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Query: UNIPROT:P47989 (xanthine oxidase)
 8,633 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have studied the effect of H2O2 and O2- produced by xanthine and xanthine oxidase on NAD catabolism, poly(ADP-ribose) synthesis, and production of DNA single-strand breaks in C3H10T1/2 cells. The results show a correlation between the induction of DNA single-strand breaks, the decrease of NAD pool, and the accumulation of polymer. New techniques, based on affinity chromatography and reversed-phase high pressure liquid chromatography, have allowed an accurate determination of polymer contents and showed a 20-fold stimulation of polymer biosynthesis induced by active oxygen species. Inhibition experiments performed with 3-aminobenzamide have shown that the decrease in NAD levels after exposure of cells to active oxygen species was caused by stimulation of poly(ADP-ribosyl)ation and of another cellular process.
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PMID:Stimulation of poly(ADP-ribose) synthesis by free radicals in C3H10T1/2 cells: relationship with NAD metabolism and DNA breakage. 216 10

To investigate mechanisms of ATP depletion in human umbilical vein endothelial cells after oxidant injury, we studied the relationship between DNA damage, activation of the DNA-repairing enzyme poly ADP-ribose polymerase, NAD depletion, and ATP depletion. We found that oxidant stress generated with hypoxanthine-xanthine oxidase and glucose-glucose oxidase resulted in profound DNA damage. When endothelial cells were exposed to 25 and 50 mU/ml xanthine oxidase for 60 min, the percentage of double-stranded DNA was significantly reduced (p less than 0.05) to 15.2 +/- 1.2 and 4.6 +/- 0.5%, respectively, compared to 75.7 +/- 3.9% for control cells. When endothelial cells were exposed to 25 and 50 mU/ml glucose oxidase for 60 min, the percentage of double-stranded DNA was significantly (p less than 0.05) reduced to 35.0 +/- 1.5% and 9.9 +/- 7.7%, respectively, compared to 73.2 +/- 2.4% for control cells. ATP and NAD levels declined simultaneously with DNA damage. Because activation of the DNA-repairing enzyme poly ADP-ribose polymerase can consume NAD sufficient to interfere with ATP synthesis, we studied NAD and ATP levels after oxidant injury when ADP-ribose polymerase was inhibited with 3-aminobenzamide and nicotinamide. When poly ADP-ribose polymerase was inhibited, NAD levels remained normal, but ATP depletion was not prevented. We conclude that oxidant injury to human umbilical vein endothelial cells results in profound DNA damage and NAD and ATP depletion. NAD depletion results from activation of poly ADP-ribose polymerase, but this phenomenon is not the mechanism of ATP depletion in human umbilical vein endothelial cells.
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PMID:Mechanisms of endothelial cell ATP depletion after oxidant injury. 252 33

The metabolic causes for immune impairment in patients with severe chronic inflammatory diseases have not been clearly defined. Recently, the overproduction of poly(ADP-ribose) in resting lymphocytes with unrepaired DNA strand breaks has been suggested to contribute to immune dysfunction in adenosine deaminase-deficient patients. Our experiments have determined to what extent DNA damage and poly(ADP-ribose) synthesis might also explain the impaired mitogen responsiveness of PBL exposed to toxic oxygen species. Treatment of normal resting human lymphocytes with xanthine oxidase and hypoxanthine dose-dependently induced DNA strand breaks and triggered the rapid synthesis of poly(ADP-ribose). Subsequently, NAD+ and ATP pools decreased precipitously. Lymphocytes exposed previously to the enzymatic oxidizing system did not synthesize DNA after stimulation with PHA. However, if the medium was supplemented with 3-aminobenzamide or nicotinamide, two compounds that inhibit poly(ADP-ribose) formation, cellular NAD+ and ATP pools were preserved, and the lymphocytes responded vigorously to a mitogenic challenge. Excessive poly(ADP-ribose) synthesis, provoked by DNA strand breakage, may represent a common pathway that connects the immunodeficiency syndromes associated with (a) exposure of lymphocytes to toxic oxygen species during chronic inflammatory states, (b) adenosine deaminase deficiency, and (c) certain DNA repair disorders.
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PMID:Lymphocyte dysfunction after DNA damage by toxic oxygen species. A model of immunodeficiency. 395 May 45

When cultures of pancreatic islet cells are exposed to the nitric oxide donor sodium nitroprusside, to enzymatically generated reactive oxygen intermediates or to streptozotocin cell lysis occurs after 4-12 h. We report here that a heat shock at 43 degrees C for 90 min reduces cell lysis from nitric oxide (0.45 mM sodium nitroprusside) by 70%, from reactive oxygen intermediates (12 mU xanthine oxidase and 0.05 mM hypoxanthine) by 80% and from streptozotocin (1.5 mM) by 90%. Heat shock induced resistance was observed immediately after termination of the 90 min culture at 43 degrees C and correlated with enhanced expression of hsp70. The occurrence of DNA strand breaks, a major early consequence of nitric oxide, reactive oxygen intermediates, or streptozotocin action, was not suppressed by heat shock treatment. However, the depletion of NAD+, the major cause of radical induced islet cell death, was suppressed after heat shock (P < 0.01). We conclude that pancreatic islet cells can rapidly activate defence mechanisms against nitric oxide, reactive oxygen intermediates and streptozotocin by culture at 43 degrees C. Islet cell survival is due to the prevention of lethal NAD+ depletion during DNA repair, probably by slowing down poly(ADP-ribose)polymerase activation.
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PMID:Heat shock induces resistance in rat pancreatic islet cells against nitric oxide, oxygen radicals and streptozotocin toxicity in vitro. 776 24

Despite extensive studies on streptozotocin, alloxan and nitric oxide toxicity in pancreatic islets the mechanism of oxygen radical induced islet cell death has not been determined. The present study shows at the level of single cells that following exposure to oxygen radicals generated from xanthine oxidase DNA strand breaks occur in cell nuclei within 5-60 min and precede cell death by several hours. Similar kinetics were seen when treating islet cells with the alkylating agent streptozotocin. Immunofluorescence studies demonstrated the endogenous formation of ADP-ribose polymers in nearly all islet cell nuclei within minutes of treatment with xanthine oxidase, indicating activation of the enzyme poly(ADP-ribose) polymerase (PARP). Concomitantly, cellular NAD+ depletion was noted. Nicotinamide largely prevented NAD+ depletion and in parallel resulted in islet cell survival. These findings identify islet cell nuclear DNA as a primary target of oxygen radical toxicity and suggest related pathways of oxygen radical, nitric oxide and streptozotocin toxicity.
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PMID:Analysis of oxygen radical toxicity in pancreatic islets at the single cell level. 784 Sep 1

These experiments are a continuation of our work describing the effect of H2O2 and O2- on DNA strand breaks, NAD pools and poly(ADP-ribose) synthesis in C3H10T1/2 cells (Lautier et al. (1990) Biochem. Cell Biol. 68, 602-608). The current experiments were carried out firstly to evaluate the polymer synthesis in C3H10T1/2 cells exposed to benzamide, oxygen radicals and hyperthermia. Secondly, using four different protocols for the time of addition and removal of benzamide, the lowest benzamide levels shown to inhibit polymer synthesis were used to study the effect on plating efficiency and colony-forming ability of cells exposed to H2O2 and O2(-). Plating efficiency and colony-forming ability were affected by the active oxygen-species-generating system xanthine-xanthine oxidase and 100 microM benzamide. With higher levels of benzamide, this effect disappeared, and 0.5 to 1 mM benzamide were actually protective against the effects of xanthine-xanthine oxidase, suggesting the involvement of other processes in addition to poly(ADP-ribosyl)ation in response to oxygen radical damage.
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PMID:The role of poly(ADP-ribose) metabolism in response to active oxygen cytotoxicity. 816 42

Reactive oxygen metabolites have an important role in ischemia-reperfusion injury. One of the sources of reactive oxygen metabolites is xanthine oxidase, which is present in several tissues but is also released into the circulation after ischemia. We studied the effect of several potentially protective compounds on adenine nucleotide depletion induced by extracellular xanthine oxidase and hypoxanthine, in concentrations relevant to human pathophysiology. In umbilical vein endothelial cells prelabeled with 14C-adenine, cellular adenine nucleotides retained 64 +/- 9% of the initial radioactivity over a 4-h incubation with culture medium (controls), whereas in the presence of xanthine oxidase (80 mU/mL) and hypoxanthine (100 microM), only 3 +/- 4% of radioactivity remained in cellular nucleotides, the rest appearing in catabolic products in the medium. Glutathione and 3-aminobenzamide, an inhibitor of poly-ADP-ribose polymerase, partly prevented the nucleotide depletion (adenine nucleotide radioactivity 15 +/- 6% to 33 +/- 13% of total), but scavengers of the hydroxyl radical, dimethylthiourea and DMSO, as well as vitamins E and C, were without effect. Superoxide dismutase prevented the leakage of nucleotides into the culture medium but not intracellular nucleotide catabolism, whereas the latter process was decreased by catalase, consistent with predominant effects of superoxide and hydrogen peroxide at the cell membrane and interior, respectively.
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PMID:Nucleotide depletion due to reactive oxygen metabolites in endothelial cells: effects of antioxidants and 3-aminobenzamide. 828 91

The formation of poly(ADP-ribose) in primary cultures of rabbit synovial fibroblasts after treatment with active oxygen released by xanthine/xanthine oxidase is inhibited by addition of 1 and 10 microM 4-hydroxy-2,3-trans-nonenal (HNE). The endogenous formation of HNE by the xanthine/xanthine oxidase system is not responsible for the inhibitory effect of the aldehyde, owing to the low accumulation rate of the lipid peroxidation product in the system used. HNE is able to inhibit the isolated nuclear enzyme ADP-ribosyltransferase, as shown by an in vitro assay with an Ki of 4 mumol/litre. Therefore the molecular basis of HNE-mediated effects on cell proliferation, differentiation and transformation might be due to the inhibitory effect of poly(ADP-ribos)ylation.
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PMID:Inhibition of poly(ADP-ribose) formation by 4-hydroxynonenal in primary cultures of rabbit synovial fibroblasts. 864 46

Treatment of rabbit synovial fibroblasts with active oxygen (AO) released by xanthine/xanthine oxidase resulted in an induction of procollagenase in these cells in concentrations ranging from 12.5 micrograms/ml xanthine plus 0.0025 U/ml xanthine oxidase to 50 micrograms/ml xanthine plus 0.01 U/ml xanthine oxidase. Preceding this there was an accumulation of poly(ADP-ribose) for the same concentration range of xanthine/xanthine oxidase. Furthermore, it was found that AO caused activation of the latent procollagenase to the active enzyme in concentrations ranging from 0.1 micrograms/ml xanthine plus 0.00002 U/ml xanthine oxidase to 1 microgram/ml xanthine plus 0.0002 U/ml xanthine oxidase. It is suggested that poly(ADP-ribosyl)ation participates in the induction of procollagenase by relaxing chromatin. Furthermore, it is proposed that AO activates latent procollagenase under physiological conditions.
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PMID:Induction and activation of procollagenase in rabbit synovial fibroblasts after treatment with active oxygen released by xanthine/xanthine oxidase. 883 93

V79mut1 cells are resistant to the toxic effects of 5-hydroxymethyl-2'-deoxyuridine (hmdUrd) and are deficient in the DNA repair enzyme hydroxymethyluracil-DNA glycosylase (hmUDG). We have therefore proposed that the toxicity of hmdUrd results from the repair of the lesion from DNA. In order to clarify the biological role of hmUDG, we have determined whether the repair-deficient cells showed resistance or sensitivity to the toxic or mutagenic effects of other DNA-damaging agents. Cells were exposed to hmdUrd, ionizing or ultraviolet radiation, to the alkylating agent MNNG, and to oxidative stress produced by hypoxanthine/xanthine oxidase, glucose/glucose oxidase, nitric oxide donor SNAP, or to H2O2. The V79mut1 cells did not show increased mutagenesis in response to hmdUrd. Relative to the V79 parent cells, the V79mut1 cells were not markedly altered in sensitivity to oxidizing agents and ionizing radiation (which produce hmdUra in DNA). The repair-deficient cells wee equally sensitive as the parent V79 cells to DNA damage induced by ultraviolet radiation or by MNNG. No significant differences were seen between the parent and the repair-deficient cells in terms of synthesis of poly(ADP-ribose) in response to damage or in their sensitization to 3-aminobenzamide. Thus, the loss of the 5-hydroxymethyluracil (hmUra)-DNA glycosylase activity in mammalian cells in culture confers no obvious deleterious effect on cell survival or mutagenicity in response to a wide range of DNA damage. These studies indicate that the major lesion known to be repaired by hmUra-DNA glycosylase, an hmUra residue replacing thymine, is produced in cells only in small quantities as the result of exposure to common DNA-damaging agents. These results raise the possibility that hmUra-DNA glycosylase may have evolved to respond to other lesions than hmUra residues formed from the oxidation of thymine.
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PMID:Lack of phenotypic alteration of hmUra-DNA glycosylase-deficient hamster cells exposed to DNA-damaging agents. 910 Aug 52


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