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)

Vascular smooth muscle cells (VSMCs) proliferate in response to arterial injury. Recent findings suggest that, in addition to platelet-derived growth factors, growth factors from inflammatory cells and endothelial cells at the site of injury may contribute to VSMC proliferation. We hypothesized that a common mechanism by which endothelial cells and inflammatory cells stimulate VSMC growth could be the active oxygen species (i.e., O2-, H2O2, and .OH) generated during arterial injury. Using xanthine/xanthine oxidase to generate active oxygen species, we studied the effects of these agents on VSMC growth. Xanthine/xanthine oxidase (100 microM xanthine and 5 microunits/ml xanthine oxidase) stimulated DNA synthesis in growth-arrested VSMCs by 180% over untreated cells. Administration of the scavenging enzymes superoxide dismutase and catalase demonstrated that H2O2 was primarily responsible for xanthine/xanthine oxidase-induced VSMC DNA synthesis. H2O2 directly increased VSMC DNA synthesis and cell number (maximal at 200 microM) but decreased DNA synthesis of endothelial cells and fibroblasts. This effect was protein kinase C independent: sphingosine, a potent protein kinase C inhibitor, failed to block H2O2-induced VSMC DNA synthesis. H2O2 (200 microM) stimulated c-myc and c-fos mRNA levels by fourfold and 20-fold, respectively, as compared with quiescent levels. In contrast to DNA synthesis, H2O2 induction of c-myc and c-fos mRNA was primarily protein kinase C dependent. These findings show that H2O2 specifically increases VSMC DNA synthesis and suggest a role for this oxidant in intimal proliferation, especially after arterial injury.
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PMID:Active oxygen species stimulate vascular smooth muscle cell growth and proto-oncogene expression. 2411 68

Human interferon-alpha A/D (Bg/II) (IFN-alpha A/D) and mouse interferon-gamma (IFN-gamma) are shown to induce xanthine dehydrogenase (XD) mRNA in L929 fibroblastic cells. XD mRNA accumulation after IFN-alpha A/D treatment is relatively fast, being already evident after 4 h and reaching its maximum after 24 h. IFN-alpha A/D is active in inducing XD mRNA at 0.1 unit/ml and it is maximally active at 10(3) units/ml. The half-life of the XD message is unaffected by IFN-alpha A/D treatment, whereas the transcriptional activity of the XD gene and the concentrations of XD heterogeneous nuclear RNA are increased by 2- and 6-fold respectively. The effect of IFN-alpha A/D on XD mRNA is insensitive to cycloheximide, suggesting that protein synthesis de novo is not required. Experiments conducted with specific inhibitors suggest that protein kinase C, cyclic AMP and arachidonic acid metabolites derived from lipoxygenase or cyclooxygenase do not act as second-messenger molecules in the induction of XD mRNA by IFN-alpha A/D. XD mRNA is also induced in NIH3T3 fibroblastic cells, but not in F9 teratocarcinoma or B16 melanoma cells after treatment with IFN-alpha A/D. NIH3T3 are the only cells so far tested that have detectable XD and xanthine oxidase activities under basal conditions and after IFN-alpha A/D treatment, although their responsiveness to the cytokine is much less than that observed in L929 cells.
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PMID:Interferons induce xanthine dehydrogenase gene expression in L929 cells. 137 96

Two superoxide dismutase-mimetic lipophilic copper complexes, Cu(II)2(indomethacin)4 [Cu(II)2(indo)4] and Cu(II)2(3,5-diisopropylsalicylate)4 [Cu(II)2(3,5-DIPS)4], were tested for their effects on the respiratory burst of intact human granulocytes and on xanthine oxidase, under conditions where superoxide and hydrogen peroxide were generated. The effect of the copper complexes on these enzyme systems (as opposed to their dismutase effect on superoxide) was determined by measuring oxygen uptake with an oxygen meter. It was found that, after a short delay, both systems were inhibited markedly by micromolar amounts of these complexes. This inhibition was prevented by treatment with EDTA or catalase if added prior to starting the reaction. Similar inhibitory effects were seen using copper sulfate. It appears that these lipophilic SOD-mimetic compounds can, in the presence of H2O2 and O2-, give rise to a species that can inhibit some component of the respiratory burst oxidase or protein kinase C in intact granulocytes and xanthine oxidase in solution. The observed decrease in O2- levels observed upon addition of these compounds is likely due to inhibition of the source and not to their SOD-mimetic properties.
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PMID:Inhibition by superoxide dismutase-mimetic copper complexes of phorbol ester-induced respiratory burst in human granulocytes. 155 79

Reactive oxygen species (at least relatively high doses) cause contraction of pulmonary arterial smooth muscle. The objective of the present study was to elucidate the possible cellular mechanisms involved in reactive oxygen-mediated contraction. Isolated arterial rings from Sprague-Dawley rats were placed in tissue baths containing Earle's balanced salt solution. The maximum active force production (Po) in response to 80 mM KCl was obtained. All other responses were normalized as percentages of Po for comparative purposes. Exposure to reactive oxygen (generated from either the xanthine oxidase reaction (XO) or the glucose oxidase reaction) resulted in pulmonary arterial muscle developing mean active tension of 17.1 +/- 3.0% Po. This contraction was independent of extracellular calcium, since it was not affected by verapamil (a calcium channel blocker) or by placement of the arterial muscle in calcium-free media. Phentolamine (an alpha 1-receptor blocker) and propranolol (a beta-receptor blocker) did not diminish the response to XO. Ryanodine (a SR calcium release inhibitor), while reducing the response to norepinephrine, did not affect the response to XO. However, H-7 (an inhibitor of protein kinase C) decreased the XO-mediated contraction by 49%. These results indicate that while Ca2+ may not be involved as a second messenger, protein kinase C activity appears to play a role in the transduction pathway of reactive oxygen species mediated contraction of pulmonary arterial smooth muscle.
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PMID:Reactive oxygen-mediated contraction in pulmonary arterial smooth muscle: cellular mechanisms. 167 38

Oxidative stress plays an important role in various types of cell injury and tumor promotion. Cells respond to oxidative stress in many ways including changes in membrane organization, ion movements, and altered gene expression, all of which contribute to the subsequent fate of affected cells. In this study, we investigated the expression of the proto-oncogenes c-fos, c-myc, and c-jun, which play a key role in proliferation and differentiation, using primary cultures of rat proximal tubular epithelium exposed to oxidative stress generated by the xanthine/xanthine oxidase system. This system generates superoxide and H2O2 in the extracellular space stimulating the release of active oxygen species from inflammatory cells. c-fos mRNA was expressed within 15 min, peaked at 30 min, and returned to constitutive levels by 3 h. c-jun mRNA began to rise after 30 min, peaked at 120 min, and remained above the constitutive levels up to 180 min. c-myc mRNA expression was less affected by the treatment, with levels increasing gradually over the 180 min period. The expression of c-fos was inhibited by superoxide dismutase but not by catalase and was super-induced by cycloheximide. H2O2 alone did not induce any c-fos mRNA in this system. Chelation of extracellular ionized calcium by EGTA or of intracellular ionized calcium by Quin 2/AM resulted in a marked decrease of c-fos expression. Two protein kinase C inhibitors, H-7 and staurosporine, partly diminished the expression of c-fos, whereas a third, 2-aminopurine, which has a broader spectrum of inhibiting protein kinases, almost completely abolished it. A poly ADP-ribosylation inhibitor, 3-aminobenzamide, had no effect on c-fos expression in this system. Our results show that oxidative stress provokes sequential expression of c-fos, c-jun, and c-myc, mRNA in this order. This c-fos expression appears to be largely controlled by calcium ion movement, which could include protein kinase C activation. Another protein kinase or kinases also appear to play an important role.
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PMID:Role of [Ca2+]i in induction of c-fos, c-jun, and c-myc mRNA in rat PTE after oxidative stress. 174 Feb 41

The involvement of protein kinase C in the initiation of free oxygen radical generation by rat leukocytes in response to the nematode Nippostrongylus brasiliensis was investigated. Inhibitors of protein kinase C, trifluoperazine and 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H-7), inhibited free radical generation in response to N. brasiliensis in vitro. Neither inhibitor affected free radical generation by the cell-free xanthine/xanthine oxidase system, indicating that the agents did not scavenge free radicals; they also failed to affect leukocyte viability. Furthermore, activators of protein kinase C, the calcium ionophore A23187 and the diacylglycerol 1-oleoyl-2-acetyl-rac-glycerol (OAG), enhanced free radical generation by leukocytes in response to N. brasiliensis in vitro. Thus, protein kinase C apparently plays an important role in the initiation of free radical generation in response to N. brasiliensis; since free radicals may play a critical role in worm expulsion, this implies that protein kinase C may also be important in the rejection of N. brasiliensis from the small intestine of the rat.
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PMID:A role for protein kinase C in the production of free oxygen radicals in response to Nippostrongylus brasiliensis. 192 60

We have studied changes in intracellular localization and phosphorylating activity of protein kinase C (PKC) in mouse epidermal JB6 cells treated with oxidants. Exposure to hydrogen peroxide, reagent grade or generated enzymatically by glucose/glucose oxidase, at concentrations known to result in elevated intracellular free Ca2+ resulted in an increase in binding of [3H]phorbol dibutyrate to intact cells. Ca2+ chelation, either intracellularly by quin 2 or extracellularly by ethylene glycol bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid, abolished the increase in radioligand binding. In contrast to H2O2, superoxide generated extracellularly by xanthine/xanthine oxidase or intracellularly by menadione was inactive. Scatchard plot analysis revealed that the enhancement in binding resulted from both increased receptor affinity and increased maximal binding capacity. Treatment of cells with superoxide, generated extracellularly by xanthine/xanthine oxidase or intracellularly by menadione, diminished the [3H]phorbol dibutyrate-binding capacity of the cytosol fractions prepared at low Ca2+ concentration. This decrease was not accompanied by a compensatory increase in the binding to membrane components. In contrast to superoxide, reagent H2O2, H2O2 produced by glucose/glucose oxidase, and the Ca2+ ionophore A23187 had no significant effect on the [3H]phorbol dibutyrate-binding capacities of either cellular fraction. Exposure of cells to low concentrations of extra- or intracellular superoxide resulted in an increase in the Ca2+- and phospholipid-dependent phosphorylating activity of cytosolic extracts towards adenosine diphosphoribose transferase which has been reported to be a specific substrate for PKC. The increase in phosphorylation could be diminished by the extracellular addition of copper-zinc-containing superoxide dismutase but not catalase suggesting that superoxide rather than H2O2 represents the active oxygen species in this reaction. The observation that reagent H2O2 or glucose/glucose oxidase failed to increase the phosphorylating activity of cytosolic preparations supports this conclusion. Treatment of cells or cytosolic extracts with the sulfhydryl reagent diamide stimulated the Ca2+/phospholipid-dependent phosphorylating activity toward adenosine diphosphoribose transferase. In a reconstituted system containing purified PKC, diamide induced a 25-30% increase in phospholipid-dependent phosphorylation of H1 whereas no change in activity was observed with the reducing agent dithiothreitol. It is concluded that H2O2 but not superoxide induces an increase in the phorbol ester binding, presumably to PKC, of intact JB6 cells. On the other hand
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PMID:Translocation and enhancement of phosphotransferase activity of protein kinase C following exposure in mouse epidermal cells to oxidants. 250 33

Exposure of isolated SENCAR mouse epidermal cells to the tumor promoter 12-0-tetradecanoylphorbol-13-acetate (TPA) in vitro resulted in the production of oxidant species detected as chemiluminescence. This oxidant response can be inhibited by superoxide dismutase and copper complexes but not catalase or scavengers of hydroxyl radical or singlet oxygen, suggesting that the oxidant is superoxide anion. Inhibitors of various parts of the arachidonate cascade affect the TPA-induced oxidant response in a manner that corresponds to their effects on in vivo tumor promotion experiments. Agents that inhibit lipoxygenase activity, i.e. nordihydroguaiaretic acid, benoxaprofen, but not agents that are cyclooxygenase inhibitors, i.e. indomethacin, are effective in suppressing the oxidant response to TPA. Phospholipase C but not phospholipase A2 or D produced an oxidant response kinetically similar to that elicited by TPA. The inhibitors of TPA-induced oxidants inhibited the phospholipase C response to the same extent, suggesting that TPA and phospholipase C may produce an oxidant species through a common mechanism, via phospholipid turnover-protein kinase C activation. The relevance of oxidant production to the tumor promotion process is suggested by the ability of exogenous xanthine/xanthine oxidase, a superoxide anion-generating system, to induce ornithine decarboxylase, a characteristic of TPA-treated cells. In addition, oxidant production is significantly lower in cells from the TPA-promotion resistant C57BL/6J mouse. These studies provide further support for a role for reactive oxygens in the tumor promotion process.
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PMID:Reactive oxygen in the tumor promotion stage of skin carcinogenesis. 284 22

The effect of l-carnitine on human neutrophil oxidative metabolism was investigated, both on superoxide production and luminol amplified chemiluminescence (CL) in phorbol-myristate-acetate (PMA) stimulated cells. L-carnitine either preincubated 10 minutes with the cells, before PMA challenge, or added simultaneously to the stimulator, inhibited superoxide generation. When tested in an O2- -generating system, such as xanthine-xanthine oxidase, l-carnitine did not act as an O2- scavenger. On the PMA induced CL response the drug was ineffective as an inhibitor, if preincubated with the cell suspension before activation. When added together with PMA, l-carnitine significantly inhibited the CL. Taken together the results reveal that the drug might affect the interaction of PMA with its specific receptor in human neutrophils, that is protein kinase C.
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PMID:Effect of l-carnitine on human neutrophil activity. 302 50

The dynamics and mechanisms of extracellular release of hydrogen peroxide (H2O2) from bovine pulmonary artery endothelial cells (EC) subjected to anoxia, hypoxia, and hypoxia followed by reoxygenation were examined using various inhibitors of enzymatic systems in intact cells and by direct measurement of H2O2 production from isolated EC plasma membranes. Extracellular H2O2 was measured with a fluorometric assay. EC exposed to hypoxia (3% O2) and anoxia (0% O2) released less H2O2 (29.6 +/- 1.3% and 4.2 +/- 0.7%, respectively) compared with EC exposed to normoxia (20% O2). The extracellular release of H2O2 from EC previously exposed to hypoxia for 24 h increased immediately after reoxygenation (20% O2) to 272 +/- 48%, as compared with EC exposed continuously to normoxia (100% release). Inhibition of xanthine oxidase (XO) by allopurinol did not reduce the release of H2O2 from cells exposed to normoxia or hypoxia followed by reoxygenation. Furthermore, inhibitors of cyclooxygenase (indomethacin), phospholipase A2 (quinacrine and chlorpromazine), nitric oxide synthase (L-arginine analogs), the mitochondrial electron transport chain (rotenone and cyanide), and cytochrome P-450 (methoxypsoralen) had no or minimal effect on this release. On the other hand, inhibitors of protein kinase C (calphostin and staurosporine) and NADPH oxidase (diphenyliodonium) reduced the release of H2O2 from EC in a dose-dependent manner in both exposure groups. In separate experiments, plasma membranes isolated from EC were found to produce H2O2 in the presence of NADH or NADPH as electron donors. This was inhibited by diphenyliodonium but not by allopurinol.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Release of hydrogen peroxide in response to hypoxia-reoxygenation: role of an NAD(P)H oxidase-like enzyme in endothelial cell plasma membrane. 752 30


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