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)

DNA adduct formation by enzyme-activated antibiotics, mitomycin C (MMC) or porfiromycin (PFM), at pH 7.6 or pH 6.0 under anaerobic conditions was analyzed by a 32P-postlabeling method. Antibiotic activation by rat liver NADPH-cytochrome P-450 reductase (EC 1.6.2.4) and bovine milk xanthine oxidase (EC 1.2.3.2) produced similar results. Five 32P-labeled MMC adducts were separated by thin layer chromatography and high performance liquid chromatography from DNA alkylated at either pH. Four of the radioactive spots separated by thin layer chromatography were identified as two monofunctional monoadducts [1" alpha and 1" beta forms of N2-(2" beta,7"-diaminomitosen-1"-yl)-2'-deoxyguanylic acid], one bifunctional monoadduct [N2-(10"-decarbamoyl-2",7"-diaminomitosen-1" alpha-yl)-2'-deoxyguanylic acid], and one cross-linked adduct [N2-(2" beta,7"-diamino-10"-deoxyguanyl-N2-yl-mitosen- 1" alpha-yl)-2'-deoxyguanylic acid]. One minor radioactive spot was not identified. By comparing DNA alkylated at the two pH values, based on equal amounts of 32P radioactivity, similar amounts of cross-links were detected. However, the DNA showed different ratios of the alpha and beta isomers of the monofunctional monoadduct. Furthermore, the DNA alkylated at pH 6.0 showed more bifunctional monoadducts than did the DNA alkylated at pH 7.6. Analysis of alkylated DNA by enzyme-activated PFM showed a similar spectrum of DNA adduct formation. The effect of pH on the distribution of the five PFM-DNA adducts was similar to that observed for the five MMC-DNA adducts. The distribution of adducts in DNA alkylated at the same pH was similar irrespective of which enzyme activated MMC or PFM. The pH of the reaction during DNA and MMC interaction was the determining factor for the quantitative distribution of the adducts. This pH effect may be important for the cytotoxicity of MMC and PFM in tumor cells that have high levels of reductive enzymes with low optimal pH values.
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PMID:Effect of pH on DNA alkylation by enzyme-activated mitomycin C and porfiromycin. 839 Nov 16

Active oxygen species are generated during pathophysiologic conditions such as inflammation and ionizing radiation exposure. We tested the hypothesis that an early cellular event in response to these species involves regulation of ion channels. We exposed cells to gamma-irradiation or treated them with hydrogen peroxide, xanthine/xanthine oxidase, or [3H]thymidine and then monitored channel activity by the technique of whole-cell voltage clamping. Recordings showed that both normal and tumor cells exhibit an increase in K+ currents after treatment with radiation, H2O2, and xanthine/xanthine oxidase but not with high specific activity [3H]thymidine, suggesting that the signal for K+ channel activation originates at the cell membrane. A single noncytotoxic dose of 10 cGy induced measurable levels of K+ currents, suggesting that the induction of currents regulates biochemical changes in response to stress. To test whether channel activity is sensitive to active oxygen species, we pretreated cells with N-acetyl-L-cysteine (NAC) to increase cellular pools of free radical scavengers before radiation. In NAC-pretreated cells, K+ channel activation by gamma-irradiation was abolished. It has previously been shown that protein kinase C (PKC) is activated by ionizing radiation and can regulate K+ channels in some cells. However, the effect of radiation on induction of K+ channel activity was independent of PKC, since cells chronically exposed to phorbol esters still produced K+ currents after radiation. These results suggest that an early cellular response to oxidative stress is the activation of K+ channels.
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PMID:Potassium-channel activation in response to low doses of gamma-irradiation involves reactive oxygen intermediates in nonexcitatory cells. 843 Jan 4

The non-12-O-tetadecanoylphorbol-13-acetate (TPA)-type tumor promoters, okadaic acid (OA) and calyculin-A (CAL-A), which neither interact with the phorbol ester receptor nor directly activate protein kinase C, mimic the stimulatory effects of and thapsigargin on hydroperoxide (HPx) production in mouse epidermis in vivo. The time course and dose dependency for the stimulation of HPx production by O and TPA are similar. HPx production is maximally stimulated 16 h after two applications of 2 nmol of OA at a 48-h interval. However CAL-A is a stimulator of HPx production about 4 times more potent than OA or TPA. Combinations of TPA and OA or CAL-A have subadditive effects on HPx production. The discrepancies between the abilities of various serine/threonine protein phosphatase (PP) inhibitors to stimulate HPx production suggest that PP inhibition alone is not sufficient for this response. Cycloheximide, Ca2+ antagonists, oxypurinol, diphenyliodonium, nordihydroguaiaretic acid, bromophenacyl bromide, antiinflammatory agents, and antihistamines block or decrease OA-stimulated HPx production. Although most of these inhibitors may have more than one action, their effects suggest that protein synthesis, Ca2+, xanthine oxidase and NADPH oxidase activities, the lipoxygenase pathway of arachidonic acid metabolism, and vascular permeability may be involved in the inflammatory and HPx responses that occur after tumor promoter treatment. The increased HPx-producing activity of the epidermis, therefore, may be a common event resulting from the inflammatory and tumor-promoting actions of diverse TPA- and non-TPA-type agents.
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PMID:Ability of okadaic acid and other protein phosphatase inhibitors to mimic the stimulatory effects of 12-O-tetradecanoylphorbol-13-acetate on hydroperoxide production in mouse epidermis in vivo. 855 15

In the present study, we investigated the effects of high levels of dietary fish oil on the growth of MX-1 human mammary carcinoma and its response to mitomycin C (MC) treatment in athymic mice. We found that high levels of dietary fish oil (20% menhaden oil + 5% corn oil, w/w) compared to a control diet (5% corn oil, w/w) not only lowered the tumor growth rate, but also increased the tumor response to MC treatment. We also found that high levels of dietary fish oil significantly increased the activities of tumor xanthine oxidase and DT-diaphorase, which are proposed to be involved in the bioreductive activation of MC. Since menhaden oil is highly unsaturated, its intake caused a significant increase in the degree of fatty acid unsaturation in tumor membrane phospholipids. This alteration in tumor membrane phospholipids made the tumor more susceptible to oxidative stress, as indicated by the increased levels of both endogenous lipid peroxidation and protein oxidation after feeding the host animals the menhaden oil diet. In addition, the tumor antioxidant enzyme activities, catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPOx), and glutathione S-transferase peroxidase (GSTPx), were all significantly enhanced by feeding a diet high in fish oil. MC treatment caused further increases in tumor lipid peroxidation and protein oxidation, as well as in the activities of CAT, SOD, GPOx, and GSTPx, suggesting that MC causes oxidative stress in this tumor model which is exacerbated by feeding a diet high in menhaden oil. Thus, feeding a diet rich in menhaden oil decreased the growth of human mammary carcinoma MX-1, increased its responsiveness to MC, and increased its susceptibility to endogenous and MC-induced oxidative stress, and increased the tumor activities of two enzymes proposed to be involved in the bioactivation of MC, that is, DT-diaphorase and xanthine oxidase. These findings support a role of these two enzymes in the bioactivating of MC and indicate that the type of dietary fat may be important in tumor response to therapy.
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PMID:Dietary menhaden oil enhances mitomycin C antitumor activity toward human mammary carcinoma MX-1. 856 32

Neoxanthin, a major carotenoid pigment of spinach, is found in the Chloroplast membrane and has an unknown function in plants. Neoxanthin inhibited the production of superoxide anions in an artificial xanthine and xanthine oxidase system and depressed DNA synthesis in methylcholanthrene (MCA)-initiated C3H10T1/2 fibroblasts. in two-stage carcinogenesis experiments, neoxanthin at 0.2 micrograms/0.2 ml inhibited the formation of tumors that were induced sequentially by 7,12-dimethylbenz[a]anthracene (DMBA) and 12-O-tetradecanoylphorbol-13-acetate (TPA) in the buccal pouch of Syrian Golden hamsters. To assess the ongoing process of carcinogenesis, the activity of ornithine decarboxylase (ODC), required for cell proliferation, was analyzed. Neoxanthin inhibited the activity of ODC when animals were treated with neoxanthin one hour before the application of TPA in two-stage carcinogenesis. However, neoxanthin did not inhibit ODC activity when animals were treated with neoxanthin one hour before the application of DMBA in two-stage carcinogenesis, and there was no subsequent tumor formation. In a short-term anti-initiation experiment, neoxanthin inhibited the covalent binding of isotope-labeled DMBA to DNA by 53%. These results indicate that neoxanthin inhibits the initiation stage and the promotion stage in two-stage carcinogenesis. This suggests that neoxanthin may act as a potential chemopreventive agent.
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PMID:The inhibition of DMBA-induced carcinogenesis by neoxanthin in hamster buccal pouch. 861 51

Cytotoxicity indicated by increased release of prelabeled 51chromium (51Cr) and lactate dehydrogenase (LDH) was studied in human prostate cancer and melanoma cells in cell culture following irradiation or exposure to several injurious substances. These changes were compared to those observed in bovine aortic endothelial cells (BAEC) subjected to identical treatments. Further, the effect of irradiation on plasminogen activator (PA) secretion from prostate cancer cells, and the effect of glycine on radiation-induced cytotoxicity in BAEC were also investigated. Radiation, lipopolysaccharide and xanthine/xanthine oxidase stimulated no release of 51Cr or LDH from tumor cells, while these treatments induced a dose- and time-related loss of those cytotoxic indicators from BAEC. Protease, elastase and Triton X-100 incited loss of 51Cr and LDH from all three cell types. Radiation, lipopolysaccharide and xanthine/xanthine oxidase have been shown to cause cell injury via a common pathogenic pathway of oxidant generation. Tumor cells appear quite resistant to oxidant stress. Cell damage precipitated by protease, elastase and Triton probably involves hydrolysis of proteins and phospholipids in the cell membrane, leading to an increased leakage of intracellular proteins such as LDH and those bound with 51Cr. Radiation caused a dose- and time-related reduction in the secretion of PA from prostate cancer cells. PA is alleged to play a role in tumor metastasis; the reduced secretion could be another beneficial effect of radiation, in addition to interruption of cell proliferation, in the impediment of tumor growth and spread. Glycine diminished cytotoxic injury of BAEC inflicted by radiation. This amino acid may prove useful in offering a degree of protection of normal tissue against radiation associated side-effects.
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PMID:Injury-specific cytotoxic response of tumor cells and endothelial cells. 868 34

O6-Benzylguanine is an effective inhibitor of the DNA repair protein, O6-alkylguanine-DNA alkyltransferase, and enhances the effectiveness of 1,3-bis(2-chloroethyl)-1-nitrosourea in cells in culture and animal tumor models. To prepare O6-benzylguanine for clinical trials and to determine the availability and disposition of O6-benzyl-7,8-dihydro-8-oxoguanine (O6-benzyl-8-oxoguanine), its major metabolite, pharmacokinetic parameters of these compounds were investigated in male Sprague-Dawley rats. Noncompartmental pharmacokinetic parameters were determined following intravenous administration of O6-benzylguanine or O6-benzyl-8-oxoguanine in rats. Half-life, clearance, and volume of distribution were respectively, 1.6 hr, 160 ml/hr/kg, and 405 ml/kg for O6-benzylguanine, and 1.2 hr, 312 ml/hr/kg, and 507 ml/kg for O6-benzyl-8-oxoguanine. At least 37% of O6-benzylguanine was converted to O6-benzyl-8-oxoguanine after administration of O6-benzylguanine. Renal excretion accounted for 8 and 62% of the administered O6-benzylguanine and O6-benzyl-8-oxoguanine, respectively. Administration of phenobarbital to rats before O6-benzylguanine resulted in a 17- to 19-fold increase in the amount of oxidized product in the urine. Kinetic constants, KM and Vmax were estimated as 19.6 microM and 0.02 nmol/min/mg protein and 13.4 microM and 0.96 nmol/min/mg protein, for uninduced and induced rat liver microsomes, respectively. The use of inhibitors of cytosolic enzymes, xanthine oxidase, and aldehyde oxidase indicated that aldehyde oxidase is primarily involved in the cytosolic oxidation of O6-benzylguanine.
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PMID:Pharmacokinetics of O6-benzylguanine in rats and its metabolism by rat liver microsomes. 868 50

Reactive oxygen species (ROS) are produced and released into the extracellular spaces in numerous diseases and contribute to development and progression, for example, of inflammatory diseases, proteinuria, and tumor invasion. However, little is known about ROS-induced chemical changes of interstitial matrix proteins and their consequences for the integrity of the matrix meshwork. As basement membranes and other matrices are highly cross-linked and complex, the relatively simple matrix produced by Engelbreth-Holm-Swarm (EHS) sarcoma, and proteins isolated therefrom, were incubated in vitro with defined concentrations of ROS that were generated by the Fenton or xanthine oxidase/xanthine reactions. This resulted in two counter-current effects. Although up to approximately 15% of the EHS matrix proteins were released into the supernatant in a ROS dose-response relationship, the residual insoluble matrix was partially cross-linked by ROS. Matrix proteins released into the supernatants were examined by rotary shadowing, quantitative sodium dodecyl sulfate polyacrylamide gel electrophoresis, immunoblotting, and fluorospectrometry for loss of tryptophans and formation of bityrosine residues. At relatively low ROS concentrations, selective liberation of morphologically intact laminin/entactin was found that, however, failed to reassociate and showed oxidative damage of its tryptophan residues. At higher ROS concentrations, laminin and entactin were progressively disintegrated, partially fragmented, and eventually completely degraded. At this point oligomers of type IV collagen predominated in the supernatant, and proteoglycans were not encountered at any concentration of ROS. Similar gradual molecular changes were also obtained when fractions of isolated soluble EHS matrix proteins were incubated with graded concentrations of ROS. In these experiments, the formation of covalently linked oligomers and aggregates paralleled the ROS-dependent formation of cross-linking bityrosine groups. ROS scavengers pinpointed to the hydroxyl radical as the most damaging radical species. Protease inhibitor experiments suggested that degradation of matrix proteins was caused primarily by the direct action of ROS and not by proteolysis by potentially contaminating proteases. Collectively, these results provide evidence that EHS matrix proteins show differential sensitivity to ROS-induced damage in a reproducible, sequential pattern, in the order entactin > laminin > type IV collagen, and that ROS cause partial dissociation and cross-linking of the EHS matrix.
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PMID:Reactive oxygen species cause direct damage of Engelbreth-Holm-Swarm matrix. 921 47

The role of enzymes in the reductive activation of various chemotherapeutic agents is an area of considerable interest in studies to better understand the selective toxicities of these agents. Xanthine dehydrogenase (XDH) is an enzyme capable of reductive activation of chemotherapeutic agents. Previously, this enzyme has not been extensively studied because of difficulties in its isolation. We recently isolated this enzyme from EMT6 mouse mammary carcinoma cells and showed that this enzyme is capable of activating mitomycin C. In this study, we examined whether XDH could activate the clinically important antineoplastic agent, doxorubicin. Drug activation was determined under aerobic and hypoxic conditions and at various pHs in order to simulate the different environments found in solid tumors. The results of these studies show that XDH reacts with doxorubicin via a two-electron reduction. This reduction is different from the modified and more extensively studied form of the enzyme, xanthine oxidase (XO), which reacts with doxorubicin via a one-electron reduction. Under hypoxic conditions, the formation of large quantities of 7-deoxydoxorubicin aglycone, a deactivation product of doxorubicin metabolism, may serve to moderate doxorubicin's antineoplastic activity. Under aerobic conditions, however, XDH activation led to a greater rate of formation of oxygen radicals than XO thereby possibly potentiating doxorubicin's cytotoxicity to aerobic tumor cells. Kinetic constants were determined for doxorubicin activation by XDH.
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PMID:Reductive activation of doxorubicin by xanthine dehydrogenase from EMT6 mouse mammary carcinoma tumors. 921 77

The reaction of the antitumor drugs adriamycin and daunomycin with the self-complementary DNA oligonucleotide (GC)4 to generate DNA-drug adducts was investigated as a function of redox reaction conditions. The redox systems dithiothreitol (DTT)/Fe(III) and xanthine oxidase/ NADH both gave the same distribution of four DNA-anthracycline adducts. In each of these adducts the anthracycline is bonded via a methylene linkage between the 3'-amino group of the drug and the 2-amino group of a deoxyguanosine of the DNA. The methylene linkage results from reaction of the drug and DNA with in situ-generated formaldehyde via Schiff base chemistry [Taatjes, D.J., Gaudiano, G., Resing, K., and Koch, T.H. (1997) J. Med. Chem. 40, 1276-1286]. Formaldehyde production is promoted by iron, inhibited by metal-chelating agents, and does not require drug. Iron enhances formaldehyde production by a factor of 30, EDTA inhibits its formation by a factor of 2, and Desferal inhibits its formation by a factor of more than 20. Hydrogen peroxide accumulates in significant quantities only with xanthine oxidase/NADH in the presence of Desferal. The results are explained in terms of Fenton oxidation of Tris buffer to formaldehyde. Biological reagents also cause DNA-drug adduct formation; reduction of ferric ion with glutathione in phosphate buffer in the presence of spermine produced the same DNA-drug adducts. The observations are discussed in terms of cytotoxicity resulting from iron chelated to adriamycin catalyzing in vivo production of formaldehyde which links adriamycin to DNA and tumor cell resistance resulting from factors which decrease formaldehyde.
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PMID:Production of formaldehyde and DNA-adriamycin or DNA-daunomycin adducts, initiated through redox chemistry of dithiothreitol/iron, xanthine oxidase/NADH/iron, or glutathione/iron. 930 76


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