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)

Bone marrow stroma consists predominately of two cell types, macrophages and fibroblastoid stromal cells, which regulate the growth and differentiation of myelopoietic cells via the production of growth factors. We have previously shown that macrophages are more sensitive than fibroblastoid stromal cells (LTF cells) to the toxic effects of the benzene metabolite hydroquinone. In this study, the role of selective bioactivation and/or deactivation in the macrophage-selective effects of hydroquinone was examined. LTF and macrophage cultures were incubated with 10 microM [14C]hydroquinone to examine differential bioactivation. After 24 hr, the amount of 14C covalently bound to acid-insoluble macromolecules was determined. Macrophages had 16-fold higher levels of macromolecule-associated 14C than did LTF cells. Additional experiments revealed that hydroquinone bioactivation to covalent-binding species was hydrogen peroxide dependent in macrophage homogenates. Covalent binding in companion LTF homogenates was minimal, even in the presence of excess hydrogen peroxide. These data suggest that a peroxidative event was responsible for bioactivation in macrophages and, in agreement with this, macrophages contained detectable peroxidase activity whereas LTF cells did not. Bioactivation of [14C]hydroquinone to protein-binding species by peroxidase was confirmed utilizing purified human myeloperoxidase in the presence of hydrogen peroxide and ovalbumin as a protein source. High performance liquid chromatographic analysis of incubations containing purified myeloperoxidase, hydroquinone, and hydrogen peroxide showed that greater than 90% of hydroquinone was removed and could be detected stoichometrically as 1,4-benzoquinone. 1,4-Benzoquinone was confirmed as a reactive metabolite formed from hydroquinone in macrophage incubations using excess GSH and trapping the reactive quinone as its GSH conjugate, which was measured by high performance liquid chromatography with electrochemical detection. The activity of DT-diaphorase, a quinone reductase that has been invoked as a protective mechanism in quinone-induced toxicity, was 4-fold higher in LTF cells than macrophages. These data suggest that the macrophage-selective toxicity of hydroquinone results from higher levels of peroxidase-mediated bioactivation and/or lower levels of DT-diaphorase-mediated detoxification.
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PMID:Bone marrow stromal cell bioactivation and detoxification of the benzene metabolite hydroquinone: comparison of macrophages and fibroblastoid cells. 215 73

Dihydrodiol dehydrogenase (DD; EC 1.3.1.20) will oxidize non-K-region trans-dihydrodiols of polycyclic aromatic hydrocarbons (PAHs), a reaction that can suppress the formation of PAHs) anti-diol epoxides or ultimate carcinogens. Using benzenedihydrodiol [(+/-)-trans-1,2-dihydroxy-3,5-cyclohexadiene] as a model substrate for trans-dihydrodiol metabolites of PAHs, 23 human liver and eight human lung samples were examined for enzyme activity. In human liver, enzyme activity could be measured spectrophotometrically and specific activities ranged from 0.16 to 6.1 nmol benzenedihydrodiol oxidized min/mg protein. Western blot analysis of human liver cytosol using rabbit anti-rat DD serum detected two bands of mol. wts 34,000 and 27,000. The former mol. wt is identical to that observed for the homogeneous rat liver enzyme. Gel-filtration experiments indicate that human liver DD activity elutes as a single peak and co-elutes with the purified rat liver enzyme, suggesting that the lower mol. wt species may be an artefact of degradation. Preparations of the human liver enzyme required NADP- for activity and were in general, insensitive to inhibition by dicoumarol, indomethacin and 6-medroxyprogesterone acetate. These properties distinguish the enzyme from alcohol dehydrogenase, quinone reductase and rat liver DD. In human lung, DD activity was barely detectable using a sensitive radiochemical assay in which the oxidation of benzenedihydrodiol to catechol is linked to catechol-O-methyl transferase using [3H]S-adenosyl methionine as methyl donor. Specific activities were approximately 1000th of that observed for human liver and ranged from 1 to 4 pmol benzenedihydrodiol oxidized/min/mg protein. Western blot analysis of lung cytosol detected three bands of mol. wts 34,000, 31,000 and 28,000. The relatively high levels of DD in human liver suggest that this enzyme may play an important role in PAH detoxication in this organ, while the low levels of DD in lung may contribute to the susceptibility of this tissue to PAH-induced carcinogenesis.
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PMID:Characterization of dihydrodiol dehydrogenase in human liver and lung. 219 14

Natural and synthetic estrogens elicit normal hormonal responses in concentrations in a clearly defined yet low range. At elevated doses, metabolic reactions of the phenolic moiety, while harmless at low levels, may become the predominant biochemical activity and may exert deleterious effects. These metabolic pathways, such as i) oxidation of estrogens to catechol estrogens and further to their respective quinones, and ii) free radical generation by redox cycling between catechol estrogens or diethylstilbestrol and their quinones, are investigated for their influence in physiological or pathophysiological processes. In this review, the in vitro capacity of various enzymes to oxidize estrogen hydroquinones to quinones or to reduce corresponding quinones to hydroquinones is evaluated. The in vivo activities of enzymes supporting redox cycling of estrogens and free radical generation is correlated with induction of kidney tumors in Syrian hamsters. Concomitant changes in activities in quinone reductase and other detoxifying enzymes in kidneys of hamsters treated with estrogen support a role of free radicals in the induction of tumors by estrogen. Free radical damage to protein and possibly to DNA in kidneys of estrogen-treated hamsters may be used as markers of free radical action in vivo.
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PMID:Free radical generation by redox cycling of estrogens. 219 44

The regulation of polycyclic aromatic hydrocarbon-inducible enzymes, cytochrome P450IA1, NAD(P)H:quinone oxidoreductase, and glutathione S-transferases, by glucocorticoids was investigated using primary fetal rat hepatocyte culture. Treatment of cells in culture with 1,2-benzanthracene (100 microM, 72 hr) resulted in 60-, 2-, and 6-fold increases in cytochrome P450IA1, glutathione S-transferase, and NAD(P)H:quinone reductase activities, respectively. The inductive effect of 1,2-benzanthracene on cytochrome P450IA1 and glutathione S-transferase (1-chloro-2,4-dinitrobenzene conjugation) activities was potentiated approximately 3- and 2- to 3-fold, respectively, when dexamethasone (0.01-1 microM) was included in the culture medium. In contrast, 1 microM dexamethasone was found not to potentiate the induction of NAD(P)H:quinone oxidoreductase activity by 1,2-benzanthracene. Treatment of cultured hepatocytes with dexamethasone alone, at concentrations of up to 100 microM, resulted in a 2- to 4-fold increase in glutathione S-transferase and NAD(P)H:quinone oxidoreductase activity. Both the induction of glutathione S-transferase activity by high concentrations of dexamethasone alone and the potentiation of 1,2-benzanthracene induction by lower concentrations of dexamethasone were observed for other steroids of the glucocorticoid class in conjunction with a variety of polycyclic aromatic hydrocarbons. Western immunoblot analyses indicated that low concentrations of dexamethasone (0.1-1 microM) potentiated 1,2-benzanthracene-dependent induction of cytochrome P450IA1, glutathione S-transferase Ya/Yc subunit and NAD(P)H:quinone oxidoreductase content. Additionally, increased glutathione S-transferase activity in response to concentrations of dexamethasone exceeding 1 microM was associated with concomitant increases in Ya/Yc and Yb subunit content. Potentiation of polycyclic aromatic hydrocarbon induction of cytochrome P450IA1, glutathione S-transferase, and NAD(P)H:quinone oxidoreductase protein content by low concentrations of glucocorticoids and induction of glutathione S-transferase and NAD(P)H:quinone oxidoreductase by high concentrations of glucocorticoids alone indicates the importance of these endogenous compounds in the regulation of some hepatic enzymes involved in xenobiotic metabolism.
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PMID:Glucocorticoid regulation of polycyclic aromatic hydrocarbon induction of cytochrome P450IA1, glutathione S-transferases, and NAD(P)H:quinone oxidoreductase in cultured fetal rat hepatocytes. 230 51

NAD(P)H:(quinone-acceptor)oxidoreductase (QAO), previously known as DT-diaphorase, catalyzes the reduction of quinones to hydroquinones. Enhanced activity of the enzyme has been suggested to protect cells against the cellular toxicity and carcinogenicity of quinones, but may activate some cytotoxic anti-tumor quinones. Cytosolic levels of QAO, carbonyl reductase (CR) and total quinone reductase activity have been measured in normal and tumorous human tissues. QAO was the major component of the total cytosolic quinone reductase activity in all the tissues investigated. CR represented 10 to 28% of the total cytosolic quinone reductase activity in normal tissue. Normal tissue QAO was high in the stomach and kidney, and lower in the lung, liver, colon and breast. Primary tumor from lung, liver, colon and breast had elevated levels of QAO compared to normal tissue, while tumor from kidney and stomach had lower levels. CR was not significantly altered in tumor tissue, except in the case of lung and colon tumor which showed an increase compared to normal tissue. A major determinant of the variability of human lung tumor QAO was the cigarette-smoking history of the donor. Non-smokers and past smokers had high levels of tumor QAO compared to normal tissue. Smokers had levels of tumor QAO that were not significantly different from those of normal tissue QAO. Smokers had a small increase in normal lung QAO compared to non-smokers. Alcohol use was associated with an increase in lung tumor QAO but had no effect on QAO in normal lung. The function of QAO in tumors is not known but the elevated activity of QAO in some tumors and the apparent depressant effect of smoking could influence the response of these tumors to quinone drugs or toxic agents that are metabolized by QAO.
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PMID:Cytosolic NAD(P)H:(quinone-acceptor)oxidoreductase in human normal and tumor tissue: effects of cigarette smoking and alcohol. 230 29

DBA/2 mice have been reported to be more susceptible than C57BL/6 mice to the bone marrow toxic effects of two quinone-generating chemicals, benzo[a]pyrene and benzene. In this study we have investigated the activity of quinone reductase (QR) (NADPH:DT diaphorase), a quinone detoxifying enzyme, in whole bone marrow and bone marrow-derived stromal cells from these two strains of mice. The sensitivity of bone marrow-derived stromal cells to toxicity induced by several metabolites of benzene was also investigated. Whole bone marrow and primary cultures of stromal cells cultured from DBA/2 mice had a lower basal level of QR activity compared to those of C57Bl/6 mice and as such exhibited a greater sensitivity to the toxic effects of hydroquinone (HQ), a metabolite of benzene. However, there was no difference between the two strains of mice to benzoquinone- or phenol-induced toxicity. Increased QR activity in DBA/2 and C57Bl/6 stromal cells could be induced by prior stromal cell treatment with tert-butylhydroquinone which resulted in protection against subsequent hydroquinone treatment. Thus, differences in target organ QR activity may contribute to differential susceptibility to quinone-generating bone marrow toxins.
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PMID:Differences in quinone reductase activity in primary bone marrow stromal cells derived from C57BL/6 and DBA/2 mice. 234 85

The relationship between the NADH:lipoamide reductase and NADH:quinone reductase reactions of pig heart lipoamide dehydrogenase (EC 1.6.4.3) was investigated. At pH 7.0 the catalytic constant of the quinone reductase reaction (kcat.) is 70 s-1 and the rate constant of the active-centre reduction by NADH (kcat./Km) is 9.2 x 10(5) M-1.s-1. These constants are almost an order lower than those for the lipoamide reductase reaction. The maximal quinone reductase activity is observed at pH 6.0-5.5. The use of [4(S)-2H]NADH as substrate decreases kcat./Km for the lipoamide reductase reaction and both kcat. and kcat./Km for the quinone reductase reaction. The kcat./Km values for quinones in this case are decreased 1.85-3.0-fold. NAD+ is a more effective inhibitor in the quinone reductase reaction than in the lipoamide reductase reaction. The pattern of inhibition reflects the shift of the reaction equilibrium. Various forms of the four-electron-reduced enzyme are believed to reduce quinones. Simple and 'hybrid ping-pong' mechanisms of this reaction are discussed. The logarithms of kcat./Km for quinones are hyperbolically dependent on their single-electron reduction potentials (E1(7]. A three-step mechanism for a mixed one-electron and two-electron reduction of quinones by lipoamide dehydrogenase is proposed.
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PMID:The mechanism of the quinone reductase reaction of pig heart lipoamide dehydrogenase. 237 45

The effect of Ag+ on Na+ pumping by Na(+)-motive NADH-quinone reductase and terminal oxidase has been studied in Bacillus FTU inside-out vesicles. Very low concentrations of Ag+ (C1/2 = 1 x 10(-8) M or 2 x 10(-12) g ion.mg protein-1) are shown to inhibit the uphill Na+ uptake coupled to the oxidation of NADH by fumarate or of ascorbate + TMPD by oxygen but exert no effect on the H+ uptake by the H(+)-motive respiratory chain. Low Ag+ also induces a specific increase in the Na+ permeability of the vesicles. HQNO, added before and not after Ag+, prevents the Ag(+)-induced permeability increase, with effective HQNO concentrations being similar to those inhibiting the uphill Na(+)-uptake coupled to the NADH-fumarate oxidoreduction. Reduction of terminal oxidase by ascorbate + TMPD in the presence of cyanide sensitizes the Na+ permeability to Ag+. It is suggested that low [Ag+], known as a specific inhibitor of electron transport by the Na(+)-motive NADH-quinone reductase, uncouples the electron and Na+ transports so that the Ag(+)-modified NADH-quinone reductase operates as an Na+ channel rather than an Na+ pump. This effect is discussed in connection with the antibacterial action of Ag+.
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PMID:Submicromolar Ag+ increases passive Na+ permeability and inhibits the respiration-supported formation of Na+ gradient in Bacillus FTU vesicles. 238 16

Vitamin K hydroquinone formation in rat liver can be catalyzed by a thiol-dependent quinone reductase activity which shares several characteristics with the vitamin K 2,3-epoxide reductase activity. The possibility that a single enzyme catalyzes both reductions was investigated. Values of Vmax/Km for several different vitamin K analogs were determined and found to be similar for both reductase activities. Several different coumarins were also shown to achieve 50% inhibition at similar concentrations for both enzyme activities. The chloro analog of menaquinone-2 was shown to inhibit both reductases, and the presence of either the quinone or epoxide form of the vitamin protected both activities from inactivation. Thioredoxin was shown to function as a reductant for both reductase activities, although the maximum enzyme activity achieved by this reductant was only half that achieved with dithiothreitol as a reductant. Cofractionation of the two reductase activities on a variety of column matrices was also observed. These data strongly support the hypothesis that one microsomal enzyme is capable of catalyzing both reduction of vitamin K 2,3-epoxide to the quinone, and the quinone to vitamin K hydroquinone.
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PMID:Vitamin K epoxide and quinone reductase activities. Evidence for reduction by a common enzyme. 239 Jan 2

NAD(P)H:(quinone-acceptor) oxidoreductase (EC 1.6.99.2) is a widely distributed enzyme which promotes two-electron reductions of quinones and thereby protects cells against damage by reactive oxygen species generated during oxidative cycling of quinones and semiquinone radicals. Quinone reductase activity represents a minor component (about 0.006%) of mouse liver cytosolic proteins under basal (uninduced) conditions. Two isofunctional forms of this quinone reductase have been purified to homogeneity (1700-fold) in 30% yield from the liver cytosols of female CD-1 mice in which the enzymes were induced by administration of 2(3)-tert-butyl-4-hydroxyanisole. The purification involved ion exchange, hydrophobic, and affinity chromatographies. The two enzyme forms have been designated "hydrophilic" and "hydrophobic" based on the order of elution from phenyl-Sepharose. The more abundant hydrophilic form has been crystallized in the presence of FAD in the form of macroscopic tetragonal crystals. The two forms have similar isoelectric points (pI 9.2) and subunit molecular weights (Mr = 30,000) and probably exist as dimers in the native state. Purified preparations of the enzymes are equiactive with NADH and NADPH and show almost complete dependence on added FAD for catalytic activity. The Km values for FAD of the hydrophilic and hydrophobic forms are 2.72 and 1.72 nM, respectively. Their catalytic activities are the same and are remarkably high for nicotinamide nucleotide-linked dehydrogenases; maximum velocities (expressed per mg of pure enzyme) approach 4000 units/mg of protein under appropriate assay conditions. When menadione is the electron acceptor, the Km value for this quinone is very low (Km congruent to 2 microM). Both enzyme forms are potently inhibited by dicoumarol. Rabbit antisera against the hydrophilic quinone reductase precipitate quantitatively the entire quinone reductase activity of mouse liver cytosols obtained from animals maintained on a standard diet or those induced with 3-tert-butyl-4-hydroxyanisole. The quinone reductase activity of rat liver cytosols is also quantitatively precipitated by this antiserum.
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PMID:Purification and characterization of two isofunctional forms of NAD(P)H: quinone reductase from mouse liver. 241 14


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