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)

1. Enzyme systems responsible for formation of cyclopropane ring-cleavage metabolites (M1 and M2) of illudin S in rat liver were characterized. 2. The enzymes were localized in the cytosol fraction and utilized NADPH alone as electron donor; they were not affected by oxygen and had low pH optima. 3. Formation of metabolites M1 and M2 was inhibited completely by dicumarol (10(-4) M), an inhibitor of DT-diaphorase. 4. Menadione (10(-4) M) and quercetin (10(-4) M) both inhibited formation of M1 and M2 by 35% and 15%, respectively, but quinacrine, barbital, pyrazole and p-chloromercuribenzoic acid had no significant effect. 5. Results show that the enzyme systems may differ from DT-diaphorase, aldehyde oxidase, xanthine oxidase, ketone reductase, aldose reductase, aldehyde reductase and alcohol dehydrogenase, known cytosolic enzymes responsible for xenobiotic metabolism.
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PMID:Metabolism by rat liver cytosol of illudin S, a toxic substance of Lampteromyces japonicus. II. Characterization of illudin S-metabolizing enzyme. 137 39

Vitamin K3 (menadione), a synthetic vitamin K congener, inhibits the growth of tumor cells. Here, we examined possible effects of vitamin K3 on phospholipase D (PLD) activity, an enzyme which produces growth regulatory substances. In NIH 3T3 fibroblasts, vitamin K3 (50-100 microM) alone had no effect on PLD-catalyzed formation of phosphatidylethanol, a marker of PLD activity, but it slightly (10-21%) inhibited the stimulatory effect of phorbol 12-myristate 13-acetate (PMA), an activator of protein kinase C (PKC). Of the two major substrates of PLD, phosphatidylcholine (PtdCho) and phosphatidylethanolamine (PtdEtn), vitamin K3 (10-100 microM) preferentially inhibited PtdEtn hydrolysis when stimulated by PMA or platelet-derived growth factor, the latter being a hormonal activator of PKC. Vitamin K3 had no inhibitory effect on sphingosine- or staurosporine-induced hydrolysis of PtdEtn or PtdCho. Inhibition of PMA-induced PtdEtn hydrolysis by vitamin K3 was effectively reduced by both cysteine (1 mM) and reduced glutathione (1 mM) and was mimicked by the superoxide-generating xanthine/xanthine oxidase system. The results show that vitamin K3 preferentially inhibits the effects of PKC activators on PLD-mediated hydrolysis of PtdEtn by a mechanism which may involve oxidation of thiols in a critically important regulatory component.
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PMID:Vitamin K3 preferentially inhibits stimulation of phospholipase D-mediated hydrolysis of phosphatidylethanolamine by protein kinase C activators in NIH 3T3 fibroblasts. 794 97

Reactive oxygen metabolites have been associated with gastrointestinal injury and may play a role as mediators of inflammation. The effect of oxygen metabolites on Caco-2 cell viability (trypan blue exclusion and 51Cr release), hexose monophosphate shunt activity, and glutathione was assessed. Caco-2 cells were incubated with amino acid oxidase, xanthine oxidase, menadione, and t-butylhydroperoxide in the presence and absence of superoxide dismutase, catalase, mannitol, and butylated hydroxytoluene. With amino acid oxidase, trypan blue exclusion decreased (P < 0.01) and 51Cr release, oxidized glutathione, and shunt activity increased (P < 0.05). The addition of catalase attenuated these changes. Trypan blue exclusion decreased (P < 0.005) and 51Cr release, oxidized glutathione, and shunt activity increased (P < 0.01) with xanthine oxidase. The addition of superoxide dismutase caused a further increase in 51Cr release, oxidized glutathione, and shunt activity (P < 0.01), which was prevented by the addition of catalase or mannitol. t-Butylhydroperoxide did not effect 51Cr release or trypan blue exclusion, but oxidized glutathione and shunt activity increased (P < 0.01). The increase in shunt activity was prevented by preincubation with butylated hydroxytoluene (P < 0.01). Menadione did not alter trypan blue exclusion or 51Cr release, but caused an increase in oxidized glutathione and shunt activity (P < 0.001). The increase in shunt activity was attenuated by preincubation with butylated hydroxytoluene (P < 0.001). Menadione also caused a depletion of total glutathione.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Caco-2 cell metabolism of oxygen-derived radicals. 826 33

We studied the regulation of GSH and the enzymes involved in GSH regulation, gamma-glutamylcysteine synthetase (gamma-GCS) and gamma-glutamyl transpeptidase (gamma-GT), in response to the oxidants menadione, xanthine/xanthine oxidase, hyperoxia, and cigarette smoke condensate in human alveolar epithelial cells (A549). Menadione (100 microM), xanthine/xanthine oxidase (50 microM/10 mU), and cigarette smoke condensate (10%) exposure produced increased GSH levels (240 +/- 6, 202 +/- 12, and 191 +/- 2 nmol/mg protein, respectively; P < 0.001) compared with the control level (132 +/- 8 nmol/mg protein), which were associated with a significant increase in gamma-GCS activity (0.18 +/- 0.006, 0.16 +/- 0.01, and 0.17 +/- 0. 008 U/mg protein, respectively; P < 0.01) compared with the control level (0.08 +/- 0.001 U/mg protein) at 24 h. Exposure to hyperoxia (95% O2) resulted in a time-dependent increase in GSH levels. gamma-GCS activity increased significantly at 4 h (P < 0.001), returning to control values after 12 h of exposure. Dexamethasone (3 microM) exposure produced a significant time-dependent decrease in the levels of GSH and gamma-GCS activity at 24-96 h. The activity of gamma-GT did not change after oxidant treatment; however, it was decreased significantly by dexamethasone at 24-96 h. Thus oxidants and dexamethasone modulate GSH levels and activities of gamma-GT and gamma-GCS by different mechanisms. We suggest that the increase in gamma-GCS activity but not in gamma-GT activity may be required for the increase in intracellular GSH under oxidative stress in alveolar epithelial cells.
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PMID:Differential regulation of glutathione by oxidants and dexamethasone in alveolar epithelial cells. 968 38

Methotrexate (MTX) was investigated for possible effect on the metabolism of ethoxyresorufin, pentoxyresorufin and ethoxycoumarin, the model substrates of cytochrome P450. The investigation was carried out in liver microsomes of rats pretreated with classical inducers of cytochrome P450 as well as in microsomes of two human livers. Furthermore, we measured the conversion of MTX (100microM) to its main metabolite, 7-hydroxymethotrexate (7-OHMTX), in microsomes and cytosolic fractions of rat and human livers. The inhibition of 7-OHMTX formation by menadion (inhibitor of aldehyde oxidase) and allopurinol (inhibitor of xanthine oxidase) was studied in the cytosol of rat and human livers. In both species, MTX in the concentration range 0.5-500 microM exerted no inhibitory effect on enzymatic activities associated with cytochrome P450. Moreover, we did not observe any measurable formation of 7-OHMTX in liver microsomes. MTX was metabolized at a similar rate in the cytosol of rat and human liver. Allopurinol (100 microM) reduced the rate of MTX hydroxylation by 31.5% in the cytosol of human livers but had no effect in the rat. Menadion (100 microM) decreased the rate of 7-OHMTX formation in the cytosol of human and rat liver by 69% and 94%, respectively. Our results confirmed that MTX is oxidized by a soluble enzymatic system in both the rat and human liver. In human tissues, both aldehyde oxidase and xanthine oxidase may play an important role in the metabolism of MTX. Depression of cytochrome P450 and related enzymatic activities observed in vivo cannot be explained by a direct inhibitory action of MTX on cytochrome P450.
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PMID:An in vitro study on methotrexate hydroxylation in rat and human liver. 972 83

Cytotoxic activity of 9 polyprenylalcohols and 6 vitamin K2 derivatives (MK-1 to MK-6) with various lengths of prenyl units was investigated. Among these compounds, geranylgeraniol with 4 prenyl units, and MK-2 with 2 prenyl units, showed the highest cytotoxic activity against human oral tumor cell lines (HSC-2, HSG), without induction of internucleosomal DNA fragmentation. Higher molecular weight compounds showed selective cytotoxicity against tumor cell lines than normal human gingival fibroblasts HGF. ESR spectroscopy showed that all polyprenylalcohols did not produce radical, nor scavenged O2- generated by hypoxanthine and xanthine oxidase reaction, and only slightly enhanced the radical intensity of sodium ascorbate. Vitamin K2 derivatives scavenged O2- more efficiently, but did not produce radical (except MK-3) and only slightly modified the ascorbate radical intensity. Cytotoxic activity of these compounds might be affected by the molecular weight, hydrophobicity, van der Waals area and stabilization of hydration of the molecule.
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PMID:Cytotoxic activity of polyprenylalcohols and vitamin K2 derivatives. 1120 63

Mitochondrial (mt) DNA is damaged by free radicals. Recent data also show that there are cell type-dependent differences in mtDNA repair capacity. In this study, we explored the effects of xanthine oxidase (XO), which generates superoxide anion directly, and menadione, which enhances superoxide production within mitochondria, on mtDNA in pulmonary arterial (PA), microvascular (MV), and pulmonary venous (PV) endothelial cells (ECs). Both XO and menadione damaged mtDNA in the EC phenotypes, with a rank order of sensitivity of (from most to least) PV > PA > MV for XO and MV = PV > PA for menadione. Dimethylthiourea and deferoxamine blunted menadione- and XO-induced mtDNA damage, thus supporting a role for the iron-catalyzed formation of hydroxyl radical. Damage to the nuclear vascular endothelial growth factor gene was not detected with either XO or menadione. PAECs and MVECs, but not PVECs, repaired XO-induced mtDNA damage quickly. Menadione-induced mtDNA damage was avidly repaired in MVECs and PVECs, whereas repair in PAECs was slower. Analysis of mtDNA lesions at nucleotide resolution showed that damage patterns were similar between EC phenotypes, but there were disparities between XO and menadione in terms of the specific nucleotides damaged. These findings indicate that mtDNA in lung vascular ECs is damaged by XO- and menadione-derived free radicals and suggest that mtDNA damage and repair capacities differ between EC phenotypes.
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PMID:Oxygen radical-induced mitochondrial DNA damage and repair in pulmonary vascular endothelial cell phenotypes. 1135 Aug 11

Vitamin K1, K2 and K3 were compared for their cytotoxic activity, radical generation and O2- scavenging activity. Among these compounds, vitamin K3 showed the highest cytotoxic activity against human oral tumor cell lines (HSC-2, HSG), human promyelocytic leukemic cell line (HL-60) and human gingival fibroblast (HGF). Vitamin K3 induced internucleosomal DNA fragmentation in HL-60 cells, but not in HSC-2 or HSG cells. The cytotoxic activity of vitamins K2 and K1 was one and two orders lower, respectively, than K3. Vitamin K2, but not vitamin K3, showed tumor-specific cytotoxic action. ESR spectroscopy showed that only vitamin K3 produced radical(s) under alkaline condition and most potently enhanced the radical intensity of sodium ascorbate and scavenged O2- (generated by hypoxanthine-xanthine oxidase reaction system); vitamin K2 was much less active whereas vitamin K1 was inactive. These data suggest that the cytotoxic activity of vitamin K3 is generated by radical-mediated oxidation mechanism and that this vitamin has two opposing actions (that is, antioxidant and prooxidant), depending on the experimental conditions.
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PMID:Cytotoxic activity of vitamins K1, K2 and K3 against human oral tumor cell lines. 1172 97

During myocardial ischemia and the subsequent reperfusion, free radicals are important intermediates of the cellular damage and rhythm disturbances. We examined the effects of superoxide radicals or hydrogen peroxide (H(2)O(2)) on the action potentials in isolated rabbit Purkinje fibers, atrial muscle and ventricular muscle. Reactive oxygen species (ROS) donors such as adriamycin, xanthine/xanthine oxidase and menadione induced prolongation of APD(90) in Purkinje fibers. Menadione (30 microM), the most specific superoxide radical donor, prolonged the action potential duration at 90% repolarization (APD(90)) by 17% in Purkinje fibers, whereas it shortened the APD by 57% in ventricular muscle, and it did not affect the atrial APD. All these menadione-induced effects were completely blocked by 2,2,6,6-tetramethyl- 1-peperadinyloxy, a superoxide radical scavenger. Superoxide dismutase (SOD) activity was lowest in Purkinje fibers, it was moderate in atrial muscle and highest in ventricular muscle. H(2)O(2) shortened the APDs of all three cardiac tissues in a concentration-dependent manner. These results suggest that the different electrical responses to O(2) ([Symbol: see text]-) in different cardiac regions may result from the regional differences in the SOD activity, thereby enhancing the regional electrical heterogeneity.
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PMID:Regional differences of superoxide dismutase activity enhance the superoxide-induced electrical heterogeneity in rabbit hearts. 1587 Sep 56

The use of frozen semen in the swine industry is limited by problems with viability and fertility compared with liquid semen. Part of the reduction in sperm motility and fertility associated with cryopreservation may be due to oxidative damage from excessive or inappropriate formation of reactive oxygen species (ROS). Chemiluminescence measurements of ROS are not possible in live cells and are problematic because of poor specificity. An alternative approach, flow cytometry, was developed to identify viable boar sperm containing ROS utilizing the dyes hydroethidine and 2', 7'-dichlorodihydrofluorescein diacetate as oxidizable substrates and impermeant DNA dyes to exclude dead sperm. The percentage of sperm with high mitochondrial transmembrane potential was determined by flow cytometry using the mitochondrial probe 5, 5', 6, 6'-tetrachloro-1, 1', 3, 3'-tetraethylbenzimidazolylcarbocyanine iodide with propidium iodide staining to exclude nonviable cells. Sperm were incubated with and without ROS generators and free radical scavengers. Basal ROS formation was low (less than 4%) and did not differ (P = 0.26) between viable fresh and frozen-thawed boar sperm. In addition, fresh and frozen-thawed viable sperm were equally susceptible (P = 0.20) to intracellular formation of ROS produced by xanthine/xanthine oxidase (94.4 and 87.9% of sperm, respectively). Menadione increased (P < 0.05) ROS formation, decreased (P < 0.05) JC-1-aggregate fluorescence intensity, and decreased (P < 0.05) motion variables by 25 to 60%. The mechanism of inhibition of motility by ROS formation may be related to a decrease in mitochondrial charge potential below a critical threshold. Catalase and superoxide dismutase treatment in the presence of xanthine/xanthine oxidase indicated that hydrogen peroxide was the primary intracellular ROS measured. Further, catalase, but not superoxide dismutase, was capable of attenuating ROS-induced inhibition of motility. Whereas basal intracellular hydrogen peroxide formation was low in viable fresh and frozen-thawed boar sperm, both were quite susceptible to external sources of hydrogen peroxide.
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PMID:Determination of intracellular reactive oxygen species and high mitochondrial membrane potential in Percoll-treated viable boar sperm using fluorescence-activated flow cytometry. 1686 69


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