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)

Perfused rat liver was used to study the relationship between the hepatotoxic effects of hyperthermia and the effects of heat on lysosomes. Livers from fed rats were perfused for 180 min at 37-43 degrees C. Release of lysosomal enzymes into the perfusate during perfusion and lysosomal fragility at the end of perfusion were determined. Lysosomes were then incubated in vitro at 37-45 degrees C with xanthine and xanthine oxidase to generate superoxide in order to study lipid peroxidation as a potential causative factor in heat-induced lysosomal lability. Perfusate lysosomal enzymes p-nitrophenyl phosphatase and beta-glucuronidase increased significantly (P less than 0.05) at 42 and 43 degrees C over enzyme levels at 37 degrees C. Significant differences were not observed until after 120 min. Lysosomal fragility was found to be significantly increased (P less than 0.05) after perfusion at 42 and 43 degrees C when measuring p-nitrophenyl phosphatase, but not when measuring beta-glucuronidase activity. Xanthine oxidase acting on xanthine caused labilization of the lysosomes at all temperatures studied when compared to a control at each temperature. There was a temperature effect with an increase in release of p-nitrophenyl phosphatase and beta-glucuronidase from control lysosomes which became significant (P less than 0.05) at 43 degrees C on comparison to 37 degrees C. There were no significant increases in lysosomal lability with temperature in the presence of xanthine and xanthine oxidase. Lastly, salicylic acid peroxidation was used as a measure of superoxide formation from the action of xanthine oxidase with increasing temperature.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Hyperthermic liver perfusion and release of lysosomal enzymes. 282 85

Although salicylates have been used for centuries as treatment of inflammatory diseases, the mechanism of action of these drugs is still not clear. Aspirin (acetylsalicylic acid) and other nonsteroidal anti-inflammatory drugs (NSAID) inhibit prostaglandin biosynthesis, a property that appears to explain part of their anti-inflammatory activity. However, this mechanism does not appear to explain the anti-inflammatory properties of salicylic acid, which is a major metabolite of ASA in vivo. Results of prior studies in our laboratory have established that benzoic acid, the parent compound of the salicylate group of drugs, is decarboxylated and hydroxylated by the hydroxyl free radical (OH.) produced by stimulated granulocytes. These observations suggested that salicylates might be similarly metabolized by granulocytes. If so, the capacity of salicylates to rapidly react with OH. might relate directly to their known anti-inflammatory properties. Preliminary experiments established that salicylic acid and aspirin were decarboxylated by the hydroxyl free radical generated by the enzyme system xanthine-xanthine oxidase. We then studied the metabolism of salicylates by human granulocytes. Unstimulated granulocyte suspensions did not oxidize ASA or salicylic acid. However, suspensions stimulated by opsonized zymosan particles rapidly oxidized both substrates in pharmacological concentrations. The rate of oxidation of salicylic acid was 16-fold higher than benzoic acid, whereas the rate of oxidation of ASA was four-fold higher. The reaction was oxygen dependent and could be inhibited by known hydroxyl scavengers, particularly dimethylthiourea. The reaction could also be inhibited by superoxide dismutase and azide, indicating that O-2 and heme or an iron-dependent enzyme were required for the reaction. The reaction was not impaired by compounds known to react with the HOCL and the chloramines generated by stimulated PMN. Furthermore, salicylic acid in high concentrations did not impair the HMPS pathway, the production of O-2 or the production of H2O2 by granulocytes. These data provide evidence that salicylates are rapidly oxidized by the hydroxyl free radical produced by granulocytes and not O-2, H2O2, or HOCL. This capacity of salicylates to react rapidly and selectively react with OH. may directly relate to their anti-inflammatory properties. In addition, results of our experiments indicate that stimulated granulocytes acquire the capacity to metabolize these drugs. Therefore, several metabolites of salicylates may be produced at a site of inflammation, all of which may have altered biological activity compared with the parent compound.
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PMID:Oxidation of salicylates by stimulated granulocytes: evidence that these drugs act as free radical scavengers in biological systems. 303 Nov 58

The oxidation of 2',7'-dichlorofluorescin (DCFH) to a fluorescent product is currently used to evaluate oxidant stress in cells. However, there is considerable uncertainty as to the enzymatic and nonenzymatic pathways that may result in DCFH oxidation. Iron/hydrogen peroxide-induced DCFH oxidation was inhibited by catalase or by the hydroxyl radical scavenger dimethylsulfoxide; however, superoxide dismutase (SOD) had no effect on DCFH oxidation. The formation of hydroxyl radical (indicated by the oxidation of salicylic acid to 2,3-dihydroxybenzoic acid) was proportional to DCFH oxidation, suggesting that the hydroxyl radical is responsible for the iron/peroxide-mediated oxidation of DCFH. Utilizing a superoxide generating system consisting of hypoxanthine/xanthine oxidase, oxidation of DCFH was unaffected by SOD, catalase or desferoxamine, and stimulated by removing hypoxanthine from the reaction mixture. In contrast, SOD or elimination of hypoxanthine abolished superoxide formation. In addition, potassium superoxide did not support the oxidation of DCFH. Thus, superoxide is not involved in DCFH oxidation. Boiling xanthine oxidase eliminated its concentration-dependent oxidation of 1 microM DCFH, indicating that xanthine oxidase can enzymatically utilize DCFH as a high affinity substrate. Kinetic studies of the oxidation of DCFH by xanthine oxidase indicated a Km(app) of 0.62 microM. Hypoxanthine competed with DCFH with a Ki(app) of 1.03 mM. These studies suggest that DCFH oxidation may be a useful indicator of oxidative stress. However, other types of cellular damage may produce DCFH oxidation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Oxidation pathways for the intracellular probe 2',7'-dichlorofluorescein. 799 26

The hypoxanthine/xanthine oxidase enzyme system is known to produce the superoxide ion and hydrogen peroxide during the hydroxylation of hypoxanthine via xanthine to uric acid. When chelated iron is included in this system, superoxide reduces iron (III) to iron(II) and the iron(II)-chelate further reacts with hydrogen peroxide to form the highly reactive hydroxyl radical. Because of the limitations of colourimetric and spectrophotometric techniques by which, to date, the mechanisms of hydroxyl radical formation in the hypoxanthine/xanthine oxidase system have been monitored, a high performance liquid chromatography method utilizing the ion-pair reagent tetrabutylammonium hydroxide and salicylic acid as an aromatic probe for quantification of hydroxyl radical formation was set up. In the hypoxanthine/xanthine oxidase system the major products of hydroxyl radical attack on salicylic acid were 2,5-dihydroxy benzoic acid and 2,3-dihydroxy benzoic acid in the approximate ratio of 5:1. That the hydroxyl radical is involved in the hydroxylation of salicylic acid in this system was demonstrated by the potency especially of dimethyl sulphoxide, butanol and ethanol as scavengers. Phytic acid, which is considered to be an important protective dietary constituent against colorectal cancer, inhibited hydroxylation of salicylic acid at a concentration one order of magnitude lower than the classical scavengers, but was only effective in the absence of EDTA. The method has been applied to the study of free radical generation in faeces, and preliminary results indicate that the faecal flora are able to produce reactive oxygen species in abundance.
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PMID:A high performance liquid chromatography system for quantification of hydroxyl radical formation by determination of dihydroxy benzoic acids. 889 60

We examined the protective effect of diltiazem, a calcium antagonist, on myocardial ischemic injury associated with generation of hydroxyl free radicals (.OH). Salicylic acid in Ringer's solution (0.5 nmol.microliter-1.min-1) was infused directly through a microdialysis probe to detect the generation of .OH as reflected by the formation of 2,3-dihydroxybenzoic acid (DHBA) in the myocardium. Cardiac dialysate was assayed for 2,3-DHBA by a high-performance liquid chromatographic-electrochemical (HPLC-EC) procedure. The heart was subjected to myocardial ischemia for 15 min by occlusion of left anterior descending artery (LAD). The presence of .OH was indicated in the ischemic reperfused rat heart. However, when heart was reperfused, the elevation of 2,3-DHBA by 15-min ischemia was not observed in the ischemic zone following systemic administration of diltiazem (100 micrograms.min-1.kg-1), a calcium antagonist. When corresponding experiments were performed with allopurinol (10 mg.kg-1) administration of i.v. injection, the elevation of 2,3-DHBA was not observed. These results suggest that diltiazem may suppress the .OH generation from xanthine-xanthine oxidase system by ischemia-reperfusion.
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PMID:Protective effect of diltiazem on myocardial ischemic injury associated with .OH generation. 917 83

5-[4-(2-Carboxyethylcarbamoyl)phenylazo]salicylic acid disodium salt dihydrate (CAS 80573-04-2, BX661A) is developed as a therapeutic agent for ulcerative colitis. To clarify its mechanism of action, the effects of BX661A and its metabolites 5-aminosalicylic acid (5-ASA) and 4-aminobenzoyl-beta-alanine (4-ABA) on reactive oxygen species: superoxide radicals (O2-) generated by hypoxanthine and xanthine oxidase, hydrogen peroxide (H2O2), hypochlorite radicals (OCl-) and hydroxyl radicals (OH.), were investigated and compared with the effects of 2-hydroxy-5-[[4-[(2-pyridinylamino)sulfonyl]phenyl]azo]-benzoic acid (CAS 599-79-1, salazosulfapyridine, SASP) and its metabolite 4-amino-N-2-pyridinyl-benzenesulfonamide (CAS 144-83-2, sulfapyridine, SP). 1. BX661A, SASP and 5-ASA inhibited O2- radical production in a concentration-dependent manner (IC50 = 0.14, 0.13 and 0.19 mmol/l, respectively). The effects of 4-ABA and SP on O2- radical production were weak (IC50 = > 10 and > 3 mmol/l, respectively). In contrast, superoxide dismutase inhibited O2- radical production in a concentration-dependent manner (IC50 = 1.7 U/ml). 2. BX661A, SASP, 4-ABA and SP had no H2O2 scavenging effects. 5-ASA scavenged H2O2, but its maximal scavenging action was 51.3%. In contrast, catalase scavenged H2O2 in a concentration-dependent manner (IC50 = 0.47 U/ml). 3. BX661A, SASP and 5-ASA scavenged OCl- radicals in a concentration-dependent manner (IC50 = 69.5, 73.8 and 21.7 mumol/l, respectively). 4-ABA and SP had no OCl- radical scavenging effects. In contrast, nordihydroguaiaretic acid (NDGA) scavenged OCl- radicals in a concentration-dependent manner (IC50 = 8.7 mumol/l). 4. BX661A and SASP scavenged OH. radicals in a concentration-dependent manner; the maximal scavenging values were 39.5 (10 mmol/l) and 48.6% (3 mmol/l), respectively. 4-ABA and SP had no OH. radical scavenging effects. In contrast, 5-ASA scavenged OH. radical in a concentration-dependent manner (IC50 = 1.46 mmol/l). These results suggest that BX661A has O2- and OCl- radical scavenging effects and that 5-ASA has O2-, OCl- and OH. radical scavenging effects. Therefore, these effects may be partially involved in the therapeutic effects of BX661A on ulcerative colitis.
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PMID:Effects of BX661A, a new therapeutic agent for ulcerative colitis, on reactive oxygen species in comparison with salazosulfapyridine and its metabolite sulfapyridine. 982 18

Azathioprine, a cytostatic and immunosuppressive drug in use for some 30 years, can give rise to life-threatening neutropenia and thrombocytopenia. This may be caused by unexpectedly high concentrations of cytotoxic metabolites due to abnormally slow inactivation of 6-mercaptopurine (6-MP) by thiopurine S-methyltransferase (TPMT) and/or xanthine oxidase. Low TPMT activity may be due to genetic polymorphism or interaction with drugs such as salicylic acid derivatives, while xanthine oxidase may be inhibited by allopurinol. High TPMT activity, on the other hand, may hamper cytostatic treatment. Safer and more effective treatment with azathioprine and its metabolite 6-MP becomes possible with new laboratory methods for pharmacotherapy monitoring.
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PMID:[Bone marrow depression after azathioprine. New discoveries on an old drug]. 1082 62

Anacardic acid, 6[8(Z), 11(Z), 14-pentadecatrienyl]salicylic acid, inhibits generation of superoxide radicals by xanthine oxidase. This inhibition does not follow a hyperbolic inhibition, depends on anacardic acid concentrations, but follows a sigmoidal inhibition. The inhibition was analyzed by using a Hill equation, and slope factor and EC(50) were 4.3+/-0.5 and 53.6+/-5.1 microM, respectively. In addition, anacardic acid inhibited uric acid formation by xanthine oxidase cooperatively. Slope factor and EC(50) were 1.7+/-0.5 and 162+/-10 microM, respectively. The results indicate that anacardic acid binds to allosteric sites near the xanthine-binding domain in xanthine oxidase. Salicylic acid moiety and alkenyl side chain in anacardic acid are associated with the cooperative inhibition and hydrophobic binding, respectively.
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PMID:Characterization of xanthine oxidase inhibition by anacardic acids. 1506 75

Alcaligenes species CF8 isolated from surface water of a lake produced a novel serine type metallo-caffeine oxidase. The optimal medium for caffeine oxidase production by this strain was (w/v) NaNO(3), 0.4%; KH(2)PO(4), 0.15%; Na(2)HPO(4), 0.05%; FeCl(3).6H(2)O, 0.0005%; CaCl(2).2H(2)O, 0.001%; MgSO(4).7H(2)O, 0.02%; glucose, 0.2%; caffeine, 0.05%, pH 7.5. The enzyme was purified to 63-fold by using ammonium sulfate precipitation, dialysis, ion exchange (diethylaminoethyl-cellulose) and gel filtration (Sephadex G-100) chromatographic techniques. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed that the purified caffeine oxidase was monomeric with a molecular mass of 65 kDa. The purified caffeine oxidase with a half-life of 20 min at 50 degrees C had maximal activity at pH 7.5 and 35 degrees C. The purified caffeine oxidase had strict substrate specificity towards caffeine (K(m) 8.94 microM and V(max) 47.62 U mg protein(-1)) and was not able to oxidize xanthine and hypoxanthine. The enzyme activity was not inhibited by para-chloromercuribenzoic acid, iodoacetamide, n-methylmaleimide, salicylic acid and sodium arsenite indicating the enzyme did not belong to xanthine oxidase family. The enzyme was not affected by Ca(+2), Mg(+2) and Na(+), but was completely inhibited by Co(+2), Cu(+2) and Mn(+2) at 1mM level. The novel caffeine oxidase isolated here from Alcaligenes species CF8 may be useful in biotechnological processes including waste treatment and biosensor development.
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PMID:Purification and characterization of a novel caffeine oxidase from Alcaligenes species. 1664 78

SUMMARY The PR10 class of genes has been associated with plant defence. Previous studies with an asparagus PR10 gene (AoPR1) promoter in heterologous plants suggested that the AoPR10-GUS transgene was responsive to oxidative signals/stresses. Arabidopsis thaliana AoPR10-GUS transgenics allowed expression to be compared with that of a close homologue from the large family of PR10 class genes within the Arabidopsis genome. AoPR10-GUS was induced developmentally at sites of phenylpropanoid accumulation and by wounding, pathogen challenge and treatment with H(2)O(2) but not with salicylic acid (SA), ethylene, methyljasmonate or NO donors. Both wound- and pathogen-associated AoPR10-GUS expression could be suppressed by superoxide dismutase and the NADPH oxidase inhibitor, diphenylene iodonium. Northern blotting using an Arabidopsis PR10 homologue as a probe revealed transcript up-regulation by oxidative species generated by glucose oxidase and xanthine oxidase. In Arabidopsis, the AoPR10-GUS transgene was potentiated by SA and expressed systemically following wounding or challenge with avirulent bacteria. AoPR10-GUS x npr1-1 crosses revealed that potentiation and systemic expression was NPR1-independent. Systemic AoPR10-GUS expression following elicitation of a hypersensitive response but not wounding was abolished in NahG crosses, suggesting an SA-mediated potentiating action during SAR (systemic acquired resistance). These data suggest that the AoPR10 promoter reports the expression of reactive oxygen species-responsive PR10 genes and may indicate systemic changes in oxidative status following either wounding and/or the elicitation of a hypersensitive response in Arabidopsis.
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PMID:The AoPR10 promoter and certain endogenous PR10 genes respond to oxidative signals in Arabidopsis. 2056 19


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