uric acid, producing a superoxide anion for each molecule of hypoxanthine or xanthine oxidized. To determine if free radicals via this enzymatic source contribute to cell death in myocardial ischemia, we determined whether allopurinol, an inhibitor of xanthine oxidase, could limit infarct size in a reperfusion preparation of myocardial infarction. The circumflex coronary artery of each of 34 dogs was occluded for 40 min, followed by reperfusion for 4 days. Infarct size then was measured by histologic methods and was related to major baseline predictors of infarct size, including anatomic area at risk and collateral blood flow. Infarct size was larger (NS) in the allopurinol (n = 8) than in the control (n = 11) group, a trend that was related to slightly higher (NS) collateral blood flow in the control group. We conclude that allopurinol has no beneficial effect in this preparation of experimental myocardial infarction. The results oppose the hypothesis that free radicals, produced via the xanthine oxidase reaction, are an important contributing factor in myocardial ischemic cell death.

Allopurinol↗
PubMed1991

Xanthine oxidase inhibition does not limit canine infarct size.

BACKGROUND: Evidence supporting the role of xanthine oxidase in myocardial reperfusion injury is based on studies with pharmacological interventions used to inhibit enzyme function. Controversy exists, however, regarding the true role of xanthine oxidase in reperfusion injury. This study was performed to determine whether xanthine oxidase inhibition limits myocardial injury due to coronary artery occlusion and reperfusion. METHODS AND RESULTS: Anesthetized dogs underwent coronary artery occlusion (90 minutes) and reperfusion (6 hours). Oxypurinol (28 mg/kg) or amflutizole (30 mg/kg), chemically unrelated inhibitors of xanthine oxidase, or vehicle was infused intravenously 15 minutes before and 3 hours after reperfusion. Regional myocardial blood flow was determined with radiolabeled microspheres. Infarct size was determined with the tetrazolium method. Myocardial infarct size (percent of risk region) was less in oxypurinol-treated dogs, 32 +/- 16%, compared with that of the control group, 46 +/- 15%. Infarct size for the amflutizole-treated dogs, 40 +/- 21%, was not significantly different from that of the control group. There were no differences in rate-pressure product or collateral blood flow to account for differences in infarct size. Uric acid concentration in the coronary venous plasma increased after reperfusion in the dogs treated with vehicle but not in the drug-treated dogs. Xanthine oxidase inhibition was demonstrated in each of the drug treatment groups, but only oxypurinol limited the extent of myocardial injury. CONCLUSIONS: Previously reported cardioprotective effects of allopurinol, noted to occur only when the drug was administered chronically, may be related to a property of oxypurinol, a major metabolite of allopurinol. The beneficial effect of oxypurinol is unrelated to inhibition of superoxide formation during xanthine oxidase-catalyzed oxidation of xanthine and hypoxanthine.

Animals↗
PubMed1999

Role of xanthine oxidase in passive Heymann nephritis in rats.

Passive Heymann nephritis (PHN) in rats is a model of human membranous nephropathy characterized by formation of subepithelial immune deposits in the glomerular capillary wall and complement activation. Oxygen radicals have been implicated in the subsequent glomerular damage which leads to proteinuria. This study examines the involvement of xanthine oxidase in this process. Xanthine oxidase activity was increased nearly twofold in glomeruli isolated 1 and 12 d after induction of PHN, and this was associated with increased glomerular superoxide anion generation. Analysis of glomerular samples by Northern and Western blotting revealed no quantitative changes in xanthine oxidoreductase expression in PHN, suggesting conversion of xanthine dehydrogenase to the oxidase form as the cause of increased activity. Treatment of rats with tungsten, an inhibitor of xanthine oxidase, before induction of PHN resulted in a marked decrease in glomerular xanthine oxidase activity and superoxide anion generation, and decreased proteinuria by 80% (day 12: 423+/-245 mg/d in PHN versus 78+/-53 mg/d in tungsten-treated PHN animals, P < 0.01). These findings point to a pivotal role of xanthine oxidase in the pathophysiology of PHN and could be of importance in the therapy of human membranous nephropathy.

Animals↗
PubMedDate not supplied

Inhibition of xanthine oxidase by benzothiazinone analogues.

Fourteen synthetic benzothiazinone analogues were tested for their inhibitory effects on xanthine oxidase. The enzyme, xanthine oxidase (XO) catalyses the oxidation of hypoxanthine to xanthine and of xanthine to uric acid, which has a lambda max of 295 nm, forming the basis for a spectrophotometric assay for the activity of xanthine oxidase. The results showed that 2-amino-4H-1,3-benzothiazine-4-one (1), 2-guanidino-4H-1,3-benzothiazin-4-one (2) and rhodanine (3) display inhibitory effects on xanthine oxidase with an order of activity of IC50 = 5.54, 5.60 and 121.40 microM respectively. The apparent inhibition constants (Ki) were 5.12, 19.47 and 206.23 microM, and induced non-competitive, mixed type (non-competitive-uncompetitive) and mixed type (non-competitive-uncompetitive) inhibitions respectively with respect to the substrate xanthine.

Enzyme Inhibitors↗
PubMed2002

The measurement of theophylline in human serum or plasma using gas chromatography and isotope dilution-mass spectrometry (GC-IDMS) taking other substituted xanthines into consideration.

A method is described which uses a combination of gas chromatography and isotope dilution-mass spectrometry (GC-IDMS) to determine the concentration of theophylline (1,3-dimethyl xanthine) in human plasma or serum samples. The effects of similar substituted xanthines - namely theobromine (3,7-dimethyl xanthine), paraxanthine (1,7-dimethyl xanthine) 1,3-dimethyl-7-(2-hydroxyethyl) xanthine (internal standard HPLC) and caffeine (1,3,7-trimethyl xanthine) were tested to confirm the specificity of the method. The derivatisation of all xanthines was performed with N-methyl-N-trimethylsilyl trifluroacetamide (MSTFA). The internal standard used was 2-(13)C ,1,3-(15)N2-theophylline. The extraction and derivatisation procedures were examined in detail and optimised stepwise during the development of the method. High-performance liquid chromatography (HPLC) was used for comparison.

Acetamides↗
PubMed1991

Does xanthine oxidase cause damage during myocardial ischemia?

Xanthine oxidase is the pathological form of xanthine oxidoreductase, which generates free oxygen radicals, when it converts (hypo)xanthine to urate. We studied 1. developmental changes in rat heart, 2. urate production in catheterized patients, and 3. species differences of cardiac xanthine oxidase. First, we measured the activity of the enzyme at various ages. In rat-heart homogenate, xanthine oxidoreductase increased from 0.5 mU/g (newborn) to 25 mU/g (15 weeks, P less than 0.001). In the second part of the study, we demonstrated that patients undergoing coronary angioplasty showed some cardiac urate production. In the last part of our investigations we showed that in explanted human hearts perfused with hypoxanthine, the enzymatic activity was low, contrasting findings in some other species. The apparent xanthine oxidoreductase activity (mU/g) was: 33 (mouse), 28 (rat), 14 (guinea pig), 0.59 (rabbit), less than 0.1 (pig), 0.31 (man) and 3.7 (cow). We conclude that in several species, cardiac damage due to xanthine oxidase cannot be excluded; however in man it is unlikely to occur.

Aging↗
PubMed1990

Multiple mechanisms of xanthine actions on airway reactivity.

Xanthines are effective in the treatment of asthma, but the mechanism of action remains unclear. Pulmonary effects of seven xanthines, exhibiting a range of potencies as cyclic nucleotide phosphodiesterase (PDE) inhibitors and as adenosine antagonists, were investigated in anesthetized and ventilated guinea pigs. The bronchodilator effects of xanthines, determined from reversal of bronchoconstriction induced by aerosols of histamine and carbachol, correlated with their relative potencies as cyclic AMP-PDE inhibitors. The hypotensive effects of xanthines at bronchodilator doses were also consistent with PDE inhibition. Prophylactic effects of xanthines against bronchoconstriction induced by an aerosol of ovalbumin in sensitized guinea pigs, or by aerosols of leukotriene D4 and platelet-activating factor (PAF) in normal guinea pigs, occurred by a mechanism unrelated to bronchodilation and could not be readily attributed to PDE inhibition or adenosine A1/A2 receptor antagonism. There was a close association between inhibition of the responses to antigen and leukotriene D4, suggesting a common mechanism of action, but these effects gave a different profile from inhibition of the response to PAF. In addition, PAF-induced hypotension was unaffected in animals in which PAF-induced bronchoconstriction was inhibited, suggesting a mechanism other than PAF receptor antagonism. These results indicate that the bronchodilator, antiallergic and anti-inflammatory effects of xanthines occur through multiple molecular mechanisms of action, including at least one unknown mechanism. Furthermore, 8-phenyltheophylline produces these prophylactic effects at a dose that does not produce the cardiovascular or emetic side effects associated with xanthines, thereby exhibiting unique characteristics of potential therapeutic importance.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗
PubMed1989

Characterization of free radical generation by xanthine oxidase. Evidence for hydroxyl radical generation.

Xanthine oxidase has been hypothesized to be an important source of biological free radical generation. The enzyme generates the superoxide radical, .O2- and has been widely applied as a .O2- generating system; however, the enzyme may also generate other forms of reduced oxygen. We have applied electron paramagnetic resonance (EPR) spectroscopy using the spin trap 5,5'-dimethyl-1-pyrroline-N-oxide (DMPO) to characterize the different radical species generated by xanthine oxidase along with the mechanisms of their generation. Upon reaction of xanthine with xanthine oxidase equilibrated with air, both DMPO-OOH and DMPO-OH radicals are observed. In the presence of ethanol or dimethyl sulfoxide, alpha-hydroxyethyl or methyl radicals are generated, respectively, indicating that significant DMPO-OH generation occurred directly from OH rather than simply from the breakdown of DMPO-OOH. Superoxide dismutase totally scavenged the DMPO-OOH signal but not the DMPO-OH signal suggesting that .O2- was not required for .OH generation. Catalase markedly decreased the DMPO-OH signal, while superoxide dismutase + catalase totally scavenged all radical generation. Thus, xanthine oxidase generates .OH via the reduction of O2 to H2O2, which in turn is reduced to .OH. In anaerobic preparations, the enzyme reduces H2O2 to .OH as evidenced by the appearance of a pure DMPO-OH signal. The presence of the flavin in the enzyme is required for both .O2- and .OH generation confirming that the flavin is the site of O2 reduction. The ratio of .O2- and .OH generation was affected by the relative concentrations of dissolved O2 and H2O2. Thus, xanthine oxidase can generate the highly reactive .OH radical as well as the less reactive .O2- radical. The direct production of .OH by xanthine oxidase in cells and tissues containing this enzyme could explain the presence of oxidative cellular damage which is not prevented by superoxide dismutase.

Cyclic N-Oxides↗
PubMed1996

Immobilization of xanthine oxidase on a polyaniline silicone support.

A polyaniline silicone support to immobilize xanthine oxidase is proposed as a reactor coil to monitor the action of xanthine oxidase on hypoxanthine, xanthine and 6-mercaptopurine. A purified xanthine oxidase immobilized on this support lost 80% of the initial activity after 12 min of use. Co-immobilization of superoxide dismutase and catalase increased the stability of immobilized xanthine oxidase so that the derivative maintained 79% of its initial activity after 4.6 h of continuous use in which 1.5 mumol purine bases were converted by the immobilized enzyme system. There is no evidence of either polyaniline or protein leaching from the coil during 3 h of continuous use. When solutions (10 ml) of hypoxanthine, xanthine and 6-mercaptopurine were circulated individually through the xanthine oxidase-superoxide dismutase-catalase-polyaniline coil (1 mm internal diameter and 3 m in length, 3 ml internal volume) activities of 8.12, 11.17 and 1.09 nmol min-1 coil-1, respectively, were obtained. The advantages of the reactor configuration and the redox properties of the polymer, particularly with respect to immobilized oxidoreductases, make this methodology attractive for similar enzyme systems. This immobilized enzyme system using polyaniline-silicone as support converted 6-mercaptopurine to 6-thiouric acid with equal efficiency as resins based on polyacrylamide and polyamide 11.

Enzymes, Immobilized↗
PubMedDate not supplied

Inhibition of xanthine oxidase by synthetic cytokinin analogues.

Thirteen synthetic cytokinin analogues were tested for their inhibitory effects on xanthine oxidase. The enzyme, xanthine oxidase catalyses the oxidation of hypoxanthine to xanthine and of xanthine to uric acid, which has a gamma max of 295 nm, forming the basis for a spectrophotometric assay of the activity of xanthine oxidase. The results showed that 8-azaadenine(1), 4-amino-6-hydroxypyrazolo [3,4-d] pyrimidine(4), 4-amino-6-mercaptopyrazolo [3,4-d] pyrimidine(5) and 4-aminopyrazolo [3,4-d] pyrimidine(6) display inhibitory effects on xanthine oxidase with an order of activity of IC50 = 0.54, 5.91, 8.17 and 25.46 microM, respectively. Their apparent inhibition constants (Ki) were 0.66, 1.54, 6.61 and 26.79 microM, and induced mixed(competitive-non-competitive), competitive, mixed (competitive-non-competitive), and competitive types of inhibition respectively, with respect to the substrate xanthine.

Cytokinins↗
PubMedDate not supplied

Inhibition of xanthine oxidase by hydroxylated anthraquinones and related compounds.

Eighteen anthraquinones and related compounds were tested for their inhibitory effects on xanthine oxidase. The enzyme, xanthine oxidase catalyses the oxidation of hypoxanthine to xanthine and of xanthine to uric acid, which has a lambda max of 295nm, forming the basis for a spectrophotometric assay of the activity of xanthine oxidase. The results showed that anthrarobin and purpurin showed moderate effects on xanthine oxidase inhibition (IC50 = 68.35 and 105.13 microM; Ki = 122.38 and 130.49 microM respectively), and both of them induced mixed type (competitive-non-competitive) inhibition with respect to the substrate xanthine.

Anthraquinones↗
PubMedDate not supplied

Inhibition of xanthine oxidase by purpurogallin and silymarin group.

Thirteen phenolic compounds were tested for their inhibitory effects on xanthine oxidase. The enzyme xanthine oxidase catalyses the oxidation of hypoxanthine to xanthine and of xanthine to uric acid, which has lambda max of 295 nm, forming the basis for a spectrophotometric assay of the activity of xanthine oxidase. The results showed that purpurogallin and silymarin group displayed the inhibitory effects on xanthine oxidase (IC50 = 2.96 +/- 0.12 and 27.58 +/- 3.48 microM, respectively). Their apparent inhibition constants (Ki) were 1.16 and 5.85 microM, and induced uncompetitive and mixed type (non-competitive-uncompetitive) inhibitions respectively, with respect to the substrate xanthine.

Antioxidants↗
PubMed1992

Inhibition of xanthine oxidase by uric acid and its influence on superoxide radical production.

The inhibition of xanthine oxidase by its reaction product, uric acid, was studied by steady state kinetic analysis. Uric acid behaved as an uncompetitive inhibitor of xanthine oxidase with respect to the reducing substrate, xanthine. Under 50 microM xanthine and 210 microM oxygen, the apparent K(i) for uric acid was 70 microM. Uric acid-mediated xanthine oxidase inhibition also caused an increase in the percentage of univalent reoxidation of the enzyme (superoxide radical production). Steady-state rate equations derived by the King-Altman method support the formation of an abortive-inhibitory enzyme-uric acid complex (dead-end product inhibition). Alternatively, inhibition could also depend on the reversibility of the classical ping-pong mechanism present in xanthine oxidase-catalyzed reactions.

Free Radicals↗