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)

2,4-Dinitrotoluene (2,4-DNT) is an important industrial nitroaromatic compound. 2,4-Diaminotoluene (2,4-DAT), one of the urinary metabolites of 2,4-DNT, is carcinogenic when fed to rats. The objectives of these studies were to determine whether 2,4-DAT was formed from 2,4-DNT in rat liver and to clarify the nature of enzymes responsible for reduction of 2,4-DNT to 2,4-DAT. Data obtained from thin-layer and high-pressure liquid chromatography indicated that metabolites produced by microsomal preparations were 2-amino-4-nitrotoluene (2A4NT) and its isomer (4A2NT). This microsomal activity is probably mediated by cytochrome P-450 because the reduction is blocked by carbon monoxide and primary amines [aniline, n-octylamine, and 2,4-dichloro-6-phenylphenoxyethylamine (DPEA)]. In contrast, 2,4-DNT was metabolized via 2A4NT and 4A2NT to 2,4-DAT by cytosolic preparations. The greatest part of the reduction activity was due to cytosolic xanthine oxidase because the reduction was blocked by allopurinol. The results of this investigation suggest that reduction of 2,4-DNT to 2,4-DAT by cytosolic xanthine oxidase may play a role in 2,4-DNT hepatocarcinogenicity.
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PMID:Reduction of 2,4-dinitrotoluene by Wistar rat liver microsomal and cytosol fractions. 654 24

The carbon monoxide oxidases (COXs) purified from the carboxydotrophic bacteria Pseudomonas carboxydohydrogena and Pseudomonas carboxydoflava were found to be molybdenum hydroxylases, identical in cofactor composition and spectral properties to the recently characterized enzyme from Pseudomonas carboxydovorans (O. Meyer, J. Biol. Chem. 257:1333-1341, 1982). All three enzymes exhibited a cofactor composition of two flavin adenine dinucleotides, two molybdenums, eight irons and eight labile sulfides per dimeric molecule, typical for molybdenum-containing iron-sulfur flavoproteins. The millimolar extinction coefficient of the COXs at 450 nm was 72 (per two flavin adenine dinucleotides), a value similar to that of milk xanthine oxidase and chicken liver xanthine dehydrogenase at 450 nm. That molybdopterin, the novel prosthetic group of the molybdenum cofactor of a variety of molybdoenzymes (J. Johnson and K. V. Rajagopalan, Proc. Natl. Acad. Sci. U.S.A. 79:6856-6860, 1982) is also a constituent of COXs from carboxydotrophic bacteria is indicated by the formation of identical fluorescent cofactor derivatives, by complementation of the nitrate reductase activity in extracts of Neurospora crassa nit-l, and by the presence of organic phosphate additional to flavin adenine dinucleotides. Molybdopterin is tightly but noncovalently bound to the protein. COX, sulfite oxidase, xanthine oxidase, and xanthine dehydrogenase each contains 2 mol of molybdopterin per mol of enzyme. The presence of a trichloroacetic acid-releasable, so-far-unidentified, phosphorous-containing moiety in COX is suggested by the results of phosphate analysis.
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PMID:Molybdopterin in carbon monoxide oxidase from carboxydotrophic bacteria. 658 59

Benznidazole (Bz) (N-benzyl-2-nitro-1-imidazole-acetamide) is a drug used against Chagas' disease. Rat liver microsomal and cytosolic fractions, but not mitochondria, exhibited Bz nitroreductase activity under anaerobic conditions in the presence of NADPH. Microsomal nitroreductase activity was enhanced by FAD and was inhibited totally by oxygen and partially by carbon monoxide. Liver cystosol fraction was able to reduce Bz nitrogroups in the presence of either N-methylnicotinamide or hypoxanthine as substrates. These enzyme activities were inhibited by menadione or allopurinol respectively. Under every experimental condition leading to enzymatic reduction of Bz nitrogroups and its inhibition or enhancement, reactive metabolites that bind covalently to proteins were also produced. This covalent binding was effectively prevented by reduced glutathione. Results suggest the participation of cytochrome P-450 and cytochrome c reductase in liver microsomal processes and of xanthine oxidase and aldehyde oxidase in liver cytosolic processes of Bz nitroreduction and activation to reactive metabolites that bind covalently to proteins. Possible pharmacological and toxicological implications of the described observations were discussed.
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PMID:Reductive metabolism and activation of benznidazole. 671 14

Purified liver microsomal NADPH-cytochrome P-450 reductase is able to catalyze the activation of [14C]ronidazole to metabolite(s) which bind covalently to protein. Like the reaction catalyzed by microsomes, protein alkylation catalyzed by the reductase is (1) sensitive to oxygen, (2) requires reducing equivalents, (3) is inhibited by sulfhydryl-containing compounds and (4) is stimulated several fold by either flavin mononucleotide (FMN) or methytlviologen. A cytochrome P-450 dependent pathway of ronidazole activation can be demonstrated as judged by the inhibition of the reaction by carbon monoxide, metyrapone and 2,4-dichloro-6-phenylphenoxyethylamine but the involvement of specific microsomal cytochrome P-450 isozymes has not been definitively established. Milk xanthine oxidase is also capable of catalyzing ronidazole activation. Polyacrylamide sodium dodecyl sulfate (SDS)-gel electrophoresis reveals that the reactive intermediate(s) of ronidazole does not alkylate proteins selectively.
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PMID:Drug residue formation from ronidazole, a 5-nitroimidazole. II. Involvement of microsomal NADPH-cytochrome P-450 reductase in protein alkylation in vitro. 680 46

A variety of pyridinium, quinolinium, and benzoquinolinium cations have been investigated as potential substrates for milk xanthine oxidase at pH 9.9 and (or) pH 10.6. Steady-state kinetic parameters (kc, Km and (or) kc/Km) have been evaluated for all substrates which are enzymically oxidized. Simple N-alkyl pyridinium cations are neither substrates nor inhibitors, although N-aryl pyridinium cations are slowly oxidized to the 4-pyridinones. N-Methylpyridinium cations bearing 3-CONH2, 3-CONHCH3, 3-COCH3, 3-CO2- or 3-CN substituents are readily oxidized at C-6 and this suggests an important hydrogen-bonding interaction between an enzyme donor and the C-3 carbonyl substituent. A variety of N-methylquinolinium cations bearing C-6 substituents are enzymically oxidized at C-2. Analogous substituent effects on kc/Km for these 6-substituted 1-methylquinolinium cations and the corresponding 1-(substituted phenyl)-pyridinium cations is suggestive of the relative productive binding orientations of these two classes of substrate in the active site. N-Methylbenzoquinolinium and 1,10-phenanthrolinium cations are the best cationic substrates found to date, and suggest a relatively large active-site region for the reducing substrate, and important hydrophobic interactions between enzyme and substrate. The overall enzymic specificity observed for these cationic substrates allows a mapping of the general features of the reducing substrate binding site of this enzyme.
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PMID:Specificity of xanthine oxidase for nitrogen heteroaromatic cation substrates. 689 10

Hypoxia-induced hepatocyte injury results not only from ATP depletion but also from reductive stress and oxygen activation. Thus the NADH/NAD+ ratio was markedly increased in isolated hepatocytes maintained under 95% N2/5% CO2 in Krebs-Henseleit buffer well before plasma membrane disruption occurred. Glycolytic nutrients fructose, dihydroxyacetone or glyceraldehyde prevented cytotoxicity, restored the NADH/NAD+ ratio, and prevented complete ATP depletion. However, the NADH generating nutrients sorbitol, xylitol, glycerol and beta-hydroxybutyrate enhanced hypoxic cytotoxicity even though ATP depletion was not affected. On the other hand, NADH oxidising metabolic intermediates oxaloacetate or acetoacetate prevented hypoxic cytotoxicity but did not affect ATP depletion. Restoring the cellular NADH/NAD+ ratio with the artificial electron acceptors dichlorophenolindophenol and Methylene blue also prevented hypoxic injury and partly restored ATP levels. Ethanol which further increased the cellular NADH/NAD+ ratio increased by hypoxia also markedly increased toxicity whereas acetaldehyde which restored the normal cellular NADH/NAD+ ratio, prevented toxicity even though hypoxia induced ATP depletion was little affected by ethanol or acetaldehyde. The viability of hypoxic hepatocytes is therefore more dependent on the maintenance of normal redox homeostasis than ATP levels. GSH may buffer these redox changes as hypoxia caused cell injury much sooner with GSH depleted hepatocytes. Hypoxia also caused an intracellular release of free iron and cytotoxicity was prevented by desferoxamine. Furthermore, increasing the cellular NADH/NAD+ ratio markedly increased the intracellular release of iron. Hypoxia-induced hepatocyte injury was also prevented by oxypurinol, a xanthine oxidase inhibitor. Polyphenolic antioxidants or the superoxide dismutase mimic, TEMPO partly prevented cytotoxicity suggesting that reactive oxygen species contributed to the cytotoxicity. The above results suggests that hypoxia induced hepatocyte injury results from sustained reductive stress and oxygen activation.
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PMID:Modulating hypoxia-induced hepatocyte injury by affecting intracellular redox state. 748 48

1. Electrical field stimulation (EFS; 10 V, 10 Hz, 2 ms) of porcine coronary artery strips precontracted with 10 nM endothelin-1 (ET-1) for 5 min caused a biphasic response, consisting of a slight contraction during EFS and a marked and irreversible relaxation just after EFS. This irreversible relaxation after EFS has never been investigated. In the present study, we have investigated the mechanism of the relaxation after EFS. 2. The EFS-induced response was not affected by the presence or absence of endothelium and was insensitive to 10 microM tetrodotoxin (TTX). 3. In the presence of free radical scavengers (40 u ml-1 superoxide dismutase (SOD), 1200 u ml-1 catalase or 80 mM D-mannitol), the relaxation after EFS was significantly inhibited. Moreover, relaxation after EFS was not observed in porcine coronary artery strips precontracted with 20 mM KCl. 4. In a cascade experiment, EFS of Krebs-Ringer solution containing 10 nM ET-1 induced marked suppression of the contractile activity of ET-1 in porcine coronary artery strips, which was in accord with the observed decrease in release of immunoreactive ET-1 (ir-ET-1). This effect of EFS was significantly inhibited by each of the free radical scavengers, 3 mM vitamin C, 40 u ml-1 SOD, 1200 u ml-1 catalase and 80 mM D-mannitol. 5. The exchange of 95% O2/5% CO2 gas for 95% N2/5% CO2 gas significantly inhibited the EFS-induced decrease in release of ir-ET-1. 6. Neither superoxide anions generated by xanthine (10 JM) plus xanthine oxidase (0.1 micro ml-1) nor hydrogen peroxide (10 microM) exogenously added to Krebs-Ringer solution containing 10 nM ET-1 affected the level of ir-ET-1.7. Generation of hydroxyl radicals was detected in the EFS-applied Krebs-Ringer solution. The EFS-induced generation of hydroxyl radicals was dependent on the period of stimulation and 02-bubbling, and significant generation of hydroxyl radicals was detectable with stimulation of over 5 min.Moreover, hydroxyl radicals generated in 50 mM NaCl solution containing 10 nM ET-1 by H202 plus Fe2 , i.e. the Fenton reaction, significantly decreased the level of ir-ET-l.8. These findings suggest that oxygen-derived hydroxyl radicals generated by EFS of porcine coronary artery strips inactivate ET-1, probably by structural modification. Thus, porcine coronary artery strips precontracted with ET-1 are potently relaxed by EFS.
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PMID:Loss of contractile activity of endothelin-1 induced by electrical field stimulation-generated free radicals. 781 13

To determine whether hydroxyl radicals (.OH) are generated in the hypoxanthine (HPX)-xanthine oxidase (XOD) reaction, we examined the electron paramagnetic resonance (EPR) spectra of the spin adducts formed. In the EPR study, we used 3,3,5,5-tetramethyl-1-pyrroline-N-oxide (M4PO) as a spin trap, sodium formate (HCOONa) as a .OH scavenger, and oxygen-17 gas as an oxygen source. In the HPX-XOD reaction, both M4PO-OOH and M4PO-OH were observed in the reaction products. The formation of M4PO-OH was independently inhibited by HCOONa resulting in the formation of M4PO-CO2- and in no effects on the formation of M4PO-OOH. With oxygen-17 gas as an oxygen source in the HPX-XOD reaction, both M4PO-17OOH and M4PO-17OH were observed in the reaction products. These results indicate that M4PO-OH is not produced by decomposition of M4PO-OOH and .OH is actually generated during the HPX-XOD reaction.
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PMID:Use of M4PO and oxygen-17 in the study on hydroxyl radical generation in the hypoxanthine-xanthine oxidase reaction. 803 19

The characterization of the enzymatic step(s) involved in the reduction of 3'-azido-3'-deoxythymidine (zidovudine)(ZDV) to 3'-amino-3'-deoxythymidine (AMT) was pursued. AMT formation by human liver microsomes was NADPH dependent, enhanced under anaerobic conditions, and increased by flavin adenine dinucleotide (FAD) and FMN. Carbon monoxide inhibited AMT formation by up to 80%. The effect of theophylline (CYP1A substrate), tolbutamide (CYP2C substrate), chlorzoxazone, thiobenzamide, p-nitrophenol, mercaptoethanol, isoniazid (CYP2E substrates), cortisol (CYP3A substrate), ketoconazole, itraconazole, fluconazole, cimetidine, micronazole (CYP inhibitors), methimazole (flavin-containing mono-oxygenase inhibitor), chloramphenicol (undergoes nitroreduction), allopurinol (xanthine oxidase inhibitor) and dicoumarol (DT-diaphorase inhibitor) on AMT formation were studied to see if the reduction reaction was mediated by a particular isozyme. The greatest inhibition was observed with ketoconazole (concentration producing 50% inhibition = 78.0 microM). At this concentration ketoconazole acted as a non-selective inhibitor of several CYP isozymes. Overall, these data suggested that ZDV reduction was probably mediated by both cytochrome P450 isozymes and NADPH-cytochrome P450 reductase. Formation of AMT, as measured by intrinsic clearance (Clint), was significantly increased in microsomes from rats pre-treated with phenobarbitone, dexamethasone and clofibrate (inducers of CYP2B, CYP3A and CYP4A, respectively). Pre-treatment of rats with beta-naphthoflavone and ethanol (CYP1A and CYP2E1 inducers, respectively) had no effect on AMT formation.
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PMID:The metabolism of zidovudine by human liver microsomes in vitro: formation of 3'-amino-3'-deoxythymidine. 805 24

We earlier showed that the neuropeptide vasoactive intestinal peptide (VIP) reduces or prevents acute injury produced in rat lungs by xanthine and xanthine oxidase. We have now examined whether VIP can protect against lung injury induced by paraquat, a prooxidant pesticide. Isolated guinea pig lungs were perfused for 60 min with Krebs-4% albumin and mechanically ventilated with 95% O2-5% CO2. Infusion of paraquat (100 mg/kg) into the pulmonary artery (n = 9 observations) increased peak airway pressure from 10.1 +/- 0.6 to 54.7 +/- 6.5 cmH2O, perfusion pressure from 8.0 +/- 0.5 to 14.9 +/- 3.0 cmH2O, wet-to-dry lung weight ratio to 7.17 +/- 0.37, and bronchoalveolar lavage protein content to 2.70 +/- 0.83 mg/ml (P < 0.01). Pretreatment with 1-3 micrograms.kg-1 x min-1 VIP markedly attenuated or prevented all abnormalities. Of the related peptides tested, helodermin was as effective as VIP, but secretin and glucagon were ineffective. The results demonstrate that VIP and helodermin protect perfused guinea pig lungs against paraquat-induced injury and support the view that VIP has antioxidant activity.
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PMID:Paraquat-induced lung injury: prevention by vasoactive intestinal peptide and related peptide helodermin. 823 70


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