Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.17.3.2 (xanthine oxidase)
8,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

To determine the mechanism responsible for the enhanced susceptibility of endothelial cells to oxidant injury in the absence of glucose, we induced endothelial cell injury with oxygen radicals in the presence of various oxygen radical scavengers and measured endothelial cell levels of glutathione after oxidant injury in the presence and absence of glucose. Endothelial cells were damaged with toxic oxygen radicals generated by phorbol myristate acetate (PMA)-activated polymorphonuclear leukocytes (PMNs) or xanthine-xanthine oxidase in the presence and absence of glucose and catalase (scavenger of hydrogen peroxide), superoxide dismutase (scavenger of superoxide radical), isoleucine, valine, and serine (scavengers of hypochlorous acid), or mannitol, ethanol, benzoic acid, dimethyl sulfoxide, and dimethyl thiourea (scavengers of hydroxyl radical). Endothelial cell injury was quantitated by 2-deoxy-[1-3H] glucose or chromium 51 release assays or both. In each oxidant-generating system, in the presence and absence of glucose, only catalase significantly protected endothelial cells from oxidant injury (P less than 0.001). When endothelial cells were damaged by hydrogen peroxide generated with xanthine-xanthine oxidase in the presence of glucose, endothelial cell levels of glutathione remained unchanged. In contrast, when endothelial cells were damaged with xanthine-xanthine oxidase in the absence of glucose, endothelial cell levels of glutathione fell to less than 50% of baseline (P less than 0.05). Xanthine-xanthine oxidase-mediated endothelial cell damage and depletion of glutathione in the absence of glucose were similar to results obtained in the presence of glucose when glutathione was depleted with buthionine sulfoximine, diethyl maleate, or 1-chloro-2,4-dinitrobenzene.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Role of glutathione in protecting endothelial cells against hydrogen peroxide oxidant injury. 309 44

Recent observations indicate that OH . may be important in the microbicidal capacity of phagocytic cells, in prostaglandin metabolism, and as a mediator of inflammation. Although glucose is a weak hydroxyl scavenger, it occurs in high concentrations in biological systems. We therefore studied the capacity of glucose to scavenge OH . in biological systems known to generate this reactive oxygen species. Our experiments used a specific assay for the detection of OH .. We measured 14CO2 released during the oxidation of 14C-benzoic acid. We have previously demonstrated that benzoic acid is oxidized as a consequence of OH . in the following systems: the enzyme system xanthine-xanthine oxidase, zymosan-stimulated granulocytes, and arachidonic acid-stimulated platelets as a consequence of the lipoxygenase pathway. In all three systems the oxidation of benzoic acid was inversely proportional to the concentration of glucose in the assays. Also, platelets incubated with arachidonic acid and a high concentration of glucose increased HETE production, an effect predicted by the capacity of glucose to act as an OH . scavenger. Our results indicate that glucose acts as a scavenger of OH . in physiological concentrations and therefore may serve an antioxidant role in biological systems. In addition, the capacity of glucose to act as an OH . scavenger may explain some of the defects seen in patients with diabetes mellitus.
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PMID:Glucose: a role as a free radical scavenger in biological systems. 629 3

Benzoic acid, a specific scavenger of hydroxyl radical (OH.) is known to be oxidized as the result of a reaction with OH.. We have determined that the decarboxylation of benzoic acid can be used to detect OH. generated in cell-free systems and human granulocytes. Benzoic acid is oxidized by the xanthine-xanthine oxidase enzyme system. This system is known to generate O2-, H2O2 and OH.. This oxidation is inhibited by superoxide dismutase, catalase and mannitol. Therefore, the oxidation of benzoic acid occurs by a mechanism similar to that reported for the oxidation of methional to ethylene and involves OH.. Resting granulocytes do not oxidize benzoic acid. However, marked oxidation of this substrate occurs during the phagocytosis of opsonized zymosan particles, indicating the production of OH. by these cells. The reaction can be inhibited by superoxide dismutase, catalase, azide and mannitol. Therefore, the production of OH. in the cell may be similar to that observed in the cell-free system. The granulocytes of a patient with known chronic granulomatous disease did not oxidase benzoic acid, indicating a defect in the generation of OH. by these cells.
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PMID:A new method for the detection of hydroxyl radical production by phagocytic cells. 689 10

The rapid and spontaneous interaction between superoxide (O2-.) and nitric oxide (NO) to yield the potent oxidants peroxynitrite (ONOO-) and peroxynitrous acid (ONOOH), has been suggested to represent an important pathway by which tissue may be injured during inflammation. Although several groups of investigators have demonstrated substantial oxidizing and cytotoxic activities of chemically synthesized ONOO-, there has been little information available quantifying the interaction between O2-. and NO in the absence or the presence of redox-active iron. Using the hypoxanthine (HX)/xanthine oxidase system to generate various fluxes of O2-. and H2O2 and the spontaneous decomposition of the spermine/NO adduct to produce various fluxes of NO, we found that in the absence of redox-active iron, the simultaneous production of equimolar fluxes of O2-. and NO increased the oxidation of dihydrorhodamine (DHR) from normally undetectable levels to approximately 15 microM, suggesting the formation of a potent oxidant. Superoxide dismutase, but not catalase, inhibited this oxidative reaction, suggesting that O2-. and not hydrogen peroxide (H2O2) interacts with NO to generate a potent oxidizing agent. Excess production of either radical virtually eliminated the oxidation of DHR. In the presence of 5 microM Fe+3-EDTA to insure optimum O2-.-driven Fenton chemistry, NO enhanced modestly HX/xanthine oxidase-induced oxidation of DHR. As expected, both superoxide dismutase and catalase inhibited this Fe-catalyzed oxidation reaction. Excess NO production with respect to O2-. flux produced only modest inhibition (33%) of DHR oxidation. In a separate series of studies, we found that equimolar fluxes of O2-. and NO in the absence of iron only modestly enhanced hydroxylation of benzoic acid from undetectable levels to 0.6 microM 2-hydroxybenzoate. In the presence of 5 microM Fe+3-EDTA, HX/xanthine oxidase-mediated hydroxylation of benzoic acid increased dramatically from undetectable levels to 4.5 microM of the hydroxylated product. Superoxide dismutase and catalase were both effective at inhibiting this classic O2-.-driven Fenton reaction. Interestingly, NO inhibited this iron-catalyzed hydroxylation reaction in a concentration-dependent manner such that fluxes of NO approximating those of O2-. and H2O2 virtually abolished the hydroxylation of benzoic acid. We conclude that in the absence of iron, equimolar fluxes of NO and O2-. interact to yield potent oxidants such as ONOO-/ONOOH, which oxidize organic compounds. Excess production of either radical remarkably inhibits these oxidative reactions. In the presence of low molecular weight redox-active iron complexes, NO may enhance or inhibit O2-.-dependent oxidation and hydroxylation reactions depending upon their relative fluxes.
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PMID:Modulation of superoxide-dependent oxidation and hydroxylation reactions by nitric oxide. 855 May 95

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

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

Superoxide anions (O2-) are supposedly involved in the pathogenesis of endothelial dysfunction. We investigated whether the enhanced formation of O2- is involved in the attenuation of endothelium-dependent relaxation induced by lipopolysaccharide (LPS). Rats were injected with LPS (10 mg/kg IP), the aorta was removed after 12 or 30 hours, and generation of O2-, H2O2, and ONOO- was measured using chemiluminescence assays. Protein tyrosine nitration and expression of xanthine oxidase (XO), NAD(P)H oxidase, and manganese superoxide dismutase were determined by Western or Northern blotting, and endothelium-dependent relaxation in aortic rings was studied. LPS treatment increased vascular O2- (from 35+/-2 cpm/ring at baseline to 166+/-21 cpm/ring at 12 hours and 225+/-16 cpm/ring at 30 hours) and H2O2 formation, which was partially sensitive to the NAD(P)H oxidase inhibitor diphenylene iodonium at both time points studied and to the XO inhibitor oxypurinol only 30 hours after LPS treatment. Expression of XO and NAD(P)H oxidase (p22phox, p67phox, and gp91phox) were increased by LPS in a time-dependent manner, as were protein tyrosine nitration and ONOO- formation. LPS also induced expression of the oxidative stress-sensitive protein manganese superoxide dismutase. Endothelium-dependent relaxation was impaired after LPS treatment and could not be restored by inhibition of inducible NO synthase. Inhibition of O2- with superoxide dismutase, oxypurinol, tiron, or the superoxide dismutase mimetic Mn(III)tetrakis(4-benzoic acid)porphyrin chloride did not restore but further deteriorated the relaxation of LPS-treated rings. In summary, treatment of rats with LPS enhances vascular expression of XO and NAD(P)H oxidase and increases formation of O2- and ONOO-. Because removal of O2- compromised rather than restored endothelium-dependent relaxation, a direct role of O2- in the induction of endothelial dysfunction is unlikely. Other mechanisms, such as prolonged protein tyrosine nitration by peroxynitrite (which is formed from NO and O2-) or downregulation of the NO effector pathway, are more likely to be involved.
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PMID:Role of increased production of superoxide anions by NAD(P)H oxidase and xanthine oxidase in prolonged endotoxemia. 1033 19

We have studied neurotoxicity induced by pharmacological concentrations of 3-hydroxykynurenine (3-HK), an endogenous toxin implicated in certain neurodegenerative diseases, in cerebellar granule cells, PC12 pheochromocytoma cells, and GT1-7 hypothalamic neurosecretory cells. In all three cell types, the toxicity was induced in a dose-dependent manner by 3-HK at high micromolar concentrations and had features characteristic of apoptosis, including chromatin condensation and internucleosomal DNA cleavage. In cerebellar granule cells, the 3-HK neurotoxicity was unaffected by xanthine oxidase inhibitors but markedly potentiated by superoxide dismutase and its hemelike mimetic, MnTBAP [manganese(III) tetrakis(benzoic acid)porphyrin chloride]. Catalase blocked 3-HK neurotoxicity in the absence and presence of superoxide dismutase or MnTBAP. The formation of H(2)O(2) was demonstrated in PC12 and GT1-7 cells treated with 3-HK, by measuring the increase in the fluorescent product, 2',7'-dichlorofluorescein. In both PC12 and cerebellar granule cells, inhibitors of the neutral amino acid transporter that mediates the uptake of 3-HK failed to block 3-HK toxicity. However, their toxicity was slightly potentiated by the iron chelator, deferoxamine. Taken together, our results suggest that neurotoxicity induced by pharmacological concentrations of 3-HK in these cell types is mediated primarily by H(2)O(2), which is formed most likely by auto-oxidation of 3-HK in extracellular compartments. 3-HK-induced death of PC12 and GT1-7 cells was protected by dantrolene, an inhibitor of calcium release from the endoplasmic reticulum. The protection by dantrolene was associated with a marked increase in the protein level of Bcl-2, a prominent antiapoptotic gene product. Moreover, overexpression of Bcl-2 in GT1-7 cells elicited by gene transfection suppressed 3-HK toxicity. Thus, dantrolene may elicit its neuroprotective effects by mechanisms involving up-regulation of the level and function of Bcl-2 protein.
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PMID:Neuronal apoptosis induced by pharmacological concentrations of 3-hydroxykynurenine: characterization and protection by dantrolene and Bcl-2 overexpression. 1085 50

Doxorubicin, a broad-spectrum antitumor antibiotic, causes dose-dependent cardiomyopathy and heart failure. Although the exact molecular mechanisms of cardiotoxicity are not well established, oxidative mechanisms involving doxorubicin-induced superoxide anion production have been proposed. In this study, we show that bicarbonate, a physiologically relevant tissue component, greatly amplified doxorubicin-induced cardiomyocyte injury. Bicarbonate also enhanced inactivation of aconitase, a crucial tricarboxylic acid cycle enzyme, in cardiomyocytes exposed to doxorubicin. The cell-permeable superoxide dismutase mimetic, Mn(III)tetrakis (4-benzoic acid) porphyrin, reversed doxorubicin-induced cardiomyocyte injury. Bicarbonate enhanced the inactivation of purified mitochondrial aconitase in the xanthine/xanthine oxidase system, generating superoxide. The results suggest that bicarbonate amplifies the prooxidant effect of superoxide. Bicarbonate also caused an increased loading of cardiomyocytes with doxorubicin. We conclude that the bicarbonate-mediated increase in doxorubicin toxicity is due to increased intracellular loading of doxorubicin in cardiomyocytes and subsequent exacerbation of superoxide-mediated cardiomyocyte injury.
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PMID:Bicarbonate exacerbates oxidative injury induced by antitumor antibiotic doxorubicin in cardiomyocytes. 1104 80


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