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)

With a variety of forms of ischemic and toxic tissue injury, cellular accumulation of Ca2+ and generation of oxygen free radicals may have adverse effects upon cellular and, in particular, mitochondrial membranes. Damage to mitochondria, resulting in impaired ATP synthesis and diminished activity of cellular energy-dependent processes, could contribute to cell death. In order to model, in vitro, conditions present post-ischemia or during toxin exposure, the interactions between Ca2+ and oxygen free radicals on isolated renal mitochondria were characterized. The oxygen free radicals were generated by hypoxanthine and xanthine oxidase to simulate in vitro one of the sources of oxygen free radicals in the early post-ischemic period in vivo. With site I substrates, pyruvate and malate, Ca2+ pretreatment, followed by exposure to oxygen free radicals, resulted in an inhibition of electron transport chain function and complete uncoupling of oxidative phosphorylation. These effects were partially mitigated by dibucaine, a phospholipase A2 inhibitor. With the site II substrate, succinate, the electron transport chain defect was not manifest and respiration remained partially coupled. The electron transport chain defect produced by Ca2+ and oxygen free radicals was localized to NADH CoQ reductase. Calcium and oxygen free radicals reduced mitochondrial ATPase activity by 55% and adenine nucleotide translocase activity by 65%. By contrast oxygen free radicals alone reduced ATPase activity by 32% and had no deleterious effects on translocase activity. Dibucaine partially prevented the Ca2+-dependent reduction in ATPase activity and totally prevented the Ca2+-dependent translocase damage observed in the presence of oxygen free radicals. These findings indicate that calcium potentiates oxygen free radical injury to mitochondria. The Ca2+-induced potentiation of oxygen free radical injury likely is due in part to activation of phospholipase A2. This detrimental interaction associated with Ca2+ uptake by mitochondria and exposure of the mitochondria to oxygen free radicals may explain the enhanced cellular injury observed during post-ischemic reperfusion.
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PMID:Mechanism of calcium potentiation of oxygen free radical injury to renal mitochondria. A model for post-ischemic and toxic mitochondrial damage. 287 85

Oxidative damage to the vascular endothelium may play an important role in the pathogenesis of atherosclerosis and aging, and may account in part for reduced vascular prostacyclin (PGI2) synthesis associated with both conditions. Using H2O2 to induce injury, we investigated the effects of oxidative damage on PGI2 synthesis in cultured endothelial cells (EC). Preincubation of EC with H2O2 produced a dose-dependent inhibition (inhibitory concentration [IC50] = 35 microM) of PGI2 formation from arachidonate. The maximum dose-related effect occurred within 1 min after exposure although appreciable H2O2 remained after 30 min (30% of original). In addition, H2O2 produced both a time- and dose-dependent injury leading to cell disruption, lactate dehydrogenase release, and 51Cr release from prelabeled cells. However, in dramatic contrast to H2O2 effects on PGI2 synthesis, loss of cellular integrity required doses in excess of 0.5 mM and incubation times in excess of 1 h. The superoxide-generating system, xanthine plus xanthine oxidase, produced a similar inhibition of PGI2 formation. Such inhibition was dependent on the generation of H2O2 but not superoxide in that catalase was completely protective whereas superoxide dismutase was not. H2O2 (50 microM) also effectively inhibited basal and ionophore A23187 (0.5 microM)-stimulated PGI2 formation. However, H2O2 had no effect on phospholipase A2 activity, because ionophore A23187-induced arachidonate release was unimpaired. To determine the effects on cyclooxygenase and PGI2 synthase, prostaglandin products from cells prelabeled with [3H]arachidonate and stimulated with ionophore A23187, or products formed from exogenous arachidonate were examined. Inhibition of cyclooxygenase but not PGI2 synthase was observed. Incubation of H2O2-treated cells with prostaglandin cyclic endoperoxide indicated no inhibition of PGI2 synthase. Thus, in EC low doses of H2O2 potently inhibit cyclooxygenase after brief exposure whereas larger doses and prolonged exposure are required for classical cytolytic effects. Surprisingly, PGI2 synthase, which is known to be extremely sensitive to a variety of lipid peroxides, is not inhibited by H2O2. Lipid solubility, enzyme location within the EC membrane, or the local availability of reducing factors may explain these results, and may be important determinants of the response of EC to oxidative stress.
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PMID:Effect of hydrogen peroxide on prostaglandin production and cellular integrity in cultured porcine aortic endothelial cells. 299 39

Effect of nafamostat mesilate (FUT-175), a serine protease inhibitor, having anti-inflammatory effects was studied on superoxide (O2-) production in rat polymorphonuclear leucocytes (PMN) and compared with those of other serine protease inhibitors and typical anti-inflammatory agents. 1) O2- productions in rat PMN stimulated with concanavalin A (Con A) and cytochalasin B (Cyt B) were too weak to observe. With NADH, however, strong O2- production was induced by Con A and Cyt B. 2) FUT-175 at 10(-6) and 10(-5) M inhibited O2- production in rat PMN induced by Con A and Cyt B with NADH in a concentration-dependent manner. 3) The serine protease inhibitor L-tosylamido-2-phenylethyl-chloromethyl ketone (TPCK) and soybean trypsin inhibitor (SBTI) inhibited O2- production at 10(-5) M and 10(-4) M, respectively, while aprotinin, chymostatin and leupeptin did not. 4) Neither indomethacin nor dexamethasone, typical anti-inflammatory agents, inhibited O2- production. Mepacrine, a phospholipase A2 inhibitor, strongly inhibited it. 5) O2- production in PMN prepared from the rat administered FUT-175, 200 mg/kg, p.o., was significantly decreased in comparison with that of the control rat. 6) FUT-175 had no effect on O2- production by hypoxanthine-xanthine oxidase. These results showed FUT-175 had a strong inhibitory effect on O2- production in rat PMN which other typical anti-inflammatory agents did not have.
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PMID:[Inhibitory effect of nafamostat mesilate (FUT-175) on O2- production in rat polymorphonuclear leucocytes]. 301 53

Using [1-14C]oleate-labelled autoclaved Escherichia coli as substrate, we demonstrate that many, but not all, commercial preparations of xanthine oxidase contain phospholipase A2 activity as a contaminant. Phospholipase A2 activity (64.3-545.6 nmol phospholipid hydrolyzed per min per mg protein) was optimal in the neutral to alkaline pH range, was Ca2+-dependent, and was unaffected by the addition of xanthine. Phospholipase A2 activity was totally inhibited by 1.0 mM EDTA while radical production by xanthine plus xanthine oxidase was unaffected by EDTA. Even chromatographically purified xanthine oxidase (Sigma Grade III) contained substantial phospholipase A2 activity (64.3 nmol/min per mg). Since the preparation of xanthine oxidase employs proteolytic digestion of milk or buttermilk by pancreatin, an extract of pancreas which is an organ rich in phospholipase A2 activity, we speculate that the contaminant phospholipase A2 is introduced by this treatment. Because xanthine oxidase is used extensively to study free radical-induced cell injury and membrane phospholipid alterations, the presence of a potent extracellular phospholipase A2 may have influenced previously published reports and such studies in the future should be interpreted with care.
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PMID:Contamination of commercial preparations of xanthine oxidase by a Ca2+-dependent phospholipase A2. 375 67

The luminol-dependent chemiluminescence (CL) response in vitro of guinea-pig C. parvum-activated peritoneal macrophages to platelet activating factor (PAF) has been compared with that to opsonized zymosan (OpZ). The response to PAF (5 X 10(-6) mol/l.) reached a peak within 1 min, that to OpZ (0.17 mg/ml) within 10-20 min. Peak responses to both stimuli were dose-dependently inhibited in a similar manner by p-hydroxymercuribenzoate (10(-5) - 10(-3) mol/l), sodium benzoate (10(-5) - 10(-3) mol/l.) and quinacrine (10(-6) - 10(-3) mol/l.). In contrast, the xanthine oxidase inhibitor allopurinol (IC50 vs OpZ, 220 mumol/l.; vs PAF greater than 1000 mumol/l.), the methylation-inhibiting combination homocysteine + 3-deazaadenosine (IC50 vs OpZ, 22 mumol/l.; vs PAF greater than 100 mumol/l.), the phospholipase A2 inhibitor and alkylating agent p-bromophenacylbromide (pBPB; IC50 vs OpZ, 2.6 mumol/l.; vs PAF 15 mumol/l.) and the beta-adrenoceptor agonist isoprenaline (IC50 vs OpZ, 0.1 mumol/l.; PAF greater than 10 mumol/l.) all exerted differential inhibitory effects on the CL responses to the two stimuli, though colour quenching by adrenochrome cannot be ruled out in the differential effect of isoprenaline. In screening studies, carried out with CL responses measured 2 or 5 min after PAF and OpZ, respectively, verapamil (less than or equal to 10(-4) mol/l.), trifluoperazine (less than or equal to 10(5) mol/l.) EDTA (less than or equal to 10(6) mol/l.), mannitol (less than or equal to 10(-2) mol/l.), metyrapone (less than or equal to 10(-5) mol/l.), SQ 22536 (less than or equal to 10 micrograms/ml.), iso-butyl methylxanthine (less than or equal to 10(-5) mol/l.).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pharmacological analysis of guinea-pig macrophage chemiluminescence responses to platelet activating factor and opsonized zymosan. 380 36

Effects of protizinic acid (PRT) on prostaglandins (PG) and the production of oxygen radicals were compared with those of other non-steroidal anti-inflammatory agents. Oral administration of 30 mg/kg of PRT, indomethacin (IM), or ibuprofen (IB) significantly inhibited arachidonic acid-induced erythema in guinea pigs. Although 30 mg/kg of PRT significantly inhibited PGE2-induced erythema, IM and IB did not significantly inhibit it. PRT inhibited phospholipase A2 (PLA2) activity, and the IC50 value was 2.1 X 10-4 M. On the other hand, IM and IB exerted no effect on the PLA2 activity at 3 X 10-4 M. These results suggest that PRT possesses a broader pharmacological activity on the PG system than IM and IB. As for effects on the production of oxygen radicals, in order of relative inhibitory potency was PRT greater than metiazinic acid (MA) = IM greater than IB = phenylbutazone (PB) in the xanthine oxidase assay, PB great than IM greater than PRT greater than MA = IB in the rabbit neutrophil myeloperoxidase assay, and IM greater than PB greater than PRT greater than MA greater than IB in the guinea pig macrophage assay. In the rabbit neutrophil and aggregated IgG-bound micropore filter assay, the order was PRT greater than MA greater than PB greater than IM = IB. Thus, the inhibitory effects of PRT was verified in all experiments on the production of oxygen radicals in contrast to IB. In particular, it could be especially meaningful that PRT showed the most potent activity in the aggregated IgG-bound micropore filter assay which has been reported to be a good model for studying the pathogenesis of inflammatory diseases believed to be caused by immune complexes.
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PMID:[Effects of protizinic acid on the prostaglandins system and the production of oxygen radicals]. 629 Mar 56

Thromboxane B2 biosynthesis from arachidonic acid was increased in platelets from hypercholesterolemic rabbits. The enzymic activity of phospholipase A2 which releases arachidonic acid, the precursor for the biosynthesis of thromboxane B2, showed hardly any change in hypercholesterolemic platelets. Phospholipase C and diglyceride lipase activities also were not changed in platelets from hypercholesterolemic rabbits. Furthermore, phospholipid concentration in platelets were not increased in this state. Thus, I conclude that the supply of precursor for thromboxane B2 biosynthesis was not increased in platelets from hypercholesterolemic rabbits as compared to controls. I have clarified this mechanism for the increased thromboxane synthesis. The biosynthesis of prostaglandin H2 and thromboxane B2 were unaffected by superoxide dismutase, xanthine, xanthine oxidase, mannitol, or benzoate in the experiments designed to study the possible involvement of reactive oxygen species. The effect of glutathione, glutathione peroxidase and H2O2 on cyclooxygenase and thromboxane synthetase were studied by using partially purified enzymes and platelet microsomes. Glutathione and glutathione peroxidase inhibited the activity of the cyclooxygenase but did not inhibit that of thromboxane synthetase. H2O2 caused the inactivation of cyclooxygenase, but the addition of H2O2 did not inhibit the formation of thromboxane B2 from prostaglandin H2. An examination of glutathione concentration and glutathione peroxidase activity in platelets from normal and experimentally hypercholesterolemic rabbits demonstrated that both were decreased in platelets from latter group. The observed alterations in glutathione levels and glutathione peroxidase activity are large enough to cause increased thromboxane B2 synthesis in platelets but the possibility that other unidentified factors may also contribute cannot be excluded.
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PMID:Thromboxane synthesis in hypercholesterolemic platelets--on the mechanism of increased thromboxane synthesis. 661 25

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

The growing evidence that glutamate may be an important agent mediating ischemic damage to neurons, led us to investigate the possible protective effects of pharmacological agents against glutamate in a model system of cortical neurons. In this study we examined, in particular, the cytoprotective effect of prostaglandins. Experiments were carried out in vitro by using rat cortical neurons in culture for 10 days. They were incubated for 3h with glutamate (10 microM) in the presence or absence of various pharmacological agents including prostaglandins (PGD2, PGE1, PGE2, PGF2 alpha, PGI2, 6-Keto-PGF1 alpha, carba-TXA2, carba-PGI2 and PGF2 alpha-methylester). Increase in lacticodehydrogenase (LDH) release into the culture medium has been measured as an index of cell injury. When neurons were incubated with glutamate they released LDH due to NMDA-receptor activation since D-L-2-amino-5-phosphonovaleric acid, a specific receptor antagonist, protected the cells. The protective activity of oxypurinol, amflutizole, superoxide dismutase, NG nitro-L-arginine and quinacrine, also suggests that xanthine oxidase activation, the generation of superoxide radical, and nitrix oxide, as well as phospholipase A2 stimulation are responsible for neuron injury (i.e. LDH release). All the tested prostaglandins, except PGF2 alpha-methylester, afforded significant protection at concentrations between 0.1 and 10 microM. The order of potency of the prostanoids was: PGF2 alpha = PGE2 > Carba-TXA2 > PGE1 > PGD2 > PGI2 = Carba-PGI2 > 6-Keto-PGF1 alpha. Additional experiments showed that prostaglandins did not compete for the NMDA binding site and that they did not inhibit free radical-related membrane damage.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Protection by prostaglandins from glutamate toxicity in cortical neurons. 791 88

Reuptake of glutamate in astrocytes, a critical mechanism involved in the maintenance of physiological excitatory amino acid neurotransmission, is inhibited by both arachidonic acid (AA) and reactive oxygen species (ROS), via incompletely defined molecular mechanisms. Because ROS are generated during AA metabolism and AA can be released as a result of ROS-mediated phospholipase A2 activation, it seems likely that their effects on uptake are mediated by a common mechanism. However, here we show that rapid (10-min) uptake inhibitions by AA or by ROS generated by the xanthine plus xanthine oxidase (XO) reaction are selectively abolished by distinct agents; bovine serum albumin (BSA) acts only on AA, whereas the scavenger enzymes superoxide dismutase (SOD) and catalase (CAT) and the disulfide-reducing agent dithiothreitol (DTT) act only on ROS. Moreover, when added together, xanthine/XO and AA decrease uptake in a fully additive manner. In particular, the effect of xanthine/XO is seen also in the presence of maximal AA inhibition. No major signs of cell damage or chemical reaction between AA and radicals accompany their cumulative effects on uptake. Finally, uptake inhibition elicited by AA and xanthine/XO together is attenuated but not blocked by either BSA, DTT, or SOD/CAT individually, whereas it is fully blocked and substantially reversed by a combination of SOD/CAT and BSA or SOD/CAT, DTT, and BSA. Together, these data indicate that AA and ROS act on glial glutamate transport via distinct noninteracting mechanisms. Therefore, they could independently and additively contribute to the impairment of reuptake function, a phenomenon observed in pathological conditions such as ischemia/reperfusion injury.
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PMID:Glutamate uptake is inhibited by arachidonic acid and oxygen radicals via two distinct and additive mechanisms. 796 90


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