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)

A modifying effect of potential DNA intercalators, belonging to a group of carbazole, acridine and anthracene derivatives, on the course of luminol-dependent chemiluminescence of neutrophils (polymorphonuclear leucocytes; PMNL) in the process of phagocytosis was studied. This effect was also examined in reactive-oxygen-species-generating non-cellular reaction systems consisted of myeloperoxidase or xanthine oxidase. Adriamycin (Doxorubicin), which is widely applied to neoplasm therapy, was used as a reference intercalator in the conducted experiments. It was demonstrated that some structurally different derivatives of carbazole inhibited the light emission from N-formyl-methionyl-leucyl-phenylalanine (fMLP)-induced neutrophils to the same degree as adriamycin. It can be suggested that the same inhibitory effect was caused by either a different cellular distribution of the derivatives or different interactions of the derivatives with reactive oxygen species in the investigated systems. Measurements of chemiluminescence suggested that the thiol group in one of the carbazole derivatives could strongly interfere with oxidative cell metabolism. In contrast to the analogous derivative of carbazole, both anthracene and acridine derivatives, possessing an N-1'-hydroxyethyl-ethylenodiamino group, induced different increases in chemiluminescence accompanying the process of neutrophil phagocytosis. Cytotoxicity of the investigated derivatives, being tested previously in cancer cells with a sulphorhodamine B assay, was found to possess a specific representation in the complex picture of the derivative-caused modification both of neutrophil and enzymatic non-cellular chemiluminescence. We suggest that chemiluminescence assays may serve as a helpful tool in the primary screening of drug cytotoxicity.
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PMID:Cytotoxicity of some potential DNA intercalators (carbazole, acridine and anthracene derivatives) evaluated through neutrophil chemiluminescence. 1094 5

Rats were acutely injected with alcohol (75 mmol/kg body weight) and at the end of 2.5 h changes in cardiac synthesis rates were assessed with a 'flooding dose' of L-[4-(3)H]phenylalanine. The results showed that acute alcohol dosage reduced the fractional rates of cardiac protein synthesis (k(S), %/day). This effect was also seen when data were expressed relative to either RNA (i.e. k(RNA), mg protein/day/mg RNA) or DNA (i.e. k(DNA), mg protein/day/mg DNA). Both left and right ventricles responded similarly to ethanol. However, propranolol pre-treatment (at doses of 17 and 170 micromol/kg body weight; i.p.) did not prevent these effect of ethanol in either the left or right ventricle. Indeed, there was evidence that propranolol per se perturbed cardiac protein synthesis in vivo in control (i.e. without ethanol) rats particularly in the right ventricle. In conclusion, the results suggest that alcohol is cardiotoxic to the myocardium, which may cause its effects on protein synthesis independently of beta-receptors and/or xanthine oxidase inhibition.
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PMID:Inability of propranolol to prevent alcohol-induced reductions in cardiac protein synthesis in vivo. 1095 58

Hydroxylation of l-phenylalanine (Phe) by hydroxyl radical (*OH) yields 4-, 3-, and 2-hydroxyl-Phe (para-, meta-, and ortho-tyrosine, respectively). Phe derivative measurements have been employed to detect *OH formation in cells and tissues, however, the specificity of this assay is limited since Phe derivatives also arise from intracellular Phe hydroxylase. d-Phe, the d-type enantiomer, is not hydroxylated by Phe hydroxylase. We evaluate whether d-Phe reacts with *OH as well as l-Phe, providing a more reliable probe for *OH generation in biological systems. With *OH generated by a Fenton reaction or xanthine oxidase, d- and l-Phe equally gave rise to p, m, o-tyr and this could be prevented by *OH scavengers. Resting human neutrophils (PMNs) markedly converted l-Phe to p-tyr, through non-oxidant-mediated reactions, whereas d-Phe was unaffected. In contrast, when PMNs were stimulated in the presence of redox cycling iron the *OH formed resulted in more significant rise of p-tyr from d-Phe (9.4-fold) than l-Phe (3.6-fold) due to the significant background formation of p-tyr from l-Phe. Together, these data indicated that d- and l-Phe were equally hydroxylated by *OH. Using d-Phe instead of l-Phe can eliminate the formation of Phe derivatives from Phe hydroxylase and achieve more specific, sensitive measurement of *OH in biological systems.
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PMID:Detection of hydroxyl radicals by D-phenylalanine hydroxylation: a specific assay for hydroxyl radical generation in biological systems. 1118 Sep 47

Methods to microencapsulate enzyme, cells, and genetically engineered cells have been described in this article. More specific examples of enzyme encapsulation include the microencapsulation of xanthine oxidase for Lesch-Nyhan disease; phenylalanine ammonia lyase for pheny, ketonuria and microencapsulation of multienzyme systems with cofactor recycling for multistep enzyme conversions. Methods for cell encapsulation include the details for encapsulating hepatocytes for liver failure and for gene therapy. This also includes the details of a novel two-step method for encapsulation of high concentrations of smaller cells. Another new approach is the detailed method of the encapsulation of genetically engineered Escherichia coli DH5 cells for lowering urea, ammonia, and other metabolites in kidney or, liver failure and other diseases.
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PMID:Procedures for microencapsulation of enzymes, cells and genetically engineered microorganisms. 1143 13

The effects of three aglycon flavonols (myricetin, quercetin, and kaempferol) and the natural glycoside rutin on superoxide anion radical generating systems were investigated. Quercetin, myricetin, and kaempferol inhibited the formation of uric acid from xanthine by xanthine oxidase, while rutin was ineffective. The generation of superoxide anion radicals by this system was determined by either reduction of cytochrome c or Pholasin luminescence. A scavenging of superoxide was only observed for myricetin and to a small extent for rutin. All flavonols tested inhibited the Pholasin luminescence of fMet-Leu-Phe-stimulated neutrophils. Rutin influenced the oxidative burst of neutrophils in the same way as wortmannin and LY294002, two inhibitors of the phosphoinositide 3-kinase gamma. Indeed, rutin inhibited the activity of this enzyme, whereas the three other flavonols showed no effect. Thus, an inhibition of enzymes involved in signaling rather than a scavenging of superoxide anion radicals dominates in fMet-Leu-Phe-stimulated neutrophils exposed to flavonols.
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PMID:Effects of flavonols on the generation of superoxide anion radicals by xanthine oxidase and stimulated neutrophils. 1167 65

The inhibition of xanthine oxidase activity by various flavonoids was assessed. All of the tested flavonoids were competitive inhibitors, and from the kinetic analysis suggested that flavonoids bind to the reactive site. To further understand the stereochemistry between these flavonoids and xanthine oxidase, structure-based molecular modeling was performed. Apigenin was the most potent inhibitor which showed the most favorable interaction in the reactive site. The bicyclic benzopyranone ring of apigenin stacked with phenyl of Phe 914, and the phenolic group stretched to the space surrounding with several hydrophobic residues. Quercetin and myricetin composed a 3-hydroxyl group on benzopyranone which resulting in reduction of binding affinity. The phenolic group of genistein positioned in opposite orientation comparison with apigenin, and resulted in a weaker interaction with xanthine oxidase. Isovitexin showed the weakest inhibitory effect among the compounds tested. The bulky group of sugar in isovitexin may hamper its interaction with xanthine oxidase.
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PMID:Molecular modeling of flavonoids that inhibits xanthine oxidase. 1205 58

The effect of Wen-Pi-Tang extract on renal injury induced by peroxynitrite (ONOO-) production was investigated using rats subjected to intravenous lipopolysaccharide (LPS) injection and then renal ischemia followed by reperfusion. The plasma level of 3-nitrotyrosine, a marker of cytotoxic ONOO formation in vivo, was enhanced markedly in control rats subjected to LPS plus ischemia-reperfusion, but was significantly reduced by the oral administration of Wen-Pi-Tang extract, at doses of 62.5 and 125 mg/kg body weight/day, for 30 days prior to LPS plus ischemia-reperfusion. The activities of inducible nitric oxide synthase (iNOS) and xanthine oxidase (XOD) in renal tissue of control and Wen-Pi-Tang extract-treated rats did not change significantly, while those of the antioxidant enzymes, superoxide dismutase, catalase and glutathione peroxidase, were significantly increased by the administration of Wen-Pi-Tang extract, indicating that Wen-Pi-Tang improved the defense system by scavenging free radicals, not by directly inhibiting nitric oxide and superoxide production by iNOS and XOD. In addition, the levels of the hydroxylated products, m- and p-tyrosine, declined, whereas that of phenylalanine increased, after oral administration of Wen-Pi-Tang extract. Furthermore, the elevated plasma urea nitrogen and creatinine levels resulting from LPS plus ischemia-reperfusion process were significantly reduced by Wen-Pi-Tang extract, implying amelioration of renal impairment. The present study indicates that Wen-Pi-Tang extract contributes to the regulation of ONOO- formation and plays a beneficial role against ONOO(-) -induced oxidative injury and renal dysfunction in vivo.
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PMID:Prevention of peroxynitrite-induced renal injury through modulation of peroxynitrite production by the Chinese prescription Wen-Pi-Tang. 1260 16

Nabumetone is a non-steroidal anti-inflammatory drug (NSAID). It works as a prodrug and is extensively metabolized to an active metabolite, 6-methoxy-2-naphthylacetic acid (6MNA). It is well known that neutrophil infiltration and activation are critical in the pathogenesis of NSAID-induced gastric injury, and nabumetone shows less incidence of gastrointestinal irritancy. We examined the effects of nabumetone on neutrophil activation and on indometacin-induced gastric damage. In the indometacin-induced gastric mucosal injury, rats were treated with indometacin and then nabumetone or 6MNA was orally administered. Nabumetone prevented gastric damage accompanied by the reduction of neutrophil infiltration into gastric mucosa, but such an effect was not observed with 6MNA. Nabumetone reduced the formyl methionyl leucyl phenylalanine (fMLP)-induced respiratory burst of human neutrophils to 30% of the control level in-vitro, but 6MNA did not. In addition, nabumetone prevented the fMLP-induced migration of neutrophils. Nabumetone did not inhibit O2- generation in the xanthine-xanthine oxidase system. These results suggest that nabumetone prevents gastric damage induced by the active metabolite, 6MNA, via the suppression of neutrophil activation in gastric mucosa.
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PMID:Non-steroidal anti-inflammatory drug, nabumetone, prevents indometacin-induced gastric damage via inhibition of neutrophil functions. 1263 55

Twenty-one phloroglucinol derivatives, belonging to 8 different carbon skeletons, were tested for their ability to influence the oxidative burst of polymorphonuclear cells (PMNs) after stimulation with N-formyl-methionyl-leucyl-phenylalanine (FMLP) or opsonized zymosan (OZ). Results revealed a strong reduction of oxygen production by PMNs after stimulation with FMLP for the compounds ialibinone E ( 5), hyperguinone B ( 15) and hyperforin ( 21). The IC 50 values obtained were 2.5 microM ( 5), 3.3 microM ( 15) and 1.8 microM ( 21), respectively. Slight modifications of the substituents or variation of the stereochemistry resulted in a significant loss of activity. None of the active compounds showed antioxidative activity after stimulation with OZ. The influence of compounds 5, 15 and 21 on the production of oxygen radicals in an H 2 O 2 /horseradish peroxidase system was investigated and revealed potent activity only for compound 5 (IC 50 1 microM). The superoxide-scavenging properties of ialibinone E ( 5) and hyperguinone B ( 15) were additionally tested in a cytochrome c assay and only ialibinone E ( 5) was found to be significantly active at lower micromolar concentrations. Ialibinone E ( 5) was not active in a xanthine oxidase assay (urate formation) in concentrations up to 100 microM and its activity is therefore not attributable to the inhibition of this enzyme. It can be assumed that the activity of compounds 5 and 15 in the different cellular and enzymatic assays, is most likely caused by different and maybe specific mechanisms and cannot be explained by a radical scavenger activity alone. None of the active phloroglucinols showed cytotoxic effects against the PMNs.
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PMID:Studies on the antioxidative activity of phloroglucinol derivatives isolated from hypericum species. 1267 21

In mammals, xanthine oxidoreductase is synthesized as a dehydrogenase (XDH) but can be readily converted to its oxidase form (XO) either by proteolysis or modification of cysteine residues. The crystal structures of bovine milk XDH and XO demonstrated that atoms in the highly charged active-site loop (Gln-423-Lys-433) around the FAD cofactor underwent large dislocations during the conversion, blocking the approach of the NAD+ substrate to FAD in the XO form as well as changing the electrostatic environment around FAD. Here we identify a unique cluster of amino acids that plays a dual role by forming the core of a relay system for the XDH/XO transition and by gating a solvent channel leading toward the FAD ring. A more detailed structural comparison and site-directed mutagenesis analysis experiments showed that Phe-549, Arg-335, Trp-336, and Arg-427 sit at the center of a relay system that transmits modifications of the linker peptide by cysteine oxidation or proteolytic cleavage to the active-site loop (Gln-423-Lys-433). The tight interactions of these residues are crucial in the stabilization of the XDH conformation and for keeping the solvent channel closed. Both oxidative and proteolytic generation of XO effectively leads to the removal of Phe-549 from the cluster causing a reorientation of the bulky side chain of Trp-336, which then in turn forces a dislocation of Arg-427, an amino acid located in the active-site loop. The conformational change also opens the gate for the solvent channel, making it easier for oxygen to reach the reduced FAD in XO.
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PMID:Unique amino acids cluster for switching from the dehydrogenase to oxidase form of xanthine oxidoreductase. 1281 83


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