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)

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

In an earlier communication, we have shown that Tephrosia purpurea ameliorates benzoyl peroxide-induced oxidative stress in murine skin (Saleem et al. 1999). The present study was designed to investigate a chemopreventive efficacy of T purpurea against N-diethylnitrosamine-initiated and potassium bromate-mediated oxidative stress and toxicity in rat kidney. A single intraperitoneal dose of N-diethylnitrosamine (200 mg/kg body weight) one hr prior to the dose of KBrO3 (125 mg/kg body weight) increases microsomal lipid peroxidation and the activity of xanthine oxidase and decreases the activities of renal antioxidant enzymes viz., catalase, glutathione peroxidase, glutathione reductase and glucose-6-phosphate dehydrogenase, phase II metabolizing enzymes such as glutathione-S-transferase and quinone reductase and causes depletion in the level of renal glutathione content. A sharp increase in blood urea nitrogen and serum creatinine has also been observed. Prophylactic treatment of rats with T. purpurea at doses of 5 mg/kg body weight and 10 mg/kg body weight prevented N-diethylnitrosamine-initiated and KBrO3 promoted renal oxidative stress and toxicity. The susceptibility of renal microsomal membrane for iron ascorbate-induced lipid peroxidation and xanthine oxidase activities were significantly reduced (P<0.01). The depleted levels of glutathione, the inhibited activities of antioxidant enzymes, phase II metabolizing enzymes and the enhanced levels of serum creatinine and blood urea nitrogen were recovered to a significant level (P<0.01). All the antioxidant enzymes were recovered dose-dependently. Our data indicate that T purpurea besides a skin antioxidant can be a potent chemopreventive agent against renal oxidative stress and carcinogenesis induced by N-diethylnitrosamine and KBrO3.
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PMID:Tephrosia purpurea ameliorates N-diethylnitrosamine and potassium bromate-mediated renal oxidative stress and toxicity in Wistar rats. 1145 68

Aristolochic acid (AA), a naturally occurring nephrotoxin and rodent carcinogen, has recently been associated with the development of urothelial cancer in humans. Understanding which enzymes are involved in AA activation and/or detoxication is important in the assessment of an individual susceptibility to this natural carcinogen. We examined the ability of enzymes of rat renal and hepatic cytosolic fractions to activate AA to metabolites forming DNA adducts by the nuclease P1-enhanced version of the (32)P-postlabeling assay. Cytosolic fractions of both these organs generated AA-DNA adduct patterns reproducing those found in renal tissues from humans exposed to AA. 7-(Deoxyadenosin-N(6)-yl)aristolactam I, 7-(deoxyguanosin-N(2)-yl)aristolactam I and 7-(deoxyadenosin-N(6)-yl)aristolactam II were identified as AA-DNA adducts formed from AAI and 7-(deoxyguanosin-N(2)-yl)aristolactam II and 7-(deoxyadenosin-N(6)-yl)aristolactam II were generated from AAII by hepatic cytosol. Qualitatively the same AA-DNA adduct patterns were observed, although at lower levels, upon incubation of AAs with renal cytosol. To define the role of cytosolic reductases in the reductive activation of AA, we investigated the modulation of AA-DNA adduct formation by cofactors, specific inducers or selective inhibitors of the cytosolic reductases, DT-diaphorase, xanthine oxidase (XO) and aldehyde oxidase. The role of the enzymes in AA activation was also investigated by correlating the DT-diaphorase- and XO-dependent catalytic activities in cytosolic sample with the levels of AA-DNA adducts formed by the same cytosolic sample. On the basis of these studies, we attribute most of the cytosolic activation of AA to DT-diaphorase, although a role of cytosolic XO cannot be ruled out. With purified DT-diaphorase, the participation of this enzyme in the formation of AA-DNA adducts was confirmed. The binding orientation of AAI in the active site of DT-diaphorase was predicted by computer modeling based on published X-ray structures. The results presented here are the first report demonstrating a reductive activation of carcinogenic AAs by DT-diaphorase.
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PMID:Carcinogenic aristolochic acids upon activation by DT-diaphorase form adducts found in DNA of patients with Chinese herbs nephropathy. 1196 Sep 15

The major insecticide imidacloprid (IMI) is known to be metabolized by human cytochrome P450 3A4 with NADPH by imidazolidine hydroxylation and dehydrogenation to give 5-hydroxy-imidacloprid and the olefin, respectively, and by nitroimine reduction and cleavage to yield the nitrosoimine, guanidine, and urea derivatives. More extensive metabolism by human or rabbit liver microsomes with NADPH or rabbit liver cytosol without added cofactor reduces the IMI N-nitro group to an N-amino substituent, i.e., the corresponding hydrazone. A major metabolite on incubation of IMI in the human microsome-NADPH system is tentatively assigned by LC/MS as a 1,2,4-triazol-3-one derived from the hydrazone; the same product is obtained on reaction of the hydrazone with ethyl chloroformate. The hydrazone and proposed triazolone are considered here together (referred to as the hydrazone) for quantitation. Only a portion of the microsomal reduction and cleavage of the nitroimine substituent is attributable to a CYP450 enzyme. The cytosolic enzyme conversion to the hydrazone is inhibited by added cofactors (NAD > NADH > NADP > NADPH) and enhanced by an argon instead of an air atmosphere. The responsible cytosolic enzyme(s) does not appear to be DT-diaphorase (which is inhibited by several neonicotinoids), aldose reductase, aldehyde reductase, or xanthine oxidase. However, the cytosolic metabolism of IMI is inhibited by several aldo-keto-reductase inhibitors (i.e., alrestatin, EBPC, Ponalrestat, phenobarbital, and quercetin). Other neonicotinoids with nitroimine, nitrosoimine, and nitromethylene substituents are probably also metabolized by "neonicotinoid nitro reductase(s)" since they serve as competitive substrates for [(3)H]IMI metabolism.
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PMID:Neonicotinoid insecticides: reduction and cleavage of imidacloprid nitroimine substituent by liver microsomal and cytosolic enzymes. 1223 Apr 9

The phenol content and antioxidant activity of extra virgin olive oils (EVOOs) differing in their origins and degradation degrees were studied. The o-diphenolic compounds typical of olive oil, namely, the oleuropein derivatives hydroxytyrosol (3',4'-dihydroxyphenylethanol, 3',4'-DHPEA), the dialdehydic form of elenolic acid linked to 3',4'-DHPEA (3',4'-DHPEA-EDA), and an isomer of oleuropein aglycon (3',4'-DHPEA-EA), were analyzed by HPLC. The antioxidant activity was studied by (a) the xanthine oxidase (XOD)/xanthine system, which generates superoxide radical and hydrogen peroxide; (b) the diaphorase (DIA)/NADH/juglone system, which generates superoxide radical and semiquinonic radical; and (c) the 2,2-diphenyl-1-picrylhydrazyl radical (DPPH) test. Results showed that EVOOs with a low degradation level (as evaluated by acidity, peroxide number, and spectroscopic indices K(232), K(270), and deltaK according to the EU Regulation) had a higher content of 3',4'-DHPEA-EDA and a lower content of 3',4'-DHPEA than oils having intermediate and advanced degradation levels. EVOOs with a low degradation degree were 3-5 times more efficient as DPPH scavengers and 2 times more efficient as inhibitors of the XOD-catalyzed reaction than oils with intermediate and advanced degradation levels. The DIA-catalyzed reaction was inhibited by EVOOs having low or intermediate degradation levels but not by the most degraded oils.
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PMID:Comparison of the antioxidant activities of extra virgin olive oils. 1247 92

The chemopreventive potential of cycloartenol on benzoyl peroxide and UVB radiation-induced cutaneous tumor promotion markers and oxidative stress in murine skin is assessed. Benzoyl peroxide treatment (20 mg/animal/0.2 ml acetone) and UVB radiation (0.420 J/m(2)/s) caused a decrease in the activities of cutaneous antioxidant enzymes namely, catalase, glutathione peroxidase, glutathione reductase, glucose-6-phosphate dehydrogenase, phase II metabolizing enzyme such as glutathione-S-transferase and quinone reductase and depletion in the level of cutaneous glutathione. There was also enhancement in cutaneous microsomal lipid peroxidation, xanthine oxidase activity, [(14)C]-ornithine decarboxylase activity and [(3)H]-thymidine incorporation into cutaneous DNA. Cycloartenol was topically applied prior to the application of benzoyl peroxide at dose levels of 0.2 mg and 0.4 mg/kg body weight in acetone, which resulted in significant inhibition of epidermal ornithine decarboxylase activity and DNA synthesis (P < 0.001). There was also significant reduction of lipid peroxidation and xanthine oxidase activity (P < 0.001). In addition, the depleted levels of glutathione, inhibited activities of antioxidant and phase II metabolizing enzymes, were also recovered to a significant level (P < 0.001). The data indicate that cycloartenol is an effective chemopreventive agent in skin carcinogenesis.
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PMID:Inhibition of benzoyl peroxide and ultraviolet-B radiation induced oxidative stress and tumor promotion markers by cycloartenol in murine skin. 1280 13

Aristolochic acid (AA), a naturally occurring nephrotoxin and carcinogen, has been associated with the development of urothelial cancer in humans. Understanding which human enzymes are involved in AA metabolism is important in the assessment of an individual's susceptibility to this carcinogen. Using the 32P-postlabeling assay we examined the ability of enzymes of cytosolic samples from 10 different human livers and from one human kidney to activate the major component of the plant extract AA, 8-methoxy- 6-nitro-phenanthro-(3,4-d)-1,3-dioxolo-5-carboxylic acid (AAI), to metabolites forming adducts in DNA. Cytosolic fractions of both organs generated AAI-DNA adduct patterns reproducing those found in renal tissues from humans exposed to AA. 7-(Deoxyadenosin-N6-yl)aristolactam I, 7-(deoxyguanosin-N2-yl)aristolactam I and 7-(deoxyadenosin-N6-yl)aristolactam II, indicating a possible demethoxylation reaction of AAI, were identified as AA-DNA adducts formed from AAI by all human hepatic and renal cytosols. To define the role of human cytosolic reductases in the activation of AAI, we investigated the modulation of AAI-DNA adduct formation by cofactors or selective inhibitors of the NAD(P)H:quinone oxidoreductase (NQO1), xanthine oxidase (XO) and aldehyde oxidase. We also determined whether the activities of NQO1 and XO in different human hepatic cytosolic samples correlated with the levels of AAI-DNA adducts formed by the same cytosolic samples. Based on these studies, we attribute most of the activation of AA in human cytosols to NQO1, although a role of cytosolic XO cannot be ruled out. With purified NQO1 from rat liver and kidney and XO from buttermilk, the major role of NQO1 in the formation of AAI-DNA adducts was confirmed. The orientation of AAI in the active site of human NQO1 was predicted from molecular modeling based on published X-ray structures. The results demonstrate for the first time the potential of human NQO1 to activate AAI by nitroreduction.
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PMID:Human cytosolic enzymes involved in the metabolic activation of carcinogenic aristolochic acid: evidence for reductive activation by human NAD(P)H:quinone oxidoreductase. 1286 22

Alpha-lipoic acid (LA) has recently been reported to exert protective effects on various forms of oxidative cardiac disorders. However, the mechanisms underlying LA-mediated cardioprotection remain to be investigated. This study was undertaken to determine whether LA treatment could increase endogenous antioxidants and phase 2 enzymes in cultured cardiomyocytes, and whether such increased cellular defenses could afford protection against oxidative cardiac cell injury. Incubation of rat cardiac H9C2 cells with low micromolar concentrations of LA resulted in a significant induction of a scope of cellular antioxidants and phase 2 enzymes in a concentration- and/or time-dependent fashion. These include catalase, reduced glutathione, glutathione reductase, glutathione S-transferase, and NAD(P)H:quinone oxidoreductase-1 (NOQ1). Induction of catalase and NOQ1 was most dramatic among the above LA-inducible antioxidants and phase 2 enzymes. To further investigate the protective effects of the LA-induced cellular defenses on oxidative cardiac cell injury, H9C2 cells were pretreated with LA (25-100 microM) for 72h and then exposed to xanthine oxidase (XO)/xanthine, a system that generates reactive oxygen species (ROS), for another 24h. We observed that LA pretreatment of H9C2 cells led to a marked protection against XO/xanthine-mediated cytotoxicity, as detected by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium reduction assay. The cytoprotective effects also exhibited a LA concentration-dependent fashion. Moreover, the LA pretreatment resulted in a great inhibition of intracellular accumulation of ROS in H9C2 cells following incubation with XO/xanthine. Taken together, this study demonstrates for the first time that a number of endogenous antioxidants and phase 2 enzymes in cultured cardiomyocytes can be induced by LA at low micromolar concentrations, and that the LA-mediated elevation of cellular defenses is accompanied by a markedly increased resistance to ROS-elicited cardiac cell injury. The results of this study have important implications for the cardioprotective effects of LA.
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PMID:Induction of endogenous antioxidants and phase 2 enzymes by alpha-lipoic acid in rat cardiac H9C2 cells: protection against oxidative injury. 1455 Mar 1

The principal aim of this study was to assess whether the two quinones, menadione (2-methyl-1,4-naphthoquinone) and lawsone (2-hydroxy-1,4-naphthoquinone), elicit differential toxicity in mussels as has been reported for higher organisms. Therefore, the effects of short-term (48 h) and long-term (20 days) exposure of the two quinones at concentrations of 0.56 and 1 mg l(-1) to zebra mussels, Dreissena polymorpha, under laboratory conditions were studied. After the short-term exposure, the specific activities of the two-electron quinone oxidoreductase (DT-diaphorase) and the one-electron catalysing quinone reductases NADPH-cytochrome c reductase and NADH-cytochrome c reductase were determined in the gills and the rest of the soft tissues (soft mussel tissues minus the gills) of both treated and control mussels. At the higher concentrations of menadione and lawsone used, a significant reduction of the activity of NADPH-cytochrome c reductase in the gills and in the rest of the soft mussel tissues (by 33-34% and 31-43%, respectively) was observed. The activities of DT-diaphorase and NADH-cytochrome c reductase were not significantly affected. Interestingly, DT-diaphorase was observed in the gills, an organ requiring protection against antioxidants. Furthermore, a single-cell electrophoretic assay (comet assay) performed with gill cells to assess DNA damage by the quinones did not show any significant difference between the treated and the control organisms. This indicates that the formation of reactive species by the quinone metabolism in vivo in the mussels was possibly suppressed through the concerted action of DT-diaphorase and antioxidant enzymes. The results of in vitro experiments with gill extracts confirmed the protective role of DT-diaphorase. The rate of the two-electron quinone reduction was found to be five times that of the one-electron quinone reduction. The results of the long-term exposure unambiguously demonstrated that in mussels menadione, unlike in higher organisms, is more toxic than lawsone. The lack of detectability of xanthine oxidase in the mussel tissues could explain the comparatively lower toxicity of lawsone in the invertebtrate, lending support to a previous suggestion that xanthine oxidase might be responsible for the mechanism of toxicity of lawsone in higher organisms in vivo.
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PMID:In vivo exposure of Dreissena polymorpha mussels to the quinones menadione and lawsone: menadione is more toxic to mussels than lawsone. 1505 9

Experiments using purified recombinant human NAD(P)H:quinone oxidoreductase 1 (NQO1) revealed that the auto-oxidation of fully reduced protein resulted in a 1:1 stoichiometry of oxygen consumption to NADH oxidation with the production of hydrogen peroxide. The rate of auto-oxidation of fully reduced NQO1 was markedly accelerated in the presence of superoxide (O(2)(*)(-)), whereas the addition of superoxide dismutase greatly inhibited the rate of auto-oxidation. The ability of reduced NQO1 to react with O(2)(*)(-) suggested a role for NQO1 in scavenging O(2)(*)(-), and this hypothesis was tested using established methods for O(2)(*)(-) production and detection. The addition of NQO1 in combination with NAD(P)H resulted in inhibition of dihydroethidium oxidation, pyrogallol auto-oxidation, and elimination of a potassium superoxide-generated ethoxycarbonyl-2-methyl-3,4-dihydro-2H-pyrrole-1-oxide:O(2)(*)(-) adduct signal (electron spin resonance). Kinetic parameters for the reduction of O(2)(*)(-) by NQO1 were estimated using xanthine/xanthine oxidase as the source of O(2)(*)(-) and after NQO1-dependent NADH oxidation at 340 nm. The ability of NQO1 to scavenge O(2)(*)(-) was also examined using cell sonicates prepared from isogenic cell lines containing no NQO1 activity (NQO1(-)) or very high levels of NQO1 activity (NQO1(+)). We demonstrated that addition of NAD(P)H and cell sonicate from NQO1(+) but not NQO1(-) cells resulted in an increased level of O(2)(*)(-) scavenging could be inhibited by 5-methoxy-1,2-dimethyl-3-[(4-nitrophenoxy)methyl]indole-4,7-dione (ES936), a mechanism-based inhibitor of NQO1. NQO1 can generate hydroquinones that are redox active, and the O(2)(*)(-) scavenging activity of NQO1 may allow protection against O(2)(*)(-) at the site of hydroquinone generation. In addition, the O(2)(*)(-) scavenging activity of NQO1 may provide an additional level of protection against O(2)(*)(-) induced toxicity.
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PMID:NAD(P)H:quinone oxidoreductase 1: role as a superoxide scavenger. 1510 52


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