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 critical role of the glutathione S-transferase (GST) multigene family in cellular protection in combination with the large interindividual variability in the expression of these enzymes has prompted an investigation of their importance in cancer prevention and susceptibility. Previous preclinical and clinical studies from this laboratory have established an association between decreased GST activity and increased risk for colorectal cancer. Based upon the increased incidence of colon malignancies among patients with ulcerative colitis, GST activity has been examined in a mouse model of induced colitis. Significant decreases (50% of controls) in the GST activity of colon tissue were observed during the establishment and progression of colitis. These data suggested that depletion of cellular protection may be an important event in the carcinogenic progression of ulcerative colitis. The ability of the dithiolthione oltipraz to induce GST expression within the murine colon has been demonstrated. Use of chemopreventive regimens to induce phase 2 detoxication enzyme expression represents a promising strategy for the prevention of cancer. Clinical studies revealed that the GST activity of blood lymphocytes from individuals with either a personal or family history of colorectal cancer or a personal history of colon polyps was decreased significantly when compared to that of healthy controls. Phase 1 clinical evaluation of oltipraz has demonstrated its ability to induce GST activity as well as the level of transcripts encoding gamma-glutamylcysteine synthetase (gamma-GCS) and DT-diaphorase in the colon mucosa of individuals at increased risk for colorectal cancer. The observed correlation between the posttreatment response in blood lymphocytes and colon mucosa suggested that blood lymphocytes may be used in future trials as a surrogate biomarker of the responsiveness of colon tissue to chemopreventive regimens.
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PMID:Glutathione S-transferases--biomarkers of cancer risk and chemopreventive response. 967 68

Glutathione is a nonenzymatic antioxidant synthesized by most animal cells and is depleted in inflammatory bowel disease. The effects of glutathione depletion on intestinal histology and inhibitory neurochemicals was examined in a mouse model. Glutathione depletion in A/J mice involved inhibition of gamma-glutamylcysteine synthetase using L-buthionine-(S,R)-sulfoximine (BSO) for 10 days. Ileum and colon were obtained from saline-control mice, BSO-treated mice, and BSO-treated mice receiving ascorbate or glutathione monoethylester. Glutathione, lipid peroxides, and nicotineamide adenine dinucleotide phosphate diaphorase activity were measured by colorimetric assays. Vasoactive intestinal peptide was measured by radioimmunoassay. Glutathione depletion induced enlargement of mucosal-submucosal lymphoid aggregates without germinal centers in ileum and colon. These aggregates were prevented by supplementation with glutathione monoethylester but not ascorbate. Tissue levels of inhibitory neurochemicals were unchanged. Depletion of glutathione appears to induce enlarged lymphoid aggregates by recruitment of lymphocytes from the peripheral circulation. A component of the inflammation that develops in inflammatory bowel disease could be related to depletion of tissue levels of glutathione.
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PMID:Induction of enlarged intestinal lymphoid aggregates during acute glutathione depletion in a murine model. 1121 24

Induction of Phase 2 enzymes is an effective and sufficient strategy for achieving protection against the toxic and neoplastic effects of many carcinogens. It is proposed that the concept of Phase 2 enzymes as being responsible only for the conjugation of functionalized xenobiotics with endogenous cellular ligands such as glutathione (glutathione S-transferases) and glucuronic acid (UDP-glucuronosyltransferases) be expanded to include proteins with the following common characteristics: (a) coordinate induction by a broad range of chemical agents that all have the capacity to react with sulfhydryl groups; (b) possible regulation by common promoter elements; and (c) catalysis of reactions that lead to comprehensive protection against electrophile and reactive oxygen toxicities, by a wide variety of mechanisms. These mechanisms include: conjugation with endogenous ligands, chemical modification of reactive features of molecules that can damage DNA and other macromolecules, and generation or augementation of cellular antioxidants. In addition to the above conjugating enzymes, a provisional and partial list of Phase 2 proteins might include: NAD(P)H:quinone reductase, epoxide hydrolase, dihydrodiol dehydrogenase, gamma-glutamylcysteine synthetase, heme oxygenase-1, leukotriene B4 dehydrogenase, aflatoxin B1 dehydrogenase, and ferritin.
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PMID:Chemoprotection against cancer by induction of phase 2 enzymes. 1121 5

An N-acetylcysteine (NAC)/oltipraz (OLZ) combination was studied in healthy volunteer smokers who received daily NAC (1200 mg/day) and were randomized to weekly placebo (Arm A), OLZ 200 mg (Arm B), or 400 mg (Arm C). Treatment was for 12 weeks with follow-up at 16 weeks. The objective was to study toxicity and the modulation of pharmacodynamic end points. After treatment of 19 of a planned 60 subjects, (Arm A, six; Arm B, four; and Arm C, nine), the study was closed because of toxicity. Eight subjects failed to complete 12 weeks of drug administration, (Arm A, two, and Arm C, six). The most frequent side effects were gastrointestinal, fatigue, conjunctival irritation, and skin rash. Pharmacodynamic end points were measured pretreatment and 48 h after the dose of OLZ at weeks 1, 5, and 12 and 4 weeks after the end of treatment. Glutathione (GSH) was measured in plasma and in peripheral blood lymphocytes (PBLs). Other end points measured in PBLs were the enzyme activities of total glutathione-S-transferase (GST), GSTpi, and NAD(P)H:quinone oxidoreductase; and the mRNA expression of gamma-glutamylcysteine synthetase gammaGCS), GSTpi, and NAD(P)H:quinone oxidoreductase. GSH in PBLs, GST (total), and the mRNA of gammaGCS showed increases at some time points in some subjects. Most consistent was the mRNA of gammaGCS, which showed a > or = 30% increase at one or more time points in 11 of 19 subjects. Other end points were unchanged. We concluded that NAC/OLZ modulates some end points related to GSH but is too toxic for chemoprevention at the doses used.
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PMID:Phase I/pharmacodynamic study of N-acetylcysteine/oltipraz in smokers: early termination due to excessive toxicity. 1130 98

Two population-based, case-control studies have documented reduced risk of prostate cancer in men who consume cruciferous vegetables. Cruciferae contain high levels of the isothiocyanate sulforaphane. Sulforaphane is known to bolster the defenses of cells against carcinogens through up-regulation of enzymes of carcinogen defense (phase 2 enzymes). Prostate cancer is characterized by an early and near universal loss of expression of the phase 2 enzyme glutathione S-transferase (GST)-pi. We tested whether sulforaphane may act in prostatic cells by increasing phase 2 enzyme expression. The human prostate cancer cell lines LNCaP, MDA PCa 2a, MDA PCa 2b, PC-3, and TSU-Pr1 were treated with 0.1-15 microM sulforaphane in vitro. LNCaP was also treated with an aqueous extract of broccoli sprouts. Quinone reductase enzymatic activity, a surrogate of global phase 2 enzyme activity, was assayed by the menadione-coupled reduction of tetrazolium dye. Expression of NQO-1, GST-alpha, gamma-glutamylcysteine synthetase-heavy and -light chains, and microsomal GST was assessed by Northern blot analysis. Sulforaphane and broccoli sprout extract potently induce quinone reductase activity in cultured prostate cells, and this induction appears to be mediated by increased transcription of the NQO-1 gene. Sulforaphane also induces expression of gamma-glutamylcysteine synthetase light subunit but not the heavy subunit, and this induction is associated with moderate increases in intracellular glutathione levels. Microsomal and alpha-class glutathione transferases were also induced transcriptionally. Sulforaphane induces phase 2 enzyme expression and activity significantly in human prostatic cells. This induction is accompanied by, but not because of, increased intracellular glutathione synthesis. Our findings may help explain the observed inverse correlation between consumption of cruciferae and prostate cancer risk.
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PMID:Potent induction of phase 2 enzymes in human prostate cells by sulforaphane. 1153 46

This article provides an overview of the mechanisms by which cancer chemopreventive blocking agents increase the expression of detoxication and antioxidant genes. These agents all appear capable of transcriptionally activating a gene battery that includes NAD(P)H:quinone oxidoreductase, aldo-keto reductases, glutathione S-transferases, gamma-glutamylcysteine synthetase, glutathione synthetase and heme oxygenase. Gene induction occurs through the antioxidant responsive element (ARE), a process that is dependent on the Nuclear Factor-Erythroid 2p45-related factors, Nrf1 and Nrf2. Under basal conditions, these basic region leucine zipper (bZIP) transcription factors are located in the cytoplasm of the cell bound to Keap1, and upon challenge with inducing agents, they are released from Keap1 and translocate to the nucleus. Within the nucleus, Nrf1 and Nrf2 are recruited to the ARE as heterodimers with either small Maf proteins, FosB, c-Jun, JunD, activating transcription factor 2 (ATF2) or ATF4. The role of protein kinases in transducing chemical stress signals to the bZIP factors that affect gene induction through the ARE is discussed.
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PMID:Molecular basis for the contribution of the antioxidant responsive element to cancer chemoprevention. 1168 85

Acrolein, an alpha,beta-unsaturated aldehyde, is by far the strongest electrophile present in cigarette smoke which is involved in several lung pathophysiological conditions. Acrolein depletes glutathione and creates thiol imbalance. Acrolein due to thiol imbalance as well as covalent modification of cysteine is known to inhibit the activity of redox sensitive transcription factors such as NF-kappaB and AP-1. Exposure of human type II lung epithelial (A549) cells to non-lethal dose of acrolein (150 fmol/cell for 1 h) depletes 80% of intracellular glutathione and increases the transcription of gamma-glutamylcysteine synthetase (gamma-GCS) at 6-12 h post-treatment, which helps in replenishing the glutathione to normal level. Acrolein treatment activates transcription of phase II genes in general, as indicated by an increase in mRNA for NAD (P) H:quinone oxidoreductase (NQO1). Western blot analysis revealed the increased level of the transcription factor, Nrf2 in the nuclear extract from acrolein treated cells. Electrophoretic mobility shift assay shows increased binding of nuclear proteins to human antioxidant response element (ARE) consensus sequence after treatment with acrolein. The involvement of Nrf2 in ARE mediated transcriptional activation in response to acrolein exposure has been confirmed by human NQO1-ARE reporter assay. The ability of acrolein to transcriptionaly activate genes responsible for phase II enzymes may form the basis of resistance against cell death and can have implications in cigarette smoke related lung carcinogenesis.
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PMID:Acrolein causes transcriptional induction of phase II genes by activation of Nrf2 in human lung type II epithelial (A549) cells. 1208 17

Electrophiles formed during metabolic activation of chemical carcinogens and reactive oxygen species generated from endogenous and exogenous sources play a significant role in carcinogenesis. Cancer chemoprevention by induction of phase 2 proteins to counteract the insults of these reactive intermediates has gained considerable attention. Nuclear factor E2 p45-related factor 2 (Nrf2), a bZIP transcription factor, plays a central role in the regulation (basal and or inducible expression) of phase 2 genes by binding to the "antioxidant response element" in their promoters. Identification of novel Nrf2-regulated genes is likely to provide insight into cellular defense systems against the toxicities of electrophiles and oxidants and may define effective targets for achieving cancer chemoprevention. Sulforaphane is a promising chemopreventive agent that exerts its effect by strong induction of phase 2 enzymes via activation of Nrf2. In the present study, a transcriptional profile of small intestine of wild-type (nrf2 +/+) and knock out (nrf2 -/-) mice treated with vehicle or sulforaphane (9 micromol/day for 1 week, p.o.) was generated using the Murine Genome U74Av2 oligonucleotide array (representing approximately 6000 well-characterized genes and nearly 6000 expressed sequence tags). Comparative analysis of gene expression changes between different treatment groups of wild-type and nrf2-deficient mice facilitated identification of numerous genes regulated by Nrf2 including previously reported Nrf2-regulated genes such as NAD(P)H:quinone reductase (NQO1), glutathione S-transferase (GST), gamma-glutamylcysteine synthetase (GCS), UDP-glucuronosyltransferases (UGT),epoxide hydrolase, as well as a number of new genes. Also identified were genes encoding for cellular NADPH regenerating enzymes (glucose 6-phosphate dehydrogenase, 6-phosphogluconate dehydrogenase, and malic enzyme), various xenobiotic metabolizing enzymes, antioxidants (glutathione peroxidase, glutathione reductase, ferritin, and haptaglobin), and biosynthetic enzymes of the glutathione and glucuronidation conjugation pathways. The data were validated by Northern blot analysis and enzyme assays of selected genes. This investigation expands the horizon of Nrf2-regulated genes, highlights the cross-talk between various metabolic pathways, and divulges the pivotal role played by Nrf2 in regulating cellular defenses against carcinogens and other toxins.
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PMID:Identification of Nrf2-regulated genes induced by the chemopreventive agent sulforaphane by oligonucleotide microarray. 1223 84

Epidemiologic studies have found an inverse association between consumption of tomato products and the risk of certain types of cancers. However, the mechanisms underlying this relationship are not completely understood. One mechanism that has been suggested is induction of phase II detoxification enzymes. Expression of phase II enzymes is regulated by the antioxidant response element (ARE) and the transcription factor Nrf2 (nuclear factor E2-related factor 2). In this study, we determined the role of this transcription system in the induction of phase II enzymes by carotenoids. We found that in transiently transfected cancer cells, lycopene transactivated the expression of reporter genes fused with ARE sequences. Other carotenoids such as phytoene, phytofluene, beta-carotene, and astaxanthin had a much smaller effect. An increase in protein as well as mRNA levels of the phase II enzymes NAD(P)H:quinone oxidoreductase and gamma-glutamylcysteine synthetase was observed in nontransfected cells after carotenoid treatment. Ethanolic extract of lycopene containing unidentified hydrophilic derivatives of the carotenoid activated ARE with similar potency to lycopene. The potency of the carotenoids in ARE activation did not correlate with their effect on intracellular reactive oxygen species and reduced glutathione level, which may indicate that ARE activation is not solely related to their antioxidant activity. Nrf2, which is found predominantly in the cytoplasm of control cells, translocated to the nucleus after carotenoid treatment. Interestingly, part of the translocated Nrf2 colocalized with the promyelocytic leukemia protein in the promyelocytic leukemia nuclear bodies. The increase in phase II enzymes was abolished by a dominant-negative Nrf2, suggesting that carotenoid induction of these proteins depends on a functional Nrf2 and the ARE transcription system.
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PMID:Carotenoids activate the antioxidant response element transcription system. 1565 64

The capacity of cells to maintain homeostasis during oxidative stress resides in activation or induction of protective enzymes. Nuclear-factor-E2-related factor (Nrf)-2 as a member of bZIP transcription factors is expressed in a variety of tissues. Transcriptional activation of antioxidant genes through an antioxidant response element (ARE) is largely dependent upon Nrf2. The genes that contain a functional ARE include those encoding GSTA1, GSTA2, NAD(P)H:quinone reductase, and gamma-glutamylcysteine synthetase heavy and light subunits that play a role in defense against oxidative stress. Previously, we showed that phosphatidylinositol 3-kinase (PI3-kinase) controls nuclear translocation of Nrf2 in response to oxidative stress, which involves rearrangement of actin microfilaments. Now, we report that PI3-kinase is responsible for the rise of cellular Ca(2+), which is requisite for nuclear translocation of Nrf2. Immunocytochemistry and subcellular fractionation analyses revealed that Nrf2 relocated from the cytoplasm to the plasma membrane prior to its nuclear translocation. We further found that CCAAT/enhancer binding protein-beta (C/EBPbeta), peroxisome proliferatoractivated receptor-gamma (PPARgamma), and retinoid X receptor (RXR) heterodimer serve as the activating transcription factors for the phase II gene induction. Hence, PI3-kinase-mediated Nrf2 activation in combination with activating PPARgamma-RXR and C/EBPbeta contributes to antioxidant phase II enzyme induction via coordinate gene transactivation.
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PMID:Molecular mechanism of nrf2 activation by oxidative stress. 1635 28


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