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)

Considerable phospholipase D (PLD) activity is localized in myocardial sarcoplasmic reticular (SR) membranes, where it may take part in the regulation of Ca2+ movements. In this study, we examined thiol group dependence as a possible regulatory mechanism for SR PLD. SR membranes isolated from rat heart were exposed to four types of thiol group modifiers, which all induced a decrease in SR PLD activity that was prevented by dithiothreitol. Furthermore, since abnormalities in thiol status and Ca2+ homeostasis are characteristic for the myocardial cell damage induced by oxidative stress, we also studied the effects of oxidants on the SR PLD activity. The enzyme was not affected by xanthine-xanthine oxidase, but was depressed by hydrogen peroxide and by hypochlorous acid. These inhibitory effects were prevented by catalase as well as by methionine and dithiothreitol, respectively. Furthermore, reduced glutathione protected against the hydrogen peroxide-induced depression, whereas oxidized glutathione inhibited SR PLD. The results indicate that SR PLD activity is inhibited by nonradical oxidants, hydrogen peroxide and hypochlorous acid, through reversible modification of associated thiol groups. Thus, the enzyme may be controlled by the glutathione redox status of the cardiac cell.
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PMID:Involvement of thiol groups in the impairment of cardiac sarcoplasmic reticular phospholipase D activity by oxidants. 778 Jun 80

1. The possible mechanisms of action of the inhibitory effect of gomisin C on the respiratory burst of rat neutrophils in vitro was investigated. 2. The peptide formyl-Met-Leu-Phe (FMLP) induced superoxide anion (O2-) formation and O2 consumption, which was inhibited by gomisin C in a concentration-dependent manner (IC50 21.5 +/- 4.2 micrograms ml-1 for O2- formation). Gomisin C also suppressed O2- formation and consumption at low concentrations of phorbol myristate acetate (PMA) with an IC50 value of 26.9 +/- 2.1 micrograms ml-1 for O2- formation. However, gomisin C did not affect the responses induced by a high concentration of PMA. 3. Gomisin C had no effect on O2- generation and uric acid formation in the xanthine-xanthine oxidase system, and failed to alter O2- generation during dihydroxyfumaric acid (DHF) autoxidation, indicating that it does not scavenge superoxide. 4. Like trifluoperazine (TFP), gomisin C attenuated the activity of PMA-activated neutrophil particulate NADPH oxidase in a concentration-dependent manner. 5. Gomisin C reduced the elevations of cytosolic free Ca2+ in neutrophils stimulated by FMLP in the presence or absence of EDTA. Cyclopiazonic acid (CPA) induced the release of Ca2+ from intracellular stores and this was also reduced by gomisin C. However, the Ca2+ influx pathway activated by CPA was not affected by gomisin C. 6. The cellular cyclic AMP level was markedly increased by forskolin, but not by gomisin C. Moreover, the inositol phosphate levels in FMLP-activated neutrophils were not affected by gomisin C. 7. These results show that the inhibitory action of gomisin C on the respiratory burst is not mediated by changes in cellular cyclic AMP or in inositol phosphates, or by scavenging O2- released from neutrophils, but may be mediated partly by the suppression of NADPH oxidase and partly by the decrease of cytosolic Ca2+ released from an agonist-sensitive intracellular store.
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PMID:Inhibition by gomisin C (a lignan from Schizandra chinensis) of the respiratory burst of rat neutrophils. 785 90

The authors investigated the mechanisms caused by oxidants (superoxide and hydrogen peroxide) and asbestos (amosite) fibers in human mesothelial cells. Immortalized human pleural mesothelial cells (MET 5A) were exposed in vitro to one of the following: hypoxanthine (100-200 microM) plus xanthine oxidase (10-20 mU/ml) as a superoxide-generating system, H2O2 (50 microM-5 mM); or amosite (1-100 micrograms/cm2). Cellular adenine nucleotide depletion, DNA single strand breaks, extracellular release of nucleotides, and their catabolites and lactate dehydrogenase (LDH) were assessed as markers of cell damage after 4-6 h exposure to the oxidants or fibers. The effect of intracellular antioxidant enzymes and exogenous antioxidants on cell damage were investigated during oxidant and amosite exposure. Superoxide radical and H2O2 exposure resulted in the depletion of adenine nucleotides, accumulation of the products of nucleotide catabolism, induction of DNA single strand breaks, and extracellular LDH release. Amosite exposure did not cause nucleotide depletion or induction of DNA single strand breaks. Inactivation of the intracellular antioxidant enzymes glutathione reductase or catalase augmented cell damage during H2O2 exposure but not during amosite exposure.
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PMID:Cytotoxicity of oxidants and asbestos fibers in cultured human mesothelial cells. 800 12

When stimulated, neutrophils undergo a respiratory burst converting oxygen to superoxide. Although superoxide is critical for microbial killing by phagocytic cells, the precise role it plays has yet to be established. It has been proposed to optimize their production of hypochlorous acid and to be required for the generation of hydroxyl radicals. Superoxide is also involved in the hydroxylation of salicylate by neutrophils. However, the mechanism of this reaction is unknown. We found that neutrophils stimulated with opsonized zymosan hydroxylated salicylate to produce mainly 2,5-dihydroxybenzoate. Its formation was dependent on superoxide and a heme protein but was independent of hydrogen peroxide and hydroxyl radicals. Production of 2,5-dihydroxybenzoate was enhanced by methionine, which scavenges hypochlorous acid. Neutrophils from an individual with myeloperoxidase deficiency hydroxylated salicylate at only 13% of the level of control cells. Purified human myeloperoxidase and xanthine oxidase plus hypoxanthine hydroxylated salicylate to produce 2,5-dihydroxybenzoate. As with neutrophils, the reaction required superoxide but not hydrogen peroxide and was unaffected by hydroxyl radical scavengers. Thus, myeloperoxidase catalyzes superoxide-dependent hydroxylation. This newly recognized reaction may be relevant to the in vivo functions of superoxide and myeloperoxidase.
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PMID:Superoxide-dependent hydroxylation by myeloperoxidase. 800 21

Both phenylbutazon and mofebutazon inhibit oxidative fragmentation of the methionine derivative, 2-keto-4-methylthio-butyric acid (KMB) by xanthine oxidase--or diaphorase mediated OH radical production. Differentiation of the two non-steroidal antiinflammatory drugs is possible by means of determining oxygen reduction by xanthine oxidase or diaphorase in the presence of the naphthoquinone, juglone, where only mofebutazon shows an inhibitory effect.
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PMID:Antioxidative properties of phenazone derivatives: differentiation between phenylbutazon and mofebutazon. 821 10

Free radical-induced injury to the arterial wall has been implicated in the pathogenesis and progression of atherosclerosis. To model the in vitro effects of free radicals on endothelial cell function, protein and lipid synthesis were measured after exposing cells to a superoxide generating system of xanthine (X = 100 microM) and xanthine oxidase (XO = 0.2 units). Total protein synthesis, measured by [35S]methionine uptake, decreased by 87.65 +/- 2.04% over 4 hr compared to controls (P < 0.05). Examination of lipid synthesis by high-performance liquid chromatography in cells prelabeled with either [3H]oleic acid or [3H]sodium acetate revealed alterations in all lipid classes. Phospholipid and neutral glyceride synthesis significantly decreased in a time- and dose-dependent fashion compared to controls (two-way ANOVA). In contrast, cholesterol synthesis and lipid peroxidation increased in a time- and dose-dependent fashion. When X = 200 microM and XO = 0.3 units, there was a statistically significant increase in cholesterol synthesis and lipid peroxidation within 24 hr (Tukey's HSD). We conclude that there is evidence of endothelial cell injury as measured by decreases in protein, glyceride, and phospholipid synthesis. The concurrent increases in lipid peroxidation and cholesterol synthesis may explain the relationship between free radical injury and the pathogenesis of atherosclerosis.
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PMID:Free radical-induced alterations in endothelial cell function. 827 66

The main pathway for the hepatic oxidation of ethanol to acetaldehyde proceeds via ADH and is associated with the reduction of NAD to NADH; the latter produces a striking redox change with various associated metabolic disorders. NADH also inhibits xanthine dehydrogenase activity, resulting in a shift of purine oxidation to xanthine oxidase, thereby promoting the generation of oxygen-free radical species. NADH also supports microsomal oxidations, including that of ethanol, in part via transhydrogenation to NADPH. In addition to the classic alcohol dehydrogenase pathway, ethanol can also be reduced by an accessory but inducible microsomal ethanoloxidizing system. This induction is associated with proliferation of the endoplasmic reticulum, both in experimental animals and in humans, and is accompanied by increased oxidation of NADPH with resulting H2O2 generation. There is also a concomitant 4- to 10-fold induction of cytochrome P4502E1 (2E1) both in rats and in humans, with hepatic perivenular preponderance. This 2E1 induction contributes to the well-known lipid peroxidation associated with alcoholic liver injury, as demonstrated by increased rates of superoxide radical production and lipid peroxidation correlating with the amount of 2E1 in liver microsomal preparations and the inhibition of lipid peroxidation in liver microsomes by antibodies against 2E1 in control and ethanol-fed rats. Indeed, 2E1 is rather "leaky" and its operation results in a significant release of free radicals. In addition, induction of this microsomal system results in enhanced acetaldehyde production, which in turn impairs defense systems against oxidative stress. For instance, it decreases GSH by various mechanisms, including binding to cysteine or by provoking its leakage out of the mitochondria and of the cell. Hepatic GSH depletion after chronic alcohol consumption was shown both in experimental animals and in humans. Alcohol-induced increased GSH turnover was demonstrated indirectly by a rise in alpha-amino-n-butyric acid in rats and baboons and in volunteers given alcohol. The ultimate precursor of cysteine (one of the three amino acids of GSH) is methionine. Methionine, however, must be first activated to S-adenosylmethionine by an enzyme which is depressed by alcoholic liver disease. This block can be bypassed by SAMe administration which restores hepatic SAMe levels and attenuates parameters of ethanol-induced liver injury significantly such as the increase in circulating transaminases, mitochondrial lesions, and leakage of mitochondrial enzymes (e.g., glutamic dehydrogenase) into the bloodstream. SAMe also contributes to the methylation of phosphatidylethanolamine to phosphatidylcholine. The methyltransferase involved is strikingly depressed by alcohol consumption, but this can be corrected, and hepatic phosphatidylcholine levels restored, by the administration of a mixture of polyunsaturated phospholipids (polyenylphosphatidylcholine). In addition, PPC provided total protection against alcohol-induced septal fibrosis and cirrhosis in the baboon and it abolished an associated twofold rise in hepatic F2-isoprostanes, a product of lipid peroxidation. A similar effect was observed in rats given CCl4. Thus, PPC prevented CCl4- and alcohol-induced lipid peroxidation in rats and baboons, respectively, while it attenuated the associated liver injury. Similar studies are ongoing in humans.
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PMID:Role of oxidative stress and antioxidant therapy in alcoholic and nonalcoholic liver diseases. 889 26

Nitric oxide (NO) is a widespread signaling molecule involved in the regulation of an impressive spectrum of diverse cellular functions. Superoxide anions (O-2) not only contribute to the localization of NO action by rapid inactivation, but also give rise to the formation of the potentially toxic species peroxynitrite (ONOO-) and other reactive nitrogen oxide species. The chemistry and biological effect of ONOO- depend on the relative rates of formation of NO and O-2. However, the simultaneous quantification of NO and O-2 has not been achieved yet due to their high rate of interaction, which is almost diffusion-controlled. A sensitive spectrophotometric assay was developed for the simultaneous quantification of NO and O-2 in aqueous solution that is based on the NO-induced oxidation of oxyhemoglobin (oxyHb) to methemoglobin and the O-2-mediated reduction of ferricytochrome c. Using a photodiode array photometer, spectral changes of either reaction were analyzed, and appropriate wavelengths were identified for the simultaneous monitoring of absorbance changes of the individual reactions. oxyHb oxidation was followed at 541.2 nm (isosbestic wavelength for the conversion of ferri- to ferrocytochrome c), and ferricytochrome c reduction was followed at 465 nm (wavelength at which absorbance changes during oxyHb to methemoglobin conversion were negligible), using 525 nm as the isosbestic point for both reactions. At final concentrations of 20 microM ferricytochrome c and 5 microM oxyHb, the molar extinction coefficients were determined to be epsilon465-525 = 7.3 mM-1 cm-1 and epsilon541.2-525 = 6.6 mM-1 cm-1, respectively. The rates of formation of either NO or O-2 determined with the combined assay were virtually identical to those measured with the classical oxyhemoglobin and cytochrome c assays, respectively. The assay was successfully adapted to either kinetic or end point determination in a cuvette or continuous on-line measurement of both radicals in a flow-through system. Maximal assay sensitivity was approximately 25 nM for NO and O-2. Cross-reactivity with ONOO- was controlled for by the presence of L-methionine. Generation of NO from the NO donor spermine diazeniumdiolate could be reliably quantified in the presence and absence of low, equimolar, and high flux rates of O-2. Likewise, O-2 enzymatically generated from hypoxanthine/xanthine oxidase could be specifically quantified with no difference in absolute rates in the presence or absence of concomitant NO generation at different flux rates. Nonenzymatic decomposition of 3-morpholinosydnonimine hydrochloride (100 microM) in phosphate buffer, pH 7.4 (37 degrees C), was found to be associated with almost stoichiometric production of NO and O-2 (1.24 microM NO/min and 1.12 microM O-2/min). Assay selectivity and applicability to biological systems were demonstrated in cultured endothelial cells and isolated aortic tissue using calcium ionophore and NADH for stimulation of NO and O-2 formation, respectively. Based on these data, a computer model was elaborated that successfully predicts the reaction of NO and O-2 with hemoprotein and may thus help to further elucidate these reactions. In conclusion, the nitric oxide/superoxide assay allows the specific, sensitive, and simultaneous detection of NO and O-2. The simulation model developed also allows the reliable prediction of the reaction between NO and O-2 as well as their kinetic interaction with other biomolecules. These new analytical tools will help to gain further insight into the physiological and pathophysiological significance of the formation of these radicals in cell homeostasis.
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PMID:The nitric oxide/superoxide assay. Insights into the biological chemistry of the NO/O-2. interaction. 909 31

1. The possible mechanisms of the inhibitory effect of ethyl 2-(3-hydroxyanilino)-4-oxo-4,5-dihydrofuran-3-carboxylate (HAJ11) on the respiratory burst of rat neutrophils in vitro was investigated. 2. HAJ11 caused a reversible and a concentration-dependent inhibition of formyl-Met-Leu-Phe (fMLP)-induced superoxide anion (O2.-) generation (IC50 4.9 +/- 0.7 microM) and O2 consumption (IC50 4.9 +/- 1.5 microM). Concanavalin A (Con A)- and NaF-induced O2.- generation were also suppressed by HAJ11. However, HAL11 was a weak inhibitor of the phorbol 12-myristate 13-acetate (PMA)-induced responses. 3. HAJ11 did not scavenge the /2.- generation in the xanthine-xanthine oxidase system and dihydroxyfumaric acid (DHF) autoxidation. 4. HAJ11 showed no activity on fMLP-induced inositol phosphates formation and [Ca2+]i elevation in intact neutrophils. In addition, HAJ11 had no effect on neutrophil cytosolic phospholipase C (PLC) activity. 5. HAJ11 reduced fMLP-induced phosphatidic acid (PA) (IC50 29.1 +/- 6.5 microM) and phosphatidylethanol (PE+) (IC50 22.6 +/- 1.9 microM) formation in a concentration-dependent manner. HAJ11 also reduced protein tyrosine phosphorylation in neutrophils stimulated by fMLP. 6. HAJ11 was a weak inhibitor of neutrophil cytosolic protein kinase C (PKC) activity, and had a negligible effect on brain PKC. Cellular cyclic nucleotides levels were not altered by HAJ11. In addition, HAJ11 did not affect protein kinase A (PKA) activity. 7. HAJ11 had not effect on the O2.- generation of PMA-activated and arachidonic acid (AA)-activated NADPH oxidase preparations. 8. Taken together these results indicate that the inhibition of respiratory burst by HAJ11 probably mainly occurs through inhibition of protein tyrosine phosphorylation and phospholipase D (PLD) activity.
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PMID:Inhibition by HAJ11 of respiratory burst in neutrophils and the involvement of protein tyrosine phosphorylation and phospholipase D activation. 911 3

We determined that lisofylline, a potent inhibitor of oleate- and linoleate-containing phosphatidic acid formation (half-maximal inhibitory concentration = 40 nM), prevented oxidant-mediated capillary leak in isolated rat lungs given interleukin-8 (IL-8) intratracheally and perfused with human neutrophils. Lung leak was prevented by lung, but not neutrophil, lisofylline pretreatment. Furthermore, although lisofylline inhibited IL-8-stimulated neutrophil production of phosphatidic acid in vitro, it did not prevent IL-8-stimulated neutrophil adherence, chemotaxis, or intracellular calcium mobilization or N-formyl-Met-Leu-Phe (fMLP)-stimulated oxidant production in vitro. Lisofylline also prevented acute capillary leak in isolated rat lungs perfused only with the oxidant generator purine-xanthine oxidase but did not scavenge O2-(+) or H2O2 in vitro. Finally, lisofylline-mediated protection against lung leak in both models was associated with alterations in lung membrane free fatty acid acyl composition (as reflected by the decreased ratio [linoleate + oleate]/[palmitate]). We conclude that lisofylline prevented both neutrophil-dependent and neutrophil-independent oxidant-induced capillary leak in isolated rat lungs and that protection appears to be mediated by blocking intrinsic lung linoleoyl phosphatidic acid metabolism. We speculate that lisofylline, in addition to our previously reported effects on cytokine signaling by intrapulmonary mononuclear cells, alters intrinsic pulmonary capillary membrane composition and renders this barrier less vulnerable to oxidative damage.
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PMID:Modulating phosphatidic acid metabolism decreases oxidative injury in rat lungs. 937 22


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