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)

The literature on the toxicity of aminoxyl radicals was critically reviewed. It was concluded that, in general, the aminoxyl radicals possess a very low toxicity and are not mutagenic. In support of this contention, several aminoxyl radicals were evaluated in vitro. Thus, aminoxyl radicals 3-carboxy-2,2,5,5-tetramethylpyrroline-1-oxyl (1), 3-carboxy-2,2,5,5-tetramethylpyrrolidine-1-oxyl (PCA; 2), 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (Tempol;3), and N-(1-hydroxymethyl-2,3-dihydroxypropyl)-3-carboxyamino-2,2,5,5- tetramethylpyrrolidine-1-oxyl (NAT; 4) were evaluated using Salmonella typhimurium tester strains TA 102 and TA 104, with a supplement of xanthine oxidase enzyme. 1, 2, and 4 were found to be nonmutagenic, while 3 elicited in TA 104 only about a twofold increase in the number of revertants above the control. This response is considered to be, at best, marginal in view of wide fluctuations of experimental scores. The results of the present study are in agreement with those of other studies confirming the nonmutagenicity of aminoxyl radicals investigated to date. However, these conclusions are different from those of a study where 3 was tested in the presence of a generated toxic oxygen species that can cause mutagenic changes of the environment.
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PMID:A critical evaluation of the present status of toxicity of aminoxyl radicals. 152 84

Nitroxide compounds are stable free radicals which were previously investigated as hypoxic cell radiosensitizers. The stable nitroxide 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (Tempol) has recently been shown to protect aerated cells in culture against superoxide generated from hypoxanthine/xanthine oxidase, hydrogen peroxide, and radiation-induced cytotoxicity and to modestly sensitive hypoxic cultured cells. To extend these observations from the cellular level to the whole animal, the toxicity, pharmacology, and in vivo radioprotective effects of Tempol were studied in C3H mice. The maximum tolerated dose of Tempol administered i.p. was found to be 275 mg/kg, which resulted in maximal Tempol levels in whole blood 5-10 min after injection. Mice were exposed to whole-body radiation in the absence or presence of injected Tempol (275 mg/kg) 5-10 min after administration. Tempol treatment provided significant radioprotection (P less than 0.0001); the dose of radiation at which 50% of Tempol-treated mice die at 30 days was 9.97 Gy, versus 7.84 Gy for control mice. Tempol represents a new class of in vivo, non-sulfur-containing radiation protectors. Given the potential for hypoxic radiosensitization and aerobic cell radioprotection, Temporal or other analogues may have potential therapeutic application.
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PMID:Tempol, a stable free radical, is a novel murine radiation protector. 155 Nov 4

The specificity of 2,2,6,6-tetramethylpiperidine to singlet oxygen was shown using Rose Bengal as a singlet oxygen generator, and Xanthine-Xanthine Oxidase and KO2 as the sources for the superoxide radical. The highest concentration of produced-singlet oxygen occurred at 25% of O2 by Rose Bengal photosensitization. The linewidth of the EPR signal for photosensitized nitroxyl radical, increasing solvent polarity. Deuterated solvents enlarge the EPR signal intensity in a dose-dependent manner. No EPR signal increase was observed in xanthine-xanthine oxidase reaction or KO2 systems, indicating that TEMP does not react with the superoxide anion. Thus, reaction of TEMP with 1O2 is highly specific.
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PMID:The specificity and product of quenching singlet oxygen by 2,2,6,6-tetramethylpiperidine. 867 11

The direct effects of the neurohormone melatonin on reactive oxygen species (ROS) were investigated. Melatonin was found to inhibit DMPO-O-2 formation in a dose-dependent manner. At the level of 1. 7+/-0.07 mM, melatonin caused 50% inhibition of EPR signal intensity of DMPO-O-2 during the reaction of xanthine and xanthine oxidase. The reaction rate constant of melatonin with O2- was found to be 1.25+/-0.07x103 M-1 s-1. However, melatonin (up to 1.2 mM) did not exhibit significant effect toward OH radical, produced by the Fenton reaction. In addition, we found no evidence for the formation of the melatonin indolyl cation radical that presumably precedes conversion of melatonin to its stable N1-acetyl-N2-5-methoxykynuramine (AMK) metabolite following sequential reactions of melatonin with O2- and OH. On the other hand, melatonin was capable of scavenging H2O2 in a dose-dependent manner with an IC50=0.5+/-0.02 mM. The reaction rate constant of melatonin with H2O2 was found to be 2.52+/-0.19x105 M-1 s-1. Furthermore, melatonin was also found to inhibit 1O2-dependent 2,2,6,6-tetramethylpiperidine oxide (TEMPO) radical formation during rose bengal photodynamic reaction. The results suggest that melatonin's antioxidant properties, in part, may involve a direct effect on scavenging of ROS.
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PMID:Scavenging of reactive oxygen species by melatonin. 983 10

A stable nitroxide radical named Metexyl (4-methoxy-2,2,6,6-tetramethylpiperidine-1-oxyl) was synthesized and its antioxidant and antitumor properties were investigated and compared with these of another nitroxide derivatives previously designed in our laboratories. Three experimental models were used: xanthine/xanthine oxidase system, pulse radiolysis and experimental rat cancer (Yoshida Sarcoma) in vivo. In this work we measured the rate constant of the reactions of Metexyl with enzymatically generated O2.- or radiolytically produced .OH. For comparison, the reactions of non radical derivative (4-acetamide-2,2,6,6-tetramethylpiperidinium acetate) or nitroxide Tempace (4-acetamide-2,2,6,6-tetramethylpiperidine-1-oxyl) with the above mentioned reactive oxygen radicals were also studied. The comparative ability of Metexyl to act as an inducer of apoptosis in vivo was also investigated in pharmacological test. The ring substituent (-OCH3) at position 4 of the Metexyl molecule had significant influence on its properties as antioxidant and apoptosis inducer. The results in this study suggest that Metexyl is a promising nitroxide antioxidant, which can induce apoptosis of tumor cells in vivo, thus providing a base for its further investigations in vitro and pharmacological applications.
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PMID:Metexyl (4-methoxy-2,2,6,6-tetramethylpiperidine-1-oxyl) as an oxygen radicals scavenger and apoptosis inducer in vivo. 1069 46

Free radicals play an important role in the initiation and progression of inflammatory bowel disease (IBD). Therefore, the reduction or elimination of adverse oxidant effects can provide novel therapy for IBD. Here, the antioxidant capacity and protective effects of a new class of chemically modified hetastarch (polynitroxyl starch, or PNS) plus 4-hydroxyl-2,2,6,6-tetramethylpiperidine-N-oxyl (Tempol or TPL) (PNS/TPL) were assessed in a model of colitis. The superoxide scavenging capacity of PNS/TPL-that is, the inhibition of the reduction of cytochrome c in the presence of xanthine/xanthine oxidase (X/XO)-was evaluated in vitro. The effects of PNS/TPL on X/XO-induced neutrophil endothelial adhesion in vitro were investigated. Also, this study tested the protection produced by PNS/TPL in a mouse model of trinitrobenzene sulfonic acid (TNBS)-induced colitis. PNS/TPL was given intravenously immediately before (< 30 min) and intraperitoneally at 24 and 72 hr after TNBS induction. The body weight and survival rate of the mice were checked daily. Colonic mucosal damage was assessed on the 7th day by measuring intestinal permeability to Evans blue (EB) in vivo. The ability of PNS to reoxidize bioreduced TPL was documented by whole-body electron paramagnetic resonance (EPR) detection. We found that PNS or TPL exhibits superoxide dismutase (SOD)-like activity, with approximately 2% of SOD activity occurring on a molar basis. The endothelial-neutrophil adherence induced by X/XO was significantly inhibited by PNS/TPL but not by TPL alone. PNS/TPL protected against cachexia and mortality, both usually induced by TNBS. Epithelial permeability was increased significantly in TNBS mice but was ameliorated by the administration of PNS/TPL. In conclusion, PNS/TPL may be beneficial in the treatment or prevention of IBD through its antioxidant effects, which inhibit oxidant-mediated leukocyte adhesion and injury to endothelial cells.
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PMID:Polynitroxylated starch/TPL attenuates cachexia and increased epithelial permeability associated with TNBS colitis. 1193 50

Curcumin (diferuloylmethane) is a major component of food flavoring turmeric (Curcuma longa), and has been reported to be anticarcinogenic and anti-inflammatory. Although curcumin was shown to have antioxidant properties, its exact antioxidant nature has not been fully investigated. In this report we have investigated the possible antioxidant properties of curcumin using EPR spectroscopic techniques. Curcumin was found to inhibit the (1)O(2)-dependent 2,2,6,6-tetramethylpiperidine N-oxyl (TEMPO) formation in a dose-dependent manner. (1)O(2) was produced in a photosensitizing system using rose bengal as sensitizer, and was detected as TEMP-(1)O(2) adducts by electron paramagnetic resonance (EPR) spectroscopic techniques using TEMP as a spin-trap. Curcumin at 2.75 microM caused 50% inhibition of TEMP-(1)O(2) adduct formation. However, curcumin only marginally inhibited (24% maximum at 80 microM) reduction of ferricytochrome c in a xanthine-xanthine oxidase system demonstrating that it is not an effective superoxide radical scavenger. Additionally, there was minor inhibition of DMPO-OH adduct formation by curcumin (solubilized in ethanol) when an ethanol control was included in the EPR spin-trapping study, suggesting that curcumin may not be an effective hydroxyl radical scavenger. Together these data demonstrate that curcumin is able only to effectively quench singlet oxygen at very low concentration in aqueous systems.
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PMID:Curcumin (diferuloylmethane), a singlet oxygen ((1)O(2)) quencher. 1208 67

Quantitation of superoxide radical (O2.-) production at the site of radical generation remains challenging. Microdialysis sampling is an advantageous tool for sampling from localized environments. It is difficult to combine electron spin resonance (ESR) spin traps with microdialysis because O2.- adducts with common nitrone spin traps have shorter half-lives than typical microdialysis collection times. Furthermore, typical dialysate samples (5-15 microL) suffer significant sensitivity loss when diluted for detection in a conventional ESR flat cell (200 microL). To overcome these difficulties, a cyclic hydroxylamine, 1-hydroxy-4-phosphonooxy-2,2,6,6-tetramethylpiperidine (PP-H), which produces a stable nitroxide radical (PP.) product upon reaction with O2.- was employed. Capillary cells (1.4 microL effective volume) coupled with a loop-gap resonator were utilized to measure PP. in microliter microdialysis samples (LOD 0.36 pmol). A xanthine/xanthine oxidase (X/XO) model system provided sustained O2.- production. When PP-H was included in the X/XO medium external to the microdialysis probe, a relative recovery of 22.1 +/- 1.1 and 57.2 +/- 5.7% for PP. was achieved at perfusion fluid flow rates of 0.5 and 1.0 microL/min, respectively. The respiratory burst in interferon-gamma and zymosan-stimulated RAW 264.7 macrophages was also investigated.
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PMID:Microdialysis sampling combined with electron spin resonance for superoxide radical detection in microliter samples. 1530 84

Oxygen radicals play an important role in signal transduction and have been shown to influence epithelial sodium channel (ENaC) activity. We show that aldosterone, the principal hormone regulating renal ENaC activity, increases superoxide (O2*) production in A6 distal nephron cells. Aldosterone (50 nM to 1.5 microM) induced increases in dihydroethidium fluorescence in a dose-dependent manner in confluent A6 epithelial cells. Using single-channel measurements, we showed that sequestering endogenous O2* (with the O2* scavenger 2,2,6,6-tetramethylpiperidine 1-oxyl) significantly decreased ENaC open probability from 0.10 +/- 0.03 to 0.03 +/- 0.01. We also found that increasing endogenous O2* in A6 cells, by applying a superoxide dismutase inhibitor, prevented nitric oxide (NO) inhibition of ENaC activity. ENaC open probability values did not significantly change from control values (0.23 +/- 0.05) after superoxide dismutase and 1.5 microM NO coincubation (0.21 +/- 0.04). We report that xanthine oxidase and hypoxanthine compounds increase local concentrations of O2* by approximately 30%; with this mix, an increase in ENaC number of channels times the open probability (from 0.1 to 0.3) can be achieved in a cell-attached patch. Our data also suggest that O2* alters NO activity in a cGMP-independent mechanism, since pretreating A6 cells with ODQ compound (a selective inhibitor of NO-sensitive guanylyl cyclase) failed to block 2,2,6,6-tetramethylpiperidine 1-oxyl inhibition of ENaC activity.
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PMID:Aldosterone-induced increases in superoxide production counters nitric oxide inhibition of epithelial Na channel activity in A6 distal nephron cells. 1780 82

Upregulation of xanthine oxidoreductase (XOR) increases vascular reactive oxygen species (ROS) levels and contributes to nitroso-redox imbalance. However, XOR can generate nitric oxide (NO) from nitrite, and increased superoxide could inactivate NO formed from nitrite. This study tested the hypothesis that XOR contributes to the cardiovascular effects of nitrite in renovascular hypertension, and that treatment with the antioxidant tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl) improves XOR-mediated effects of nitrite. Blood pressure was assessed weekly in two-kidney one-clip (2K1C) and control rats. After six weeks of hypertension, the relaxing responses to nitrite were assessed in aortic rings in the presence of the XOR inhibitor oxypurinol (or vehicle), either in the absence or in the presence of tempol. Moreover, in vivo hypotensive responses to nitrite were also examined in the presence of oxypurinol (or vehicle) and tempol (or vehicle). Aortic XOR activity and expression were evaluated by fluorescence and Western blot, respectively. Vascular ROS production was assessed by the dihydroethidium assay. 2K1C hypertensive rats showed increased aortic XOR activity and vascular ROS production compared with control rats. Oxypurinol shifted the nitrite concentration-response curve to the right in aortic rings from 2K1C rats (but not in controls). Oxypurinol also attenuated the hypotensive responses to nitrite in 2K1C rats (but not in controls). These functional findings agree with increased aortic and plasma XOR activity found in 2K1C rats. Tempol treatment enhanced oxypurinol-induced shift of the nitrite concentration-response curve to the right. However, antioxidant treatment did not affect XOR-mediated hypotensive effects of nitrite. Our results show that XOR is important to the cardiovascular responses to nitrite in 2K1C hypertension, and XOR inhibitors commonly used by patients may cancel this effect. This finding suggests that nitrite treatment may not be effective in patients being treated with XOR inhibitors. Moreover, while tempol may improve the vascular responses to nitrite, antihypertensive responses are not affected.
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PMID:Tempol improves xanthine oxidoreductase-mediated vascular responses to nitrite in experimental renovascular hypertension. 2707 69


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