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)

To evaluate the regulation of endothelial cell Cu,Zn-SOD, we have exposed bovine pulmonary artery endothelial cells in culture to hyperoxia and hypoxia, second messengers or related agonists, hormones, free radical generating systems, endotoxin, and cytokines and have measured Cu,Zn-SOD protein of these cells by an ELISA developed in our laboratory. Control preconfluent and confluent cells in room air contained 196 +/- 18 ng Cu,Zn-SOD/10(6) cells. A23187 (0.33 microM), forskolin (10 microM), isobutylmethylxanthine (0.1 mM), dexamethasone (1 microM), triiodothyronine (1 microM) and retinoic acid (1 microM) failed to alter this level of Cu,Zn-SOD. Exposure to anoxia and hyperoxia both elevated the level approximately 1.5-2.0-fold over 20% oxygen-exposed controls at 48-72 hr. Similarly, exposures to glucose oxidase (0.0075 units/ml), menadione (12.5 microM), xanthine-xanthine oxidase (10 microM, 0.03 units/ml) and H2O2 (0.0005%) increased the level up to two-threefold over controls at 24-48 hr. Lipopolysaccharide, TGF beta 1, TNF alpha, and Il-1 also increased levels of cellular Cu,Zn-SOD, but only in proliferating cells. Il-2, Il-4, interferon-gamma, and GM-CSF had no effect on Cu,Zn-SOD. All treatments that elevated SOD resulted in inhibition of cellular growth, but decreased growth of cells at confluence alone was not associated with increased Cu,Zn-SOD. We propose from these studies that Cu,Zn-SOD of endothelial cells is not under conventional second messenger or hormonal regulation, but that up-regulation of the enzyme is associated with (and perhaps stimulated by) free-radical or oxidant production that also may be influenced by availability of certain cytokines under replicating conditions.
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PMID:Regulation of Cu,Zn-superoxide dismutase in bovine pulmonary artery endothelial cells. 133 80

We examined the effects of tumor necrosis factor-alpha (TNF alpha) stimulation of endothelial cells on the increase in endothelial permeability induced by H2O2. Bovine pulmonary microvascular endothelial cells (BPMVEC) were grown to confluence on a microporous filter and the 125I-albumin clearance rate across the monolayer was determined. Pretreatment with TNF alpha (100 U/ml) for 6 h had no direct effect on transendothelial 125I-albumin permeability. However, TNF alpha pretreatment enhanced the susceptibility of BPMVEC to H2O2; that is, H2O2 (10 microM) alone had no direct effect, whereas H2O2 increased 125I-albumin permeability more than threefold when added to monolayers pretreated for 6 h with TNF alpha. Determination of lactate dehydrogenase release indicated that increased permeability was not due to cytolysis. We measured the intracellular contents of GSH and catalase to determine their possible role in mediating the increased susceptibility to H2O2. TNF alpha treatment (100 U/ml for 6 h) decreased total GSH content and concomitantly increased the oxidized GSH content, but did not alter the cellular catalase activity. The role of GSH was examined by pretreating endothelial cells with 2 mM GSH for 3 h, which produced an 80% increase in intracellular GSH content. GSH repletion inhibited the increased sensitivity of the TNF alpha-treated endothelial cells to H2O2. We tested the effects of xanthine oxidase (XO) inhibition since XO activation may be a source of oxidants responsible for the decrease in cellular GSH content. Pretreatment with 0.5 mM oxypurinol attenuated the synergistic effect of TNF alpha and H2O2 on endothelial permeability. The results indicate that decreased oxidant buffering capacity secondary to TNF alpha-induced reduction in intracellular GSH content mediates the increased susceptibility of endothelial cells to H2O2. This mechanism may contribute to oxidant-dependent vascular endothelial injury in septicemia associated with TNF alpha release.
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PMID:Tumor necrosis factor-alpha-mediated decrease in glutathione increases the sensitivity of pulmonary vascular endothelial cells to H2O2. 154 73

Exposure to recombinant human tumor necrosis factor-alpha (TNF-alpha) or calcium ionophore (A23187) for 4 h increased (P less than 0.05) lactate dehydrogenase (LDH) release from cultured bovine brain endothelial cells (EC). In contrast, treatment with endotoxin or interleukin-1 did not increase (P greater than 0.05). LDH release from brain EC. Pretreatment with tungsten decreased (P less than 0.05) xanthine oxidase activity in brain EC and decreased (P less than 0.05) LDH release from brain EC following exposure to TNF. Our results suggest that TNF-alpha injures brain microvascular EC and that this effect may be mediated by xanthine oxidase.
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PMID:Tungsten treatment prevents tumor necrosis factor-induced injury of brain endothelial cells. 154 79

Pretreatment with the reactive oxygen species scavengers superoxide dismutase (SOD) and catalase or with the xanthine oxidase inhibitor allopurinol protected mice against hepatitis induced by the combined administration of lipopolysaccharide (endotoxin) and D-galactosamine. In the sera of protected animals no tumor necrosis factor (TNF alpha) was detectable in contrast to abundant amounts in the sera of injured control animals. A similar protection by the suppression of systemic TNF alpha was observed following the pretreatment of mice with polystyrene-coupled SOD prior to endotoxic challenge. Both pretreatments were ineffective when hepatitis was evoked by administration of the mediator TNF alpha instead of endotoxin. These findings indicate that the formation of extracellular reactive oxygen species is a condition needed to induce the release of TNF alpha and thus to mediate endotoxin-induced toxicity.
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PMID:A link between extracellular reactive oxygen and endotoxin-induced release of tumour necrosis factor alpha in vivo. 155 88

Interactions between rat pulmonary artery endothelial cells and hydrogen peroxide or toxic oxygen products from phorbol ester-activated human neutrophils result in endothelial cell killing defined by 51Cr release. It has been shown that this cytotoxic reaction can be blocked by the presence of catalase, iron chelators, or scavengers of the hydroxyl radical. Evidence shows that products from xanthine oxidase of endothelial cells are necessary for the toxic effects of hydrogen peroxide or phorbol ester-activated neutrophils. Addition of xanthine oxidase inhibitors protects against phorbol ester-mediated injury of endothelial cells. Preloading of endothelial cells with superoxide dismutase attenuates injury caused either by hydrogen peroxide or phorbol ester-activated neutrophils. Conversion of xanthine dehydrogenase to xanthine oxidase in endothelial cells occurs during contact of endothelial cells by activated neutrophils. This conversion is not related to oxygen products of neutrophils. Conversion of xanthine dehydrogenase to xanthine oxidase in endothelial cells is also induced by endothelial cell contact with C5a, N'-formyl-methionyl-leucyl-phenylalanine (fMLP), or tumor necrosis factor alpha (TNF alpha). Interaction of hydrogen peroxide with endothelial cells rapidly depletes adenosine triphosphate (ATP) and causes the extracellular appearance of xanthine and hypoxanthine. Agents that protect endothelial cells from the toxic effects of hydrogen peroxide do not prevent falls in cellular ATP caused by hydrogen peroxide, indicating that ATP levels do not necessarily correlate with cytotoxic events. A synergy between hydrogen peroxide and proteases in endothelial cell killing has been demonstrated. TNF alpha causes alterations in endothelial cells, the result of which is increased susceptibility to killing by PMA-activated neutrophils.
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PMID:Mechanisms of endothelial cell killing by H2O2 or products of activated neutrophils. 192 18

Activated human neutrophils (PMN) degrade rTNF-alpha resulting in a loss of cytotoxic activity against murine L-929 cells (L cells). This inactivation is mediated through proteases released from activated PMN. Exposure of TNF to H2O2, glucose oxidase, xanthine oxidase, or myeloper-oxidase-H2O2-halide did not affect TNF cytotoxicity for L cells. Exposure to trypsin, chymotrypsin, pronase E, or elastase, however, did diminish TNF bioactivity. FMLP-stimulated PMN in the presence, but not in the absence, of cytochalasin B reduced TNF activity, whereas PMA-stimulated PMN did not affect TNF. Stimulation of PMN with opsonized bacteria also induced TNF inactivation as well as the supernatant of FMLP-stimulated cells. Addition of protease inhibitors to the FMLP-stimulated cytochalasin B-treated PMN abrogated the inactivation of TNF cytotoxicity for L cells, whereas scavengers were not protective. In addition, PMN from a chronic granulomatous disease patient also decreased TNF bioactivity. Inactivation of TNF by activated PMN correlated with granule release and not with superoxide production. Exposure of TNF to proteases and FMLP-activated PMN also resulted in a loss of reactivity with anti-TNF antibodies, as measured by ELISA, and in the formation of an approximately 10-kDa split product from the 17-kDa rTNF molecule. Partial degradation of TNF by proteases released from activated PMN may result in a diminished TNF bioactivity and thereby contribute to the regulation of local inflammatory reactions.
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PMID:Inactivation of recombinant human tumor necrosis factor-alpha by proteolytic enzymes released from stimulated human neutrophils. 194 Mar 72

Regulation of induced nitric oxide synthase in rat hepatocyte primary cultures was explored. Nitric oxide synthase (NOS) induction by tumor necrosis factor-alpha (TNF alpha) is synergized by interferon-gamma, and both NOS activity and gene expression are maximal by 10 h and maintained through 24 h. Glutathione depletion by diethylmaleate, which conjugates reduced glutathione, 1,3-bis(chloroethyl)-1-nitrosourea (BCNU), a glutathione reductase inhibitor, or buthionine sulfoxamine, a glutathione synthesis inhibitor, abolishes or reduces NOS induction in TNF alpha-treated hepatocytes, whereas N-acetylcysteine has little effect. Thus, reduced glutathione is critical to NOS mRNA induction and activity in TNF alpha-treated hepatocytes. NOS induction in TNF alpha-treated cells is reduced by rotenone, a mitochondrial complex 1 inhibitor. Concurrent treatment with TNF alpha and the antioxidant, Trolox, or the iron-chelating agent, desferrioxamine, also reduces NOS activity. Dithiothreitol, a thiol antioxidant, reduced TNF alpha induction of NOS. Trolox and BCNU, combined, blocked TNF alpha stimulation of NOS greater than either agent alone. These results suggest that TNF alpha increases mitochondrial production of reactive oxygen intermediates (ROI), which contributes to NOS induction. Hepatocytes exposed to extracellular ROI generation through a xanthine/xanthine oxidase superoxide-generating system expressed increased NOS activity and mRNA levels. NOS induction by superoxide also requires reduced glutathione since diethylmaleate blocks induction by xanthine/xanthine oxidase while N-acetylcysteine elevates NOS expression. Thus, the generation of ROI by cytokines or other physiological processes stimulates the induction of NOS and this process is regulated by cellular levels of reduced glutathione.
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PMID:Regulation of hepatic nitric oxide synthase by reactive oxygen intermediates and glutathione. 753 84

Cellular signalling by the inflammatory cytokine tumour necrosis factor alpha (TNF alpha) has been suggested to involve generation of low levels of reactive oxygen species (ROS). Certain antioxidants and metal chelators can inhibit cytotoxicity and gene expression in response to TNF alpha in numerous cell types. However, neither the source nor function of TNF alpha-induced oxidant generation is known. Using specific inhibitors, we ruled out involvement of several oxidant-generating enzymes [cyclo-oxygenase (indomethacin), cytochrome P-450 (metyrapone), nitric oxide synthase (NG-methyl-L-arginine), NADPH oxidase (iodonium diphenyl), xanthine oxidase (allopurinol), ribonucleotide reductase (hydroxyurea)] in TNF alpha-mediated apoptosis of the murine fibrosarcoma line, L929. We also demonstrated no role for mitochondrial-derived radicals/respiratory chain in the lytic pathway using specific inhibitors/uncouplers (rotenone, KCN, carboxin, fluoroacetate, antimycin, malonate, carbonyl cyanide p-trifluoromethoxyphenylhydrazone) and chloramphenicol-derived respiration-deficient cells. Significant ROS (H2O2, O2-.) generation was not observed in response to TNF alpha in L929 cells using four separate assays. Also, prevention of intracellular H2O2 removal by inhibition of catalase did not potentiate TNF alpha-mediated cell death. These data suggest that neither H2O2 nor O2-. plays a direct role in TNF alpha cytotoxicity. Finally, we suggest a central role for lipoxygenase in TNF alpha-mediated lysis. Three inhibitors of this radical-generating signalling pathway, including an arachidonate analogue (5,8,11,14-eicosatetraynoic acid), could protect cells against TNF alpha. The inhibitor nordihydroguaiaretic acid is also a radical scavenger, but it could not protect cells from ROS toxicity at concentrations that effectively prevented TNF alpha killing. Therefore protection by nordihydroguaiaretic acid cannot be due to scavenging of cytotoxic H2O or O2-.. The lipoxygenase product, (12S)-hydroxyeicosatetraenoic acid, was also significantly protective. As this analogue can act as a substrate for certain lipoxygenases, this effect may be due to prevention of generation of physiological products.
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PMID:Involvement of oxidants and oxidant-generating enzyme(s) in tumour-necrosis-factor-alpha-mediated apoptosis: role for lipoxygenase pathway but not mitochondrial respiratory chain. 764 35

Using the human erythroleukaemic cell line K562 cl.6 and its daunorubicin-resistant subline K/DAU600, and the human T-lymphoblastic leukaemic cell line CCRF-CEM and its vinblastine-resistant subline CEM/VLB100, we have shown that the drug-resistant cell lines were more sensitive to cytotoxicity induced by tumour necrosis factor-alpha (TNF alpha). Drug-resistant cell lines showed increased activities of copper/zinc superoxide dismutase (Cu/ZnSOD) and catalase compared with their parental drug-sensitive cell lines. However, the greater susceptibility of drug-resistant cells to TNF alpha cytotoxicity was, in part, related to their decreased activities of manganese superoxide dismutase (MnSOD). Persistence of this differential sensitivity when MnSOD is inhibited by sodium nitroprusside (SNP) suggests that the greater susceptibility of drug-resistant cells to TNF alpha was not entirely due to their decreased level of MnSOD activity. K562 cl.6 and K/DAU600, which were more resistant to TNF alpha, both expressed greater levels of endogenous plasma membrane-bound TNF alpha than the CCRF-CEM cell line. All cell lines examined were (more or less) equal in susceptibility to the cytolytic effect of exogenous O2-. generated by xanthine/xanthine oxidase. These results demonstrate that both MnSOD and endogenous TNF alpha play a role in protecting leukaemic cells against TNF alpha cytotoxicity, but there is an unknown mechanism that causes drug-resistant cells to be more susceptible to TNF alpha cytotoxicity.
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PMID:TNF-mediated killing of human leukaemic cells: effects of endogenous antioxidant levels and TNF alpha expression in leukaemic cell lines. 770 80

In the present study we have examined the potential role of xanthine oxidase (XO) in the intracellular oxidative stress induced by combinations of recombinant murine TNF alpha (rMuTNF alpha) and murine interferon-gamma (IFN gamma) in cultured mouse hepatocytes. IFN gamma alone and the combination of rMuTNF alpha and IFN gamma increased XO activity after a 4 hr exposure period. rMuTNF alpha alone increased XO activity only after 24 hr. At the later time point, the increased XO activity was accounted for by decreased XDH activity. However, the apparent conversion of XDH to XO cannot account for the early effects of rMuTNF alpha on hepatocyte function, particularly the onset of an oxidative stress (as indicated by efflux of GSSG from the hepatocytes). This effect is observed after two hours, and it is temporally the earliest sign of alteration of cellular function caused by rMuTNF alpha. Increased XO activity was not observed until 4 hr after treatment with rMuTNF alpha/IFN gamma. In addition, inhibition of XO activity with allopurinol did not ameliorate GSSG efflux from hepatocytes treated with the cytokines. However, the ATP depletion caused by the combination of rMuTNF alpha and IFN gamma and the cytotoxicity observed with the combined cytokines in cells pre-treated with BCNU (to inhibit glutathione reductase) was inhibited by allopurinol. These results show that the onset of oxidative stress in cultured mouse hepatocytes is not due to conversion of XDH to XO. However, events which follow the efflux of GSSG, such as ATP depletion and cytotoxicity in cells with impaired anti-oxidant defenses, may be partially due to increased XO activity, especially in cells treated with both rMuTNF alpha and IFN tau.
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PMID:The role of xanthine oxidase in oxidative damage caused by cytokines in cultured mouse hepatocytes. 796 49


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