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)

The oxidation of GSH coupled to the redox transitions of 1,4-naphthoquinone derivatives during DT-diaphorase catalysis was examined. The quinones studied included 1,4-naphthoquinone and its dimethoxy- and hydroxy derivatives and were selected according to their different ability to undergo nucleophilic addition with GSH and the dual effect of superoxide dismutase on hydroquinone autoxidation. GSH was oxidized to GSSG during the redox transitions of the above quinones, regardless of their substitution pattern. This effect was accompanied by an increase of total O2 consumption, indicating the ability of GSH to support quinone redox cycling. The values for the relationship [O2]consumed/[GSSG]formed were, with every quinone examined, above unity, thus pointing to the occurrence of autoxidation reactions other than those involved during GSSG formation. These results are discussed in terms of the functional group chemistry of the quinones and the thermodynamic properties of the reactions involved in the reduction of the semi- to the hydro-quinone by GSH.
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PMID:Effect of glutathione on the redox transitions of naphthohydroquinone derivatives formed during DT-diaphorase catalysis. 211 28

Bioactivation of diaziquone (AZQ) in HT-29 human colon carcinoma cells and detoxification of benzene metabolites in bone marrow stromal cells were used as examples of the potential role of DT-diaphorase in both activation and deactivation processes. HT-29 cell cytosol contained high levels of DT-diaphorase activity and removed AZQ in the presence of either NADH or NADPH. Prior boiling of cytosol, omission of NADH or NADPH or inclusion of dicoumarol, an inhibitor of DT-diaphorase, inhibited removal of AZQ. AZQ-induced cytotoxicity in HT-29 cells was also inhibited by dicoumarol. Chemical reduction of AZQ in a cell free system enhanced formation of a GSH conjugate of AZQ. Two of the major cell types in bone marrow stroma are macrophages and fibroblastoid stromal cells. A fibroblastoid cell line derived from stromal cells contained approximately fourfold higher levels of DT-diaphorase than macrophages. Inclusion of dicoumarol in incubations containing 14C-hydroquinone and the respective stromal cell type, significantly increased covalent binding of radiolabel to macromolecules in stromal fibroblasts but not in macrophages.
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PMID:Activation and deactivation of quinones catalyzed by DT-diaphorase. Evidence for bioreductive activation of diaziquone (AZQ) in human tumor cells and detoxification of benzene metabolites in bone marrow stroma. 211 30

The level of quinone oxidoreductases (microsomal and cytosolic DT-diaphorase, NADPH-cytochrome P450 reductase and NADH-cytochrome b5 reductase), superoxide dismutase and glutathione-related enzymatic activities in diethylstilbestrol (DES)-induced carcinogenesis in kidney from Syrian golden hamsters are presented. Animals that exhibited two different stages of DES-induced carcinogenesis in kidney--pre- and neoplastic lesions and tumorous lesions (after 6 and 8 months of continuous exposure to DES respectively)--were studied in comparison to kidneys from control animals. A dramatic decrease in microsomal and cytosolic DT-diaphorase activities (13.6 and 37.8% of controls), as well as in glutathione disulphide reductase (39.5%), and less marked in superoxide dismutase (45.6%), NADH cytochrome b5 reductase (61.9%) glutathione transferase (GST) towards 1-chloro-2,4-dinitrobenzene (CDNB) (66.2%) and glutathione peroxidase (GSH-Px) (80%) activities, were observed in kidneys with pre- and neoplastic lesions. NADPH-cytochrome P450 reductase and GST activity towards 4-hydroxy-2,3-trans-nonenal (4-HNE) showed no statistically significant variation at this stage of carcinogenesis. In kidney from animals with tumorous lesions, all the enzymatic activities mentioned above decreased, except for superoxide dismutase, which was increased to 186% of the control activity. GST activity towards 4-HNE again showed no statistically significant variation. These results suggest that if one-electron reduction of diethylstilbestrol-4',4''-quinone (DESQ) occurs, it may play a very important role in the development of DES carcinogenesis (pre- and neoplastic lesions), since at this stage of carcinogenesis the primary defense mechanisms against the oxygen free radicals generated in this way, i.e. SOD activity, is reduced to less than a half of control values. Both cytosolic and microsomal DT-diaphorase activities are unable at this stage of carcinogenesis to promote effectively the two-electron reduction of DESQ, which would avoid the initial formation of superoxide anion. The consequences of these decreases may be an increased steady-state concentration of superoxide anion and hydrogen peroxide, which in the presence of iron might lead to lipid peroxidation. GST activity towards 4-HNE could be responsible for the possible higher steady-state concentration of this lipid peroxidation product during DES treatment. The induction of DT-diaphorase and its protective role in the prevention of the development of pre- and neoplastic lesions in kidney from Syrian golden hamster during DES treatment is also discussed.
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PMID:The levels of quinone reductases, superoxide dismutase and glutathione-related enzymatic activities in diethylstilbestrol-induced carcinogenesis in the kidney of male Syrian golden hamsters. 211 5

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

Generation of radicals in vivo depends on metabolic activities. The reactions are usually influenced by (i) the presence and concentration of oxygen; (ii) the availability of transition metals (effects of binding and compartimentalization); (iii) the level of reductants and antioxidants (e.g. nutritional effects). The effects of radicals are thought to be due to (i) membrane damage (affecting passive or active transport through altered fluidity/function interrelationships, intercellular messenging through modifications in the synthesis of prostaglandins and leukotrienes); (ii) protein damage (e.g. affecting membrane transporters, channel proteins, receptor or regulatory proteins, immunomodulators); (iii) damage to DNA. Defense mechanisms consist of (i) prevention of the 'spreading' of primary damage by low molecular weight antioxidants (e.g. vitamin E, GSH, vitamin C, beta-carotene, uric acid); (ii) prevention or limitation of 'secondary' damage by enzymes (e.g. GSH-peroxidase, catalase, superoxide dismutase, DT-diaphorase) and/or chelators; (iii) repair processes, e.g. lipid degradation/membrane repair enzymes (phospholipases, peroxidases, some transferases and reductases), protein disposal or repair enzymes (proteases, GSSG-reductase), DNA degradation repair enzymes (exonuclease III, endonucleases III and IV, glycosylases, polymerases). Recent hypotheses on a messenging function of the superoxide anion O2- are discussed and possible implications of cross-reactions between O2- and nitric oxide (endothelium-derived relaxing factor EDRF) are shortly mentioned.
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PMID:Radical reactions in vivo--an overview. 228 Nov 32

Many anticancer drugs exert their cytotoxic effects via formation of oxygen free radicals. Cellular thiols, glutathione (GSH)-dependent enzymes and other redox enzymes are involved in the metabolism of these anticancer drugs and of the oxygen free radicals that may be generated during their metabolism. We quantified these biochemical parameters in cytosol from human ovarian tissues. We compared non-protein thiol levels, GSH transferase, GSH peroxidase, superoxide dismutase, catalase, DT diaphorase and aldehyde dehydrogenase activity in serous ovarian tumors (n = 15), other malignant ovarian tumors (n = 12), benign ovarian tissue (n = 10) and histologically normal ovarian tissue (n = 12). Mean GSH transferase and DT diaphorase activities were similar in serous and other malignant ovarian tumors. GSH transferase activity was decreased in malignant tissues relative to normal and benign tissues. Mean DT diaphorase and superoxide dismutase activities were increased in the malignant tissues, although this was not statistically significant. The mean levels of all enzymes except superoxide dismutase and aldehyde dehydrogenase in benign tissues were fairly similar to the mean levels found in normal tissue samples. Tissues from patients with serous ovarian tumors, who had received cyclophosphamide and cisplatin prior to surgery, also were analyzed (n = 7). Except for aldehyde dehydrogenase, all the parameters measured were decreased in these samples relative to serous tissue from untreated patients. These biochemical analyses may be useful in understanding the mechanisms involved in the response to chemotherapy.
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PMID:Detoxifying enzymes in human ovarian tissues: comparison of normal and tumor tissues and effects of chemotherapy. 239 58

At variance with Cr(III), Cr(VI) compounds easily cross cell membranes and exert genotoxic effects. No metabolic oxidation of Cr(III) could be detected, whereas Cr(VI) reduction was observed in the presence of body fluids and subcellular fractions of various tissues from several animal species. The differential efficiency of this process may account for the selection of target tissues in Cr(VI) carcinogenesis. For instance, reduction by saliva and gastric juice may explain a lack of carcinogenicity by the oral route; reduction inside erythrocytes may explain a lack of carcinogenicity at a distance from administration sites; reduction by the epithelial-lining fluid of terminal airways and by alveolar macrophages may be consistent with the occurrence of thresholds in lung carcinogenesis. Liver preparations displayed the top efficiency in reducing Cr(VI), whereas skeletal muscle, i.e., a typical target in experimental Cr(VI) carcinogenesis, had no detectable activity. Bronchial tree and peripheral lung parenchyma preparations from almost 100 individuals reduced Cr(VI) to a variable extent. The efficiency of lung parenchyma and of isolated alveolar macrophages was enhanced in cigarette smokers. In rats, Cr(VI) reduction by lung preparations was significantly stimulated by the repeated i.t. instillation of Cr(VI) itself. Among the electron donors (chiefly GSH) and enzymatic mechanisms responsible for the intracellular Cr(VI) reduction, such as cytochrome P-450 reductase, glutathione reductase, and aldehyde oxidase, an important role can be ascribed to cytosolic DT diaphorase activity, usually catalyzing a 2-electron reduction.
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PMID:Metabolic reduction of chromium, as related to its carcinogenic properties. 248 84

Naphthazarin (5,8-dihydroxy-1,4-naphthoquinone), the basic unit of several tetracyclic antitumor antibiotics, and its glutathione conjugate were reduced by the one- and two-electron transfer flavoproteins NADPH-cytochrome P450 reductase and DT-diaphorase to their semi- and hydroquinone forms, respectively. Kinetic studies performed on purified DT-diaphorase showed the following results: KNADPHm = 68 microM, KQuinonem = 0.92 microM, and Vmax 1300 nmol X min-1 X microgram enzyme-1. Similar studies performed on purified NADPH-cytochrome P450 reductase indicated a lower KNADPHm (10.5 microM) and higher KQuinonem (2.3 microM). The Vmax values were 20-fold lower (46 nmol X min-1 X micrograms enzyme-1) than those observed with DT-diaphorase. DT-diaphorase reduced the naphthazarin-glutathione conjugate with an efficiency 5-fold lower than that observed with the parent quinone. The nucleophilic addition of GSH to naphthazarin proceeded with GSH consumption at rates slower than those observed with 1,4-naphthoquinone and its monohydroxy derivative, 5-hydroxy-1,4-naphthoquinone. The initial rate of GSH consumption during these reactions did not vary whether the assay was carried out under anaerobic or aerobic conditions. Autoxidation accompanied the DT-diaphorase and NADPH-cytochrome P450 reductase catalysis of naphthazarin and its glutathionyl adduct as well as the 1,4-reductive addition of GSH to naphthazarin. Superoxide dismutase at catalytic concentrations (nM range) enhanced slightly (1.1- to 1.6-fold) the autoxidation following the enzymatic catalysis of naphthazarin. Autoxidation during the GSH reductive addition to 1,4-naphthoquinones decreased with increasing number of -OH substituents, 1,4-naphthoquinone greater than 5-hydroxy-1,4-naphthoquinone greater than 5,8-dihydroxy-1,4-naphthoquinone, thus revealing that the contribution of redox transitions other than autoxidation, e.g., cross-oxidation, to the decay of the primary product of nucleophilic addition increases with increasing number of -OH substituents. Superoxide dismutase enhanced substantially the autoxidation of glutathionyl-naphthohydroquinone adducts, thereby affecting only slightly the total GSH consumed and GSSG formed during the reaction. The present results are discussed in terms of the relative contribution of one- and two-electron transfer flavoproteins to the bioreductive activation of naphthazarin and its glutathionyl conjugate as well as the importance of autoxidation reactions in the mechanism(s) of quinone cytotoxicity.
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PMID:Study of the redox properties of naphthazarin (5,8-dihydroxy-1,4-naphthoquinone) and its glutathionyl conjugate in biological reactions: one- and two-electron enzymatic reduction. 251 57

2-Methyl-1,4-naphthoquinone (menadione) inhibits Ca2+-ATPase activity of cardiac sarcoplasmic reticulum membrane vesicles in a time- and concentration-dependent way; after 60 min of preincubation an apparent Ki value of 33.5 microM was calculated. Inhibition is not reversible in that it persists even after the drug is removed and Ca2+-ATPase activity is assayed in a menadione-free medium. GSH (2 mM), but not DTT, is able to prevent and reverse the inhibition of Ca2+-ATPase by menadione. The relative importance of menadione metabolism in the inhibition of Ca2+-ATPase was studied in cell-free systems composed of vesicles and subcellular fractions containing metabolizing enzymes. Under these experimental conditions, 105,000g supernatants isolated from heart or liver that biotransform menadione through DT-diaphorase reduce the inhibition of Ca2+-ATPase activity determined by menadione. Also liver microsomes that biotransform menadione through NADPH-cytochrome P450 reductase decrease the inhibition by menadione. By contrast, cardiac microsomes that do not biotransform the drug do not influence the effect of menadione. These results indicate that, under the experimental conditions used for this study, menadione does not require metabolism to inhibit cardiac sarcoplasmic reticulum Ca2+-ATPase activity.
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PMID:Inhibition of cardiac sarcoplasmic reticulum Ca2+-ATPase activity by menadione. 252 55

Dopamine (DA) is rapidly oxidized by Mn3(+)-pyrophosphate to its cyclized o-quinone (cDAoQ), a reaction which can be prevented by NADH, reduced glutathione (GSH) or ascorbic acid. The oxidation of DA by Mn3+, which appears to be irreversible, results in a decrease in the level of DA, but not in a formation of reactive oxygen species, since oxygen is neither consumed nor required in this reaction. The formation of cDAoQ can initiate the generation of superoxide radicals (O2-.) by reduction-oxidation cycling, i.e. one-electron reduction of the quinone by various NADH- or NADPH-dependent flavoproteins to the semiquinone (QH.), which is readily reoxidized by O2 with the concomitant formation of O2-.. This mechanism is believed to underly the cytotoxicity of many quinones. Two-electron reduction of cDAoQ to the hydroquinone can be catalyzed by the flavoprotein DT diaphorase (NAD(P)H:quinone oxidoreductase). This enzyme efficiently maintains DA quinone in its fully reduced state, although some reoxidation of the hydroquinone (QH2) is observed (QH2 + O2----QH. + O2-. + H+; QH. + O2----Q + O2-.). In the presence of Mn3+, generated from Mn2+ by O2-. (Mn2+ + 2H+ + O2-.----Mn3+ + H2O2) formed during the autoxidation of DA hydroquinone, the rate of autoxidation is increased dramatically as is the formation of H2O2. Furthermore, cDAoQ is no longer fully reduced and the steady-state ratio between the hydroquinone and the quinone is dependent on the amount of DT diaphorase present. The generation of Mn3+ is inhibited by superoxide dismutase (SOD), which catalyzes the disproportionation of O2-. to H2O2 and O2. It is noteworthy that addition of SOD does not only result in a decrease in the amount of H2O2 formed during the regeneration of Mn3+, but, in fact, prevents H2O2 formation. Furthermore, in the presence of this enzyme the consumption of O2 is low, as is the oxidation of NADH, due to autoxidation of the hydroquinone, and the cyclized DA o-quinone is found to be fully reduced. These observations can be explained by the newly-discovered role of SOD as a superoxide:semiquinone (QH.) oxidoreductase catalyzing the following reaction: O2-. + QH. + 2H+----QH2 + O2. Thus, the combination of DT diaphorase and SOD is an efficient system for maintaining cDAoQ in its fully reduced state, a prerequisite for detoxication of the quinone by conjugation with sulfate or glucuronic acid. In addition, only minute amounts of reactive oxygen species will be formed, i.e. by the generation of O2-., which through disproportionation to H2O2 and further reduction by ferrous ions can be converted to the hydroxyl radical (OH.). Absence or low levels of these enzymes may create an oxidative stress on the cell and thereby initiate events leading to cell death.
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PMID:On the mechanism of the Mn3(+)-induced neurotoxicity of dopamine:prevention of quinone-derived oxygen toxicity by DT diaphorase and superoxide dismutase. 255 82


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