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-(Dimethylamino) fluorene (1a) and 5-benzoyloxy-2,3,7,8,12,13,17,18-octaethylporphyrin (4) react with superoxide anion radical (generated from KO2/18-crown-6 polyether) in aprotic media. Yet, when incorporated into the lipid bilayer of dimyristoyl phosphatidylcholine liposomes, these two substrates are inert to superoxide, generated enzymatically (xanthine oxidase/acetaldehyde) or radiolytically (60Co or 137Cs source/formate solution). On the other hand, 7-acetoxy-4-methylcoumarin (6), which reacts with superoxide in aprotic media yielding the corresponding 4-methylumbelliferone (7), also gives the same product when incorporated within the liposomal bilayer and reacted with radiolytically or enzymatically generated superoxide. In the latter case, the reaction is inhibited by SOD. NMR studies indicate that in contradistinction to the highly lipophilic 1a and 4, which presumably lie well within the lipid bilayer, 7 lies in a highly polar region of the bilayer. These results suggest that superoxide anion does not penetrate deep into the liposomal bilayer; nevertheless, superoxide reactions can, indeed, be observed, provided the active site of the substrate lies at or near the lipid-water interface.
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PMID:Can superoxide organic chemistry be observed within the liposomal bilayer? 872 33

The acetone-H2O (9:1) extract from the stem of Cistanche deserticola showed a strong free radical scavenging activity. Nine major phenylethanoid compounds were isolated from this extract. They were identified by NMR as acteoside, isoacteoside, 2'-acetylacteoside, tubuloside B, echinacoside, tubuloside A, syringalide A 3'-alpha-rhamnopyranoside, cistanoside A and cistanoside F. All of these compounds showed stronger free radical scavenging activities than alpha-tocopherol on 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical and xanthine/xanthine oxidase (XOD) generated superoxide anion radical (O2-.). Among the nine compounds, isoacteoside and tubuloside B, whose caffeoyl moiety is at 6'-position of the glucose, showed an inhibitory effect on XOD. We further studied the effects of these phenylethanoids on the lipid peroxidation in rat liver microsomes induced by enzymatic and non-enzymatic methods. As expected, each of them exhibited significant inhibition on both ascorbic acid/Fe2+ and ADP/NADPH/Fe3+ induced lipid peroxidation in rat liver microsomes, which were more potent than alpha-tocopherol of caffeic acid. The antioxidative effect was found to be potentiated by an increase in the number of phenolic hydroxyl groups in the molecule.
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PMID:Antioxidative effects of phenylethanoids from Cistanche deserticola. 899 43

Xanthine oxidase (XO), catalyzes the sequential oxidation of hypoxanthine to xanthine and then to uric acid. The enzyme also catalyzes the oxidation of aldehydes to their corresponding carboxylic acids. In the present work we investigate the extent of inhibition of the xanthine oxidase-catalyzed oxidation of hypoxanthine by acetaldehyde/acetaldehyde hydrate system. At room temperature, aqueous solutions of acetaldehyde exist as equilibrated mixtures containing similar quantities of the aldehyde, CH3CHO and its hydrate CH3CH(OH)2. To determine whether acetaldehyde or its hydrate interacts with the enzyme to cause inhibition, the time course of enzymatic inhibition was observed in deoxygenated solutions of xanthine oxidase initially incubated with neat acetaldehyde and compared to that in which the enzyme was initially incubated with aqueous solutions containing both the aldehyde and its hydrate. Our results show that unhydrated acetaldehyde inhibits XO and that the inhibition of the XO-catalyzed oxidation of hypoxanthine progressively increases as the aldehyde is incubated with the enzyme. The data, taken together, suggest that enzymatic inhibition is the result of the reversible formation of covalently bound XO-acetaldehyde inhibitory compound. This investigation also demonstrates that the enzymatic oxidations of hypoxanthine and acetaldehyde take place on the same active site in XO.
Physiol Chem Phys Med NMR 1996
PMID:The inhibition of xanthine oxidase by acetaldehyde in aqueous solution. 909 92

The radical modulation activity of hot water and alkaline extracts from leaf of Ceriops decandra, a mangrove plant, was investigated using ESR spectroscopy. IR and NMR analyses demonstrate that the leaf extracts have a lignin-like polyphenolic structure. All these extracts produced radical(s) under alkaline conditions. The radical intensity of sodium ascorbate was slightly reduced at lower concentrations of the extracts, but it was synergistically enhanced at higher concentrations. All the extracts effectively scavenged superoxide anion, produced by hypoxanthine-xanthine oxidase reaction. Pretreatment of mice with the extracts significantly protected them from the lethal infection by E. coli. Similar activity was found in lignins from pine seed shell of Pinus parviflora Sieb. et Zucc. These data further support the medicinal efficacy of plant extracts.
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PMID:Radical modulation activity of lignins from a mangrove plant, Ceriops decandra (Griff.) Ding Hou. 970 79

In this study we have investigated some chemical properties and the biological role of thiazolidine compounds, obtained by condensation of aminothiols (L- or D-cysteine, cysteamine) with pyridoxal-5'-phosphate. These products have been tested in presence of rat liver extracts (supernatant and mitochondria); bacterial suspensions and enzymes (L- or D-aminoacid oxidase, xanthine oxidase) with interesting results which gives evidence to a biological role. Their formation in vivo may represent the regulation of intracellular levels of pyridoxal-5'-phosphate and aminothiols. Moreover, we have analysed the two diastereoisomers of the thiazolidine compounds derived from L-cysteine and D-cysteine: we have succeeded to distinguish by NMR analysis the cis and the trans forms, concluding that the interconversion of the free forms is extremely rapid at pH 7: thus, it may be relevant for the protein bound forms.
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PMID:Some chemical properties and biological role of thiazolidine compounds. 977 14

A guanoxabenz [1-(2,6-dichlorobenzylideneamino)-3-hydroxyguanidine; an N-hydroxyguanidine] reducing enzymatic activity of rat spleen cytosol was investigated. By means of protein purification and N-terminal amino acid sequencing, the reducing activity was shown to reside in xanthine oxidase. The action of the enzyme on guanoxabenz resulted in the formation of guanabenz [1-(2,6-dichlorobenzylidene-amino)-3-guanidine]; the product formation could be monitored by HPLC and its identity was confirmed by NMR analysis. The reduction of guanoxabenz required xanthine or NADH as reducing substrates, while the process could be blocked by allopurinol, a selective inhibitor of xanthine oxidase. By using bovine milk xanthine oxidase, the guanoxabenz reducing activity of the enzyme was also verified. We conclude that guanoxabenz is a novel electron acceptor structure for xanthine oxidase.
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PMID:Identification of an N-hydroxyguanidine reducing activity of xanthine oxidase. 979 17

We determined whether DNA adducts derived from 4-nitropyrene (4-NP) are formed via nitroreduction or ring oxidation. DNA adduct markers derived from both pathways were prepared and, consequently, were compared with those obtained in vivo in rats treated with 4-NP. Following in vitro reaction of 9,10-epoxy-9,10-dihydro-4-nitropyrene (4-NP-9,10-epoxide), an intermediate metabolite derived from ring oxidation of 4-NP, with calf thymus DNA (average level of binding in two determinations was 8.5 nmol/mg of DNA), DNA was enzymatically hydrolyzed to deoxyribonucleosides and the DNA hydrolysates were analyzed by HPLC. Electrospray mass and 1H NMR spectra of the major products indicated that these adducts are deoxyguanosine (dG) derivatives that resulted from N2-dG substitution at the 9- or 10-position of the pyrene nucleus. However, these adducts were not detected in vivo in the rat mammary gland and liver following the administration of 4-NP. Nitroreduction of 4-NP catalyzed by xanthine oxidase in the presence of DNA resulted in three major putative DNA adducts (level of binding of 12.0 +/- 1.1 nmol/mg of DNA, n = 4) designated as peak 1 (46%), peak 2 (25%), and peak 3 (17%). Although peak 1 was further resolved into peaks 1a and 1b, both were unstable and gradually decomposed to peak 2, and the latter was unequivocally identified as pyrene-4,5-dione. On the basis of electrospray mass spectral analysis, peak 3 was tentatively identified as a deoxyinosine-derived 4-aminopyrene adduct. None of the adducts derived from nitroreduction of 4-NP catalyzed by xanthine oxidase coeluted with the synthetic standard N-(deoxyguanosin-8-yl)-4-aminopyrene prepared by reacting dG with N-acetoxy-4-aminopyrene. Nevertheless, HPLC analysis of the hydrolysates of liver and mammary DNA obtained from rats treated with [3H]-4-NP yielded four radioactive peaks, all of which coeluted with the markers derived from the nitroreduction pathway. These results indicate that nitroreduction is primarily responsible for DNA adduct formation in the liver and, especially, in the mammary gland which is the organ susceptible to carcinogenesis by this environmental agent.
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PMID:Nitroreduction of 4-nitropyrene is primarily responsible for DNA adduct formation in the mammary gland of female CD rats. 1002 96

N,N'-Propylenedinicotinamide (Nicaraven) is presently being developed for the treatment of cerebral stroke including subarachnoid hemorrhage. This drug is promising because some data suggest it to have an ability to scavenge the hydroxyl radical under physiological conditions in vivo, while it also has a high permeability through the blood brain barrier. Using the kinetic constant of the reaction between the hydroxyl radical and dimethyl sulfoxide, the formula derived by Babbs and Griffin (Free Rad. Biol. Med., 6 1989) was applied to obtain the kinetic constant of Nicaraven with the hydroxyl radical using a dimethyl sulfoxide-xanthine oxidase-hypoxanthine-Fe system, and this yielded the kinetic constant 3.4x10(9) M(-1) s(-1) (1 M=1 mol dm(-3)) for Nicaraven. Structurally related compounds were also investigated. The amide group of Nicaraven was thus found to play an important part in the reaction with the hydroxyl radical. Methanesulfinic acid, which was obtained from the reaction between dimethyl sulfoxide and the hydroxyl radical, was found to be stable under this adopted experimental condition and therefore was used to quantify the kinetic constant of Nicaraven. The structure of Nicaraven has also been investigated in CDCl3 using IR spectra, computer calculations and 1H-NMR analysis, and Nicaraven was thus shown to have an intramolecular hydrogen bond which forms a 7-membered ring that resembles a part of the 1H-1,4-benzodiazepines. This structure may play an important role in the penetration through the blood brain barrier.
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PMID:Quantitative analysis of the kinetic constant of the reaction of N,N'-propylenedinicotinamide with the hydroxyl radical using dimethyl sulfoxide and deduction of its structure in chloroform. 1078 63

The aim of this work was to characterize the products of metabolic activation of the antitumor drug ledakrin (Nitracrine) in model metabolic systems, where formation of drug-DNA adducts was previously discovered. The metabolic products obtained in different biological systems were compared with those obtained in experiments where chemical reducing agents were applied. Therefore, activation products were obtained in the presence of the microsomal fraction of rat liver and in the experiments with the reducing agents dithiothreitol, hydrazine hydrate, and SnCl(2). Furthermore, transformations of the drug with oxidoreductase enzymes DT-diaphorase and xanthine oxidase were observed. The ledakrin transformation products were separated and analyzed by HPLC with diode array detection. Structural studies of the products were performed by means of ESI-MS and NMR. Proton, carbon, and nitrogen assignments were made based upon DQF-COSY, ROESY, TOCSY, HSQC, and HMBC experiments. It was demonstrated during the reduction of ledakrin that a key metabolite, a compound with an additional five-membered ring attached to positions 1 and 9 of the acridine core and with the retained 9-aminoalkyl side chain, was formed in all the systems that were studied. It was determined that the reactive nitrogen atoms of this additional ring underwent further transformations resulting in the formation of a six-membered ring produced by the addition of a carbon atom to the dihydropyrazoloacridine ring. Furthermore, it was observed that positions 2 and 4 of ledakrin's acridine ring are susceptible to nucleophilic substitution as revealed by the studies with dithiothreitol. Additionally, although most products from the reduction of ledakrin were extremely unstable, 1-aminoacridinone, produced enzymatically and with dithiothreitol, exhibited persistent stability under the studied conditions.
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PMID:Products of metabolic activation of the antitumor drug ledakrin (nitracrine) in vitro. 1117 May 2

Thioarenes, sulfur-containing polycyclic aromatic compounds, are environmental contaminants suspected of posing human health risks. In this study, 5-nitrobenzo[b]naphtho[2,1-d]thiophene (5-nitro-BNT), a nitrated-thioarene, was examined for its mutagenicity, metabolism and subsequent formation of DNA adducts. 5-Nitro-BNT was weakly mutagenic in Salmonella typhimurium strains TA98 and TA100 without Aroclor-1254-induced rat liver S9 (S9), and its activity was increased in the presence of S9. Anaerobic metabolism of 5-nitro-BNT by S9 or xanthine oxidase (XO) produced one major metabolite, identified as 5-amino-BNT by NMR, MS, and UV spectroscopy and by comparison with an authentic standard. Aerobic S9 metabolism of 5-nitro-BNT produced a major metabolite, identified as trans-9,10-dihydroxy-9,10-dihydro-5-nitro-BNT (5-nitro-BNT-9,10-diol). Also present was a minor amount of 5-amino-BNT and trans-9,10-dihydroxy-9,10-dihydro-5-amino-BNT (5-amino-BNT-9,10-diol). DNA adduct analyses were performed using the (32)P-postlabeling assay and reversed-phase HPLC. Three major XO-derived calf thymus DNA adducts were detected. On the basis of their chromatographic mobilities, two adducts were identified as reaction products of 5-nitro-BNT with 2'-deoxyguanosine and one adduct with 2'-deoxyadenosine. Incorporation of allopurinol (a specific XO inhibitor) in the incubation mixture resulted in loss of all three adducts, confirming enzymatic mediation by XO. Aerobic S9 activation of 5-nitro-BNT with calf thymus DNA produced three adducts. On the basis of their chromatographic mobilities, two were identified as reaction products of 5-nitro-BNT with 2'-deoxyguanosine and one with 2'-deoxyadenosine. Incorporation of 1-aminobenzotriazole (a P450 inhibitor) in the incubation mixture resulted in a loss of these adducts, confirming enzymatic mediation by P450. Aerobic S9-catalyzed metabolism of 5-nitro-BNT-9,10-diol produced the same DNA adducts as observed with 5-nitro-BNT. Aerobic S9-catalyzed metabolism of 5-amino-BNT-9,10-diol produced the same deoxyadenosine-derived DNA adducts as observed with 5-nitro-BNT and 5-nitro-BNT-9,10-diol. These results provide additional information that both ring oxidation and nitroreduction are involved in the metabolism, DNA adduct formation and mutagenicity of 5-nitro-BNT.
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PMID:An evaluation of the mutagenicity, metabolism, and DNA adduct formation of 5-nitrobenzo[b]naphtho[2,1-d]thiophene. 1140 36


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