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:1.6.5.2 (NQO1)
6,196 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To investigate how perivascular NO synthase (NOS)-containing nerves in the cerebral arterial system are involved in controlling the cerebral circulation, we observed the ultrastructure of NOS-containing nerve fibers and their terminals by means of nicotinamide adenine dinucleotide hydrogen phosphate-diaphorase (NADPH-d) histochemistry. We also observed the correlation between NADPH-d stained perivascular nerves and the perivascular sympathetic nerves, by means of double staining with NADPH-d histochemistry and tyrosine hydroxylase (TH) immunohistochemistry at the light microscopic level. NADPH-d-positive nerve fibers showed dense distribution mainly in the rostral portion of the circle of Willis and proximal portions of its main branches, where some of the NADPH-d-positive fibers coexisted with TH-positive fibers in a single nerve bundle. NADPH-d-positive nerve fibers were unmyelinated and had close contact with NADPH-d-negative myelinated and unmyelinated nerve fibers in a single nerve bundle, and NADPH-d-positive nerve terminals also existed closely with NADPH-d-negative nerve terminals. The number of NADPH-d-positive nerve terminals and their ratio to all other terminals were significantly higher in the rostral portion of the circle of Willis and the proximal portion of its branches, than the caudal portion of the circle of Willis and the distal portion of its branches. Nerve terminals were observed to locate within 250 nm from the basal lamina of arterial smooth muscle cells in the rostral portion of the circle of Willis and proximal portion of its branching arteries. The present observation confirmed that NOS-containing nerve fibers truly innervate the smooth muscle cells of the arterial wall in the circle of Willis and its main branches. Close contact between NADPH-d-positive and -negative nerve fibers and terminals in these arterial portions may indicate that NOS-containing perivascular nerves may work to modulate the rest of the other perivascular nervous system, such as the sympathetic nerves, to regulate the homeostasis of the arterial tonus.
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PMID:Ultrastructure of NADPH diaphorase-positive nerve fibers and their terminals in the rat cerebral arterial system. 1142 68

Chorismate synthase catalyzes the anti-1,4-elimination of the phosphate group and the C-(6proR) hydrogen from 5-enolpyruvylshikimate 3-phosphate to yield chorismate, a central building block in aromatic amino acid biosynthesis. The enzyme has an absolute requirement for reduced FMN, which in the case of the fungal chorismate synthases is supplied by an intrinsic FMN:NADPH oxidoreductase activity, i.e. these enzymes have an additional catalytic activity. Therefore, these fungal enzymes have been termed "bifunctional." We have cloned chorismate synthase from the common bread mold Neurospora crassa, expressed it heterologously in Escherichia coli, and purified it in a three-step purification procedure to homogeneity. Recombinant N. crassa chorismate synthase has a diaphorase activity, i.e. it catalyzes the reduction of oxidized FMN at the expense of NADPH. Using NADPH as a reductant, a reduced flavin intermediate was observed under single and multiple turnover conditions with spectral features similar to those reported for monofunctional chorismate synthases, thus demonstrating that the intermediate is common to the chorismate synthase-catalyzed reaction. Furthermore, multiple turnover experiments in the presence of oxygen have provided evidence that NADPH binds in or near the substrate (5-enolpyruvylshikimate 3-phosphate) binding site, suggesting that NADPH binding to bifunctional chorismate synthases is embedded in the general protein structure and a special NADPH binding domain is not required to generate the intrinsic oxidoreductase activity.
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PMID:Spectroscopic and kinetic characterization of the bifunctional chorismate synthase from Neurospora crassa: evidence for a common binding site for 5-enolpyruvylshikimate 3-phosphate and NADPH. 1152 20

Cytochrome b561 (cyt b561) is a trans-membrane cytochrome probably ubiquitous in plant cells. In vitro, it is readily reduced by ascorbate or by juglonol, which in plasma membrane (PM) preparations from plant tissues is efficiently produced by a PM-associated NAD(P)H:quinone reductase activity. In bean hypocotyl PM, juglonol-reduced cyt b561 was not oxidized by hydrogen peroxide alone, but hydrogen peroxide led to complete oxidation of the cytochrome in the presence of a peroxidase found in apoplastic extracts of bean hypocotyls. This peroxidase active on cyt b561 was purified from the apoplastic extract and identified as an ascorbate peroxidase of the cytosolic type. The identification was based on several grounds, including the ascorbate peroxidase activity (albeit labile), the apparent molecular mass of the subunit of 27 kDa by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, the dimeric native structure, the typical spectral properties of a heme-containing peroxidase, and an N-terminal sequence strongly conserved with cytosolic ascorbate peroxidases of plants. Cyt b561 used in the experiments was purified from bean hypocotyl PM and juglonol was enzymatically produced by recombinant NAD(P)H:quinone reductase. It is shown that NADPH, NAD(P)H:quinone reductase, juglone, cyt b561, the peroxidase interacting with cyt b561, and H2O2, in this order, constitute an artificial electron transfer chain in which cyt b561 is indirectly reduced by NADPH and indirectly oxidized by H2O2.
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PMID:Ascorbate-independent electron transfer between cytochrome b561 and a 27 kDa ascorbate peroxidase of bean hypocotyls. 1173 31

A series of quinone substrates were modeled into the active site of human DT-diaphorase and minimized. Correlation of these models with the substrate specificity k(cat)/K(m) provided insights into the structural requirements of quinone substrates. The W105, F106, and H194 residues can influence the position of the quinone substrate in the active site resulting in formation of one of the two possible Michael anions resulting from hydride transfer from FADH(2). Electron withdrawing groups on the substrate can stabilize these anions resulting in excellent substrate specificity. Inspection of models indicated that the W-105 and F-106 residues form parallel walls that will accommodate large polycyclic substrates. Thus excellent polycyclic substrates of DT-diaphorase were designed. However, the placement of tetrahedral centers on these polycyclic substrates interfered with the W-105 and the F-106 residues resulting in their exclusion from the active site. The histidine (H194) residue permits recognition of substrate enantiomers as a result of hydrogen bonding interactions. As a result of this study, it will be possible to design poor to excellent substrates of DT-diaphorase and take advantage of varying levels of this enzyme in histologically different cancers.
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PMID:A comprehensive study of the active site residues of DT-diaphorase: rational design of benzimidazolediones as DT-diaphorase substrates. 1188 90

Pure thiosulfinates, R-S(O)S-R (2), where R = Me (2a), Pr (2b), or All (2c), at levels up to 4 mM were not capable of scavenging hydrogen peroxide or superoxide anion. Relative to standard antioxidants (ascorbic acid, n-propyl gallate, butylated hydroxytoluene, Trolox, and reduced glutathione), these thiosulfinates were 1-3 orders of magnitude less efficient at reducing 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical, 0.5-2 orders of magnitude less efficient at quenching singlet oxygen, and about equally effective at scavenging hydroxyl radical. Generally, AllS(O)SAll (2c) was the most effective and PrS(O)SPr (2b) was the least effective thiosulfinate in these assays, except that MeS(O)SMe (2a) exhibited no quenching effect toward singlet oxygen. These thiosulfinates were also incapable at levels up to 0.1 mM (where they were toxic) of in vitro induction of quinone reductase (QR) in murine hepatoma (hepa 1c1c7) cells. However, S-1-propenyl-L-cysteine sulfoxide (isoalliin, 1a) and cycloalliin (3) induced QR in this system at 2 mM and 1 mM, respectively, although doubling of QR required levels of 10-15 mM.
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PMID:Antioxidant functions of selected allium thiosulfinates and S-alk(en)yl-L-cysteine sulfoxides. 1195 10

Sex-specific effects of sublethal concentrations of known effective pro-oxidants such as 100,200 and 400 microM benzo[a]pyrene (B[a]p), 50 microM nitrofurantoin (NF) and 100 microM hydrogen peroxide (H2O2) on biotransformation pathways were studied in isolated hepatocytes of immature female and male European flounder (Platichthys flesus L.). Cell responses were assessed at the level of: (1) stress induction as measured by formation of reactive oxygen species (ROS), mainly superoxide radicals, and induction of cytochrome P450 (CYP450) biotransformation activity; (2) cellular antioxidant defences, both non-enzymatic (reduced glutathione) and enzymatic (DT-diaphorase (DTD) or quinone oxidoreductase, EC 1.6.99.2); (3) detoxification (aldehyde dehydrogenase (ALDH), EC 1.2.1.3); and (4) cellular damage as measured by reduced lysosomal membrane stability and cell death. As there is increasing evidence that 17-beta-estradiol interferes with certain pathways of xenobiotic biotransformation, we additionally tested the effects of different concentrations of 17-beta-estradiol (0.2-10 microM) alone and 17-beta-estradiol (1 microM) in combination with 100 microM B[a]p. Parameters were monitored after 1 and 9 days of exposure by quantitative image analysis of chromogenic or fluorogenic reaction products. Our study revealed sex-dependent differences in cellular stress responses. In hepatocytes of female flounder, biotransformation was slower and the capacity of non-enzymatic antioxidant defences and detoxification of toxic aldehydes was lower than in males. Additional administration of 17-beta-estradiol enlarged these differences between the sexes with respect to biotransformation activity and antioxidant defence in xenobiotic-induced injury. These findings may explain the higher susceptibility of female flounder to toxic and carcinogenic compounds in the marine environment.
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PMID:Sex-specific biotransformation and detoxification after xenobiotic exposure of primary cultured hepatocytes of European flounder (Platichthys flesus L.). 1208 31

In previous works we demonstrated that 2-methyl-1,4-naphthoquinone (menadione) causes a marked increase in the force of contraction of guinea pig and rat isolated atria. This inotropic effect was significantly higher in the guinea pig than in the rat and was strictly related to the amount of superoxide anion (O(2)(*-)), generated as a consequence of cardiac menadione metabolism through mitochondrial NADH-ubiquinone oxidoreductase. The present study was designed to further elucidate the basis of these quantitatively different positive inotropic responses. To this purpose, we measured O(2)(*-) and hydrogen peroxide (H(2)O(2)) produced by mitochondria isolated from guinea pig and rat hearts in the presence of 20 microM menadione. Moreover, we evaluated the menadione detoxification activity (DT-diaphorase) and the antioxidant defences of guinea pig and rat hearts, namely their GSH/GSSG content, Cu/Zn- and Mn-dependent superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (Gpx) activities. Our results indicate that DT-diaphorase activity and glutathione levels were similar in both animal species. By contrast, guinea pig mitochondria produced greater amounts of O(2)(*-) and H(2)O(2) than those of rat heart. This is probably due to both the higher Mn-SOD activity (2.93 +/- 0.02 vs. 1.95 +/- 0.06 units/mg protein; P < 0.05) and to the lower Gpx activity (10.09 +/- 0.30 vs. 32.67 +/- 1.02 units/mg protein; P < 0.001) of guinea pig mitochondria. A lower CAT activity was also observed in guinea pig mitochondria (2.40 +/- 0.80 vs. 6.13 +/- 0.20 units/mg protein; P < 0.01). Taken together, these data provide a rational explanation for the greater susceptibility of guinea pig heart to the toxic effect of menadione: because of the greater amount of O(2)(*-) generated by the quinone and the higher mitochondrial Mn-SOD activity, guinea pig heart is exposed to more elevated concentrations of H(2)O(2) that is less efficiently detoxified, because of lower Gpx and CAT levels of mitochondria.
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PMID:Role of antioxidant defences in the species-specific response of isolated atria to menadione. 1210 91

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

We have compared the effects of aqueous extracts of cooked Brussels sprouts, isolated glucosinolates and their breakdown products on the activity of quinone reductase [NADPH:quinone-reductase] (QR) and on DNA strand breaks induced by hydrogen peroxide in murine hepa1c1c7 cells. QR activity was not significantly altered after incubation of the cells with Brussels sprouts extracts. However, some of the glucosinolates and in particular their myrosinase-catalysed hydrolysis products and the degradation product of indole-glucosinolates, indole-3-carbinole (I3C), di(indol-3-yl)-methane (DIM) and 2,3-bis(indol-3-ylmethyl)indole (TRI) effectively induced QR activity. Isolated isothiocyanates did not influence the QR activity. The extracts of cooked and autolysed Brussels sprouts and some glucosinolates inhibited the DNA strand breaks induced by 100 microM hydrogen peroxide. Maximum inhibition was by 20-38% after 24 h of preincubation. Hydrolysis of the glucosinolates by myrosinase decreased the inhibitory effects, whereas I3C, DIM or TRI had no effect on DNA damage. Accordingly, the protective effect of Brussels sprouts constituents against induction of oxidative DNA damage appears to be unrelated to enzyme inducing properties via the antioxidant responsive element. Both of these effects could be part of the suggested cancer preventive effect of cruciferous vegetables.
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PMID:Effect of chemopreventive compounds from Brassica vegetables on NAD(P)H:quinone reductase and induction of DNA strand breaks in murine hepa1c1c7 cells. 1261 18

The stress-activated protein kinases SAPK/JNK and p38/mHOG are activated by diverse classes of stress stimuli, many of which induce redox perturbations. We studied the effects of reactive quinones on stress signaling pathways. Menadione (2-methyl-1,4-naphthoquinone), which undergoes both one- and two-electron reduction, completely inhibited SAPK activity at high concentrations while activating SAPK at lower concentrations. Menadione activated p38/mHOG dose responsively. 2,3-Dimethyl-1,4-naphthoquinone (DMNQ), which preferentially undergoes two-electron reduction, had similar effects. In contrast, 1,4-naphthoquinone, which preferentially undergoes one-electron reduction, inhibited SAPK at high concentrations, but failed to activate SAPK at any concentration tested. In addition, this quinone activated p38 only at lower concentrations; high concentrations inhibited p38 activity. These activity profiles correlated with the activation state of the upstream kinase, indicating that the effects were mediated by an upstream step in the kinase pathway. The quinone reductase inhibitor dicoumarol blocked activation of SAPK by menadione and DMNQ, suggesting that two-electron reduction is important. Finally, addition of increasing amounts of hydrogen peroxide mimicked the effects of menadione and DMNQ, suggesting that hydrogen peroxide may be the relevant mediator. Differential activation of stress kinases by reactive quinones demonstrates that the cellular redox environment independently modulates these pathways.
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PMID:Reactive quinones differentially regulate SAPK/JNK and p38/mHOG stress kinases. 1262 22


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