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)

Consumption of vegetables, especially crucifers, reduces the risk of developing cancer. Although the mechanisms of this protection are unclear, feeding of vegetables induces enzymes of xenobiotic metabolism and thereby accelerates the metabolic disposal of xenobiotics. Induction of phase II detoxication enzymes, such as quinone reductase [NAD(P)H:(quinone-acceptor) oxidoreductase, EC 1.6.99.2] and glutathione S-transferases (EC 2.5.1.18) in rodent tissues affords protection against carcinogens and other toxic electrophiles. To determine whether enzyme induction is responsible for the protective properties of vegetables in humans requires isolation of enzyme inducers from these sources. By monitoring quinone reductase induction in cultured murine hepatoma cells as the biological assay, we have isolated and identified (-)-1-isothiocyanato-(4R)-(methylsulfinyl)butane [CH3-SO-(CH2)4-NCS, sulforaphane] as a major and very potent phase II enzyme inducer in SAGA broccoli (Brassica oleracea italica). Sulforaphane is a monofunctional inducer, like other anticarcinogenic isothiocyanates, and induces phase II enzymes selectively without the induction of aryl hydrocarbon receptor-dependent cytochromes P-450 (phase I enzymes). To elucidate the structural features responsible for the high inducer potency of sulforaphane, we synthesized racemic sulforaphane and analogues differing in the oxidation state of sulfur and the number of methylene groups: CH3-SOm-(CH2)n-NCS, where m = 0, 1, or 2 and n = 3, 4, or 5, and measured their inducer potencies in murine hepatoma cells. Sulforaphane is the most potent inducer, and the presence of oxygen on sulfur enhances potency. Sulforaphane and its sulfide and sulfone analogues induced both quinone reductase and glutathione transferase activities in several mouse tissues. The induction of detoxication enzymes by sulforaphane may be a significant component of the anticarcinogenic action of broccoli.
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PMID:A major inducer of anticarcinogenic protective enzymes from broccoli: isolation and elucidation of structure. 154 3

The 1,2-dithiol-3-thiones are a class of five-membered cyclic sulfur compounds which have chemotherapeutic and chemoprotective properties. The parent 1,2-dithiol-3-thione nucleus and a series of six substituted analogs all induced NAD(P)H: quinone reductase (EC 1.6.99.2) activity and elevated glutathione levels in Hepa 1c1c7 murine hepatoma cells in culture thereby enhancing detoxification potential. These analogs included monosubstituted derivatives with phenyl, p-methoxyphenyl or 2-pyrazinyl groups at C-4 or C-5, and disubstituted compounds bearing phenyl or 2-pyrazinyl moieties at C-5 and an additional methyl group at C-4. This system can be used as an in vitro model for the study of the specificity and mechanism of action of the 1,2-dithiol-3-thiones as already demonstrated for several other classes of chemoprotective agents. The 1,2-dithiol-3-thiones also elevated quinone reductase and glutathione levels in the Hepa 1c1c7 cell mutants (BPrc1 and TAOBPrc1) that are defective in aryl hydrocarbon receptor functions. We conclude that the 1,2-dithiol-3-thiones are largely concerned with the stimulation of metabolic inactivation of electrophiles.
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PMID:1,2-Dithiol-3-thione analogs: effects on NAD(P)H:quinone reductase and glutathione levels in murine hepatoma cells. 370 58

The aryl hydrocarbon receptor (AHR) is a transcriptional activator of genes encoding a group of drug-metabolizing enzymes, including cytochrome P450 1A1 (CYP1A1), glutathione S-transferase, tumor-associated aldehyde dehydrogenase and quinone reductase. Both the constitutive and inducible expression of these genes in the liver is zonated, i.e., dominant in hepatocytes of the centrilobular region, a poorly understood position-dependent phenomenon. By comparing cell lysates obtained from opposite acinar regions we observed that immunoreactive AHR protein was almost exclusively confined to centrilobular cells. The AHR mRNA, as analyzed from cell lysates by reverse transcriptase polymerase chain reaction, exhibited a similar, although somewhat less pronounced zonation. By contrast, only slight zonation of the AHR nuclear translocator mRNA was observed. Treatment of rats with omeprazole, an atypical nonligand activator of the AHR, caused a zone-specific induction of CYP1A1 in the centrilobular region similar to that seen after pretreatment with the AHR ligand 3-methylcholanthrene. Our results suggest that the zone-restricted expression of AHR protein will allow the constitutive and inducible expression of AHR-regulated genes in the centrilobular region, but will limit their expression in the periportal region.
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PMID:Selective centrilobular expression of the aryl hydrocarbon receptor in rat liver. 899 35

The immortalized human epithelial cell line MCF10A has the phenotypic characteristics of normal breast cells. Exposure of MCF10A cultures to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) stimulated the transcriptional activation of cytochrome P450 1A1 (CYP1A1), and CYP1B1, and NAD(P)H:quinone oxidoreductase. Northern blot hybridization and nuclear run-on assays demonstrated that transcriptional activation of these genes was suppressed in stably transfected cultures expressing an Ha-ras oncogene (the MCF10A-NeoT line). Similar suppression did not occur in stably transfected lines carrying the expression vector or a normal c-Ha-ras protooncogene. Western blot analyses and immunofluorescence microscopy demonstrated that the lack of inducibility in MDF10A-NeoT cells reflected neither reductions in aryl hydrocarbon receptor (AHR) and aryl hydrocarbon nuclear translocator protein nor prevention of TCDD-induced AHR translocation to the nucleus. Suppression did correlate with reductions in DNA-AHR complex formation, as analyzed by gel retardation assays of soluble cell extracts treated in vitro with TCDD. The induction of Cyp1a-1 by TCDD was also analyzed in transgenic mice that expressed a v-Ha-ras oncogene exclusively in their keratinocytes. Relative to littermates lacking the transgene, the induction of Cyp1a-1 by TCDD was partially suppressed (about 50%) in the epidermises of v-Ha-ras-positive transgenic mice. However, normal levels of Cyp1a-1 induction occurred in the livers of the same mice. induction of Cyp1a-1 by TCDD was also suppressed (more than 98%) in chemically induced skin papillomas having Ha-ras mutations, relative to uninvolved surrounding skin. These studies suggest that the p21-ras protein controls signal transduction pathways capable of modulating AHR function.
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PMID:Downregulation of aryl hydrocarbon receptor function and cytochrome P450 1A1 induction by expression of Ha-ras oncogenes. 921 Sep 56

PD98059 [2-(2'-amino-3'-methoxyphenyl)-oxanaphthalen-4-one] is a flavonoid and a potent inhibitor of mitogen-activated protein kinase kinase (MEK). Concentrations of PD98059 of </=20 muM were not cytotoxic to cultures of the immortalized human breast epithelial cell line MCF10A. The agent was weakly cytostatic at concentrations of >/=10 microM. In vivo exposure of cultures to </=20 microM PD98059 for 2-22 hr did not affect overall extracellular signal-regulated kinase contents; however, exposure to PD98059 resulted in a rapid loss (>95%) of the dually phosphorylated forms of extracellular signal-regulated kinase (IC50 = 1 muM). Treatment of cultures with PD98059 of >/=1 muM either at the time of addition or up to 48 hr before the addition of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) suppressed in a concentration-dependent manner the accumulation of induced steady state CYP1A1, CYP1B1, and NQO1 mRNAs. The addition of PD98059 to rat liver cytosol just before the addition of TCDD suppressed TCDD binding (IC50 = 4 muM) and aryl hydrocarbon receptor (AHR) transformation (IC50 = 1 muM), as measured by sucrose gradient centrifugation and electrophoretic mobility shift assays. Flavone and flavanone, two closely related structural analogs of PD98059, inhibited AHR transformation by TCDD with IC50 values similar to that obtained with PD98059. However, neither analog was as potent as PD98059 in inhibiting MEK (IC50 approximately 190 muM for both). These results suggest that PD98059 is a ligand for the AHR and functions as an AHR antagonist at concentrations commonly used to inhibit MEK and signaling processes that entail MEK activation.
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PMID:PD98059 is an equipotent antagonist of the aryl hydrocarbon receptor and inhibitor of mitogen-activated protein kinase kinase. 949 9

beta-Naphthoflavone (beta-NF) is a widely used inducer of phase-I and phase-II enzymes controlled by aryl hydrocarbon receptor (AhR). Studies of competitive binding with (3)H-labelled 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD), 3-methylcholanthrene (3-MC) and benzo[a]pyrene (B[a]P) have shown that beta-NF is a high-affinity ligand for AhR and also for polycyclic aromatic hydrocarbon (PAH)-binding protein, both soluble proteins of rat liver in 8 S and 4 S fractions, respectively, of sucrose gradients. This study examined binding of [(3)H]beta-NF to liver cytosolic proteins of female Sprague-Dawley rats. Treatment of rats with beta-NF, 3-MC, TCDD or alpha-naphthoflavone (alpha-NF) increased the specific [(3)H]beta-NF binding to liver cytosol up to 125-fold that of vehicle (corn oil)-treated rats (<100 fmol/mg of protein). Sucrose gradients revealed a large 4 S and a small 8 S peak of radioactivity from [(3)H]beta-NF binding to cytosols of beta-NF-, 3-MC-, TCDD- or alpha-NF-treated rats. Whereas co-incubation with the unlabelled beta-NF eliminated both peaks, co-incubation with 2,3, 7,8-tetrachlorodibenzofuran (TCDF) eliminated only the 8 S peak. The sucrose density gradient from [(3)H]TCDD binding to cytosol of beta-NF- or TCDD-treated rats yielded a small 4 S and a larger 8 S peak; only the latter was abolished by co-incubation with TCDF. Thus, the patterns of sedimentation, distribution and elimination of radioactivity from the 8 S fraction of the liver cytosols from beta-NF-, 3-MC-, TCDD- or alpha-NF-treated rats were characteristic for the AhR, whereas those from the 4 S fraction appeared specific for [(3)H]beta-NF binding. The data indicate that potent AhR agonists, TCDD, 3-MC and beta-NF, and to a lesser extent alpha-NF, a weak AhR agonist, induce a 4 S [(3)H]beta-NF-binding protein in liver cytosol of female rats. alpha-NF, beta-NF and 3-MC were effective competitors (80-85% inhibition) of the [(3)H]beta-NF-specific binding to the beta-NF-, 3 MC- or TCDD-induced 4 S protein, whereas several PAHs including B[a]P and benzo[e]pyrene were only weak competitors. The increased [(3)H]beta-NF binding was not associated with glycine N-methyltransferase activity. Hence, the 4 S [(3)H]beta-NF-binding protein described herein differs from the constitutive 4 S PAH-binding protein of rat liver cytosols in the inducibility by beta-NF and 3-MC, ligand-binding characteristics, and lack of glycine N-methyltransferase activity. Gel filtration on Sephacryl of liver cytosols from beta-NF-treated rats indicated a molecular mass of approximately 42 kDa for [(3)H]beta-NF-bound protein and suggested that it was derived from a large mass component that before the radioligand binding was eluted with the void volume of the gel and sedimented in a 7 S fraction of the sucrose gradient. The [(3)H]beta-NF binding activity was not eluted with glutathione S-transferase Ya, aldehyde-3-dehydrogenase or DT-diaphorase [NAD(P)H: quinone oxidoreductase] activities, which are AhR-controlled and beta-NF-inducible. Further studies are needed to determine the identity and function of this novel protein which may be involved either directly or indirectly (as a carrier protein) in xenobiotic metabolism in vivo.
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PMID:A novel 4 S [3H]beta-naphthoflavone-binding protein in liver cytosol of female Sprague-Dawley rats treated with aryl hydrocarbon receptor agonists. 1076 84

Environmental pollutants, such as polychlorinated biphenyls (PCBs), may induce drug metabolism and may be substrates for the induced metabolic enzymes. Both processes may lead to oxidative stress. The goal of this study was to determine the influence of polychlorinated biphenyls, selected as inducers and substrates of drug metabolism, on oxidative events within the liver over a 3-week time course. Male and female Sprague-Dawley rats received two ip injections per week of 4-chlorobiphenyl, 2,4,4'-trichlorobiphenyl, 3,4,5-trichlorobiphenyl, 3,3',4,4'-tetrachlorobiphenyl (PCB 77), 2,2',4,4',5,5'-hexachlorobiphenyl (PCB 153), or both PCB 77 and 153 (100 micromol/kg/injection) and were euthanized at the end of 1, 2, or 3 weeks. Hepatic cytochrome P450 1A1 (EROD) activity, DT-diaphorase activity, AP-1 DNA-binding activity, conjugated dienes, and alpha-tocopherol (vitamin E) as well as alpha-tocopheryl quinone (oxidized vitamin E) were determined. While the lower chlorinated biphenyls (at these doses and times) showed little or no effect on these oxidative stress parameters, both CYP 1A1 and DT-diaphorase activities were significantly increased in both male and female rats receiving PCB 77, a ligand for the aryl hydrocarbon receptor. In addition, the DNA-binding activity of the transcription factor AP-1 was increased in rats treated with PCB 77 or PCB 153. Within the lipid fraction there was no significant increase observed in conjugated diene concentrations, but there was a significant increase in alpha-tocopheryl quinone upon treatment with all PCBs tested. These data indicate that alpha-tocopheryl quinone may be a sensitive marker for PCB exposure and is possibly increased by a wide range of PCBs.
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PMID:Polychlorinated biphenyl-induced effects on metabolic enzymes, AP-1 binding, vitamin E, and oxidative stress in the rat liver. 1122 84

Modulation of hepatic and extrahepatic detoxication enzymes Cyp1a1, Cyp2a5, glutathione S-transferse Ya (GSTYa) and NAD(P)H:quinone oxidoreductase (QOR) dependent catalytic activity and mRNA levels were investigated at 1, 2, or 4 days in liver, lung, or kidney of male, adult CD57 Bl/6 mice treated sc with a single dose (85 micromol/kg) of sodium arsenite (As3+). Maximum decreases of total hepatic cytochrome P450 (CYP) monooxygenase content and catalytic activities, occurring at 24 h, corresponded with maximum increases of heme oxygenase (HO-1) in all tissues, as well as maximum plasma total bilirubin. Extrahepatic increases in CYP were observed only in non-AHR dependent isozymes in the kidney, where both Cyp2a5 mRNA and catalytic activity increased maximally 24 h after treatment. In contrast, no significant changes in Cyp2b1/2-dependent PROD or mRNA activity and decreases in Cyp1a1-dependent-EROD activity were noted 1, 2, or 4 days after treatment. Increases in QOR catalytic activities were observed in all tissues examined with increased mRNA in kidney. On the other hand, GSTYa catalytic activity and mRNA increases were only detected in kidney. This study demonstrates the differential modulation of CYP, QOR, and GST-Ya, important drug metabolizing enzymes after acute As3+ administration. The induction of Cyp2a5, QOR, and GSTYa catalytic activity and gene expression occurred primarily in kidney during or shortly after conditions of oxidant stress.
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PMID:Acute sodium arsenite treatment induces Cyp2a5 but not Cyp1a1 in the C57Bl/6 mouse in a tissue (kidney) selective manner. 1197 26

2,3,7,8-Tetrachlorodibenzo- p-dioxin (TCDD), a ubiquitous environmental pollutant, elicits a variety of toxicities and is a well-known carcinogen. TCDD alters the expression of many genes including CYP1A1/2, CYP1B1, glutathione S-transferase Ya, aldehyde-3-dehydrogenase, NAD(P)H:quinone oxidoreductase, transforming growth factor (TGF)-alpha and TGF-beta. The present study was aimed at characterization of TCDD to induce plasminogen activator inhibitor-1 (PAI-1) in mouse hepatoma cell lines. A Hepa1c1c7 wild-type cell [H1(wt)], an aryl hydrocarbon receptor (AhR)-deficient mutant [H1(AhR(-))] and an AhR nuclear translocator (Arnt)-deficient mutant [H1(Arnt(-))] were used for this study. TCDD induced PAI-1 in H1(wt) cells, but not in H1(AhR(-)) and H1(Arnt(-)) mutants, indicating a functional role of the AhR-Arnt complex in this effect. Cycloheximide (CHX) treatment resulted in increased PAI-1 mRNA induction, indicating that this response to TCDD is a direct effect on transcription and not a secondary effect mediated by other TCDD-induced proteins. Transfection with PAI-1 promoter led to increased PAI-1 promoter activity in H1(wt) cells treated with TCDD, but no such effect occurred in H1(AhR(-)) or H1(Arnt(-)) cells, implying involvement of the AhR and Arnt. In addition, alpha-naphthoflavone and phenanthroline, two AhR antagonists, each blocked the enhancing effect of TCDD on PAI-1 promoter-coupled luciferase activity in H1(wt) cells. PAI-1 promoter deletion analysis indicated that TCDD-induced PAI-1 transcription was distinctly different from TGF-beta-dependent PAI-1 transcription, particularly in the region between -161 to +73. In summary, TCDD induced the PAI-1 gene directly via an AhR- and Arnt-dependent mechanism, which was distinctly different from TGF-beta-driven PAI-1 transcription.
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PMID:2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) induces plasminogen activator inhibitor-1 through an aryl hydrocarbon receptor-mediated pathway in mouse hepatoma cell lines. 1211 Oct 5

Oltipraz, a promising cancer chemopreventive agent, has been recognized as a monofunctional inducer selectively activating phase II carcinogen-detoxifying enzymes via the antioxidant responsive element (ARE). However, we report here that oltipraz also induces rat glutathione S-transferase A5 (GSTA5), a potent phase II detoxifying enzyme, by means of the xenobiotic responsive element (XRE). Although an ARE sequence exists in the 5' upstream of the rGSTA5 gene, this cis-acting regulatory element loses its responsiveness to oltipraz treatment because of extensive mutations in its distal-half site. Our data indicate that a XRE sequence, located downstream of the transcription initiation site of the gene, is another oltipraz-responsive element. Electrophoretic mobility shift assay showed that oltipraz steadily induces XRE-aryl hydrocarbon receptor (AhR) binding, which can be blocked specifically by excess XRE oligonucleotides or by AhR antibody. By cloning different XREs into the pGL3-promoter vector, we found that oltipraz can activate XRE enhancers from several phase II drug metabolism enzymes, including rGSTA5, rGSTA2, NAD(P)H:quinone reductase, and it also activates XRE from the phase I metabolism enzyme CYP1A1. Oltipraz's effect on XRE is AhR-dependent and is independent of the presence of active CYP1A1. Reverse transcriptase-polymerase chain reaction experiments revealed that oltipraz induces gene expression of both phase I and II drug-metabolizing enzymes in rat hepatoma cells. Thus, we conclude that, like ARE, the XRE pathway constitutes an important part of the molecular mechanism contributing to oltipraz-induced expression of the phase II metabolism enzymes. Oltipraz is a bifunctional inducer, modulating both phase I and II drug-metabolizing enzymes to enhance carcinogen detoxification.
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PMID:Oltipraz is a bifunctional inducer activating both phase I and phase II drug-metabolizing enzymes via the xenobiotic responsive element. 1286 39


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