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)

Obacunone and limonin are bitter limonoids in citrus. Their modifying effects on the development of aberrant crypt foci (ACF), the activity of detoxification enzymes, glutathione S-transferase (GST) and quinone reductase (QR), and cell proliferation activity were investigated in male F344 rats treated with azoxymethane (AOM). Obacunone and limonin were administered in the diet, during the initiation (for 4 weeks) or postinitiation phase (for 4 weeks) of AOM-induced tumorigenesis. Feeding of obacunone and limonin (0.02% or 0.05%) caused significant reduction (55-65% by "initiation" feeding and 28-42% by "postinitiation" feeding) in the yield of ACF. The ability to reduce the proliferating cell nuclear antigen-labeling index in crypts and correlated well with the prevention of ACF. In a subsequent long-term experiment (38 weeks), in which rats were initiated with AOM and fed 0.05% obacunone or 0.05% limonin during the initiation or post-initiation phase, both compounds in diet caused significant reduction (65%-92% inhibition) in the incidence of colonic adenocarcinoma. Thus, citrus bitter limonoids obacunone and limonin possess chemopreventive effects on chemically induced rat colon carcinogenesis.
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PMID:Citrus limonoids obacunone and limonin inhibit azoxymethane-induced colon carcinogenesis in rats. 1123 84

ALDH3A1 catalyzes the detoxification of cyclophosphamide, mafosfamide, 4-hydroperoxycyclophosphamide and other oxazaphosphorines. Constitutive ALDH3A1 levels, as well as those of certain other drug-metabolizing enzymes, e.g. NQO1 and CYP1A1, are relatively low in cultured, relatively oxazaphosphorine-sensitive, human breast adenocarcinoma MCF-7 cells. However, transient cellular insensitivity to the oxazaphosphorines can be brought about in these cells by transiently elevating ALDH3A1 levels in them as a consequence of transient exposure to: (1) electrophiles such as catechol that induce the transcription of a battery of genes, e.g. ALDH3A1 and NQO1, having in common an electrophile responsive element (EpRE) in their 5'-upstream regions; or (2) Ah-receptor agonists, e.g. indole-3-carbinol and polycyclic aromatic hydrocarbons such as 3-methylcholanthrene, that induce the transcription of a battery of genes, e.g. ALDH3A1, NQO1 and CYP1A1, having in common a xenobiotic responsive element (XRE) in their 5'-upstream regions. Further, MCF-7 sublines that are constitutively, i.e. when grown in the absence of the original selecting pressure, relatively oxazaphosphorine-insensitive as a consequence of constitutively relatively elevated cellular ALDH3A1 levels evolved when MCF-7 cells were: (1) continuously exposed for several months to gradually increasing concentrations of 4-hydroperoxycyclophosphamide or benz(a)pyrene; or (2) briefly exposed (once for 30 min) to a high concentration (1 mM) of mafosfamide. Each of these three stable sublines is constitutively relatively cross-insensitive to benz(a)pyrene and other polycyclic aromatic hydrocarbons. Cellular levels of NQO1, but not of CYP1A1, are also constitutively relatively elevated in each of the three sublines. RT-PCR-based experiments established that ALDH3A1 mRNA levels are constitutively elevated ( approximately 5- to 8-fold) in each of the three sublines. The elevated ALDH3A1 mRNA levels are not the consequence of gene amplification, hypomethylation of a relevant regulatory element, or ALDH3A1 mRNA stabilization. Collectively, these observations suggest that constitutively elevated levels of ALDH3A1 and certain other enzymes in the three stable sublines are probably the consequence of a constitutive change in the cellular concentration of a key component of the EpRE signaling pathway, such that the cellular concentration of the relevant ultimate transactivating factor is constitutively elevated, i.e. gene transcription promoted by transactivated EpREs is constitutively upregulated. Further, constitutively upregulated gene transcription mediated by transactivated EpREs can be relatively easily induced, whereas that mediated by transactivated XREs cannot, at least in MCF-7 cells. Still further, the three sublines may facilitate study of the signaling pathway that leads to transactivation of the EpREs present in the 5'-upstream regions of ALDH3A1, NQO1 and other gene loci.
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PMID:Three different stable human breast adenocarcinoma sublines that overexpress ALDH3A1 and certain other enzymes, apparently as a consequence of constitutively upregulated gene transcription mediated by transactivated EpREs (electrophile responsive elements) present in the 5'-upstream regions of these genes. 1130 49

To investigate the importance of NAD(P)H:quinone oxidoreductase 1 (or DT-diaphorase; NQO1) in the bioactivation of antitumor quinones, we established a series of stably transfected cell lines derived from BE human colon adenocarcinoma cells. BE cells have no NQO1 activity due to a genetic polymorphism. The new cell lines, BE-NQ, stably express wild-type NQO1. BE-NQ7 cells expressed the highest level of NQO1 and were more susceptible [determined by the thiazolyl blue (MTT) assay] to known antitumor quinones and newer clinical candidates. Inhibition of NQO1 by pretreatment with an irreversible inhibitor, ES936 [5-methoxy-1,2-dimethyl-3-[(4-nitrophenoxy)methyl]indole-4,7-dione], protected BE-NQ7 cells from toxicity induced by streptonigrin, ES921 [5-(aziridin-1-yl)-3-(hydroxymethyl)-1,2-dimethylindole-4,7-dione], and RH1 [2,5-diaziridinyl-3-(hydroxymethyl)-6-methyl-1,4-benzoquinone]. RH1 was evaluated further by clonogenic assay for cytotoxic response and was more cytotoxic to BE-NQ7 cells than to BE cells. Cytotoxicity was abrogated by inhibition of NQO1 with ES936 pretreatment. Using a comet assay to evaluate DNA cross-linking, BE-NQ7 cells demonstrated significantly higher DNA cross-links than did BE cells in response to RH1 treatment. DNA cross-linking in BE-NQ7 cells was observed at very low concentrations of RH1 (5 nM), confirming that NQO1 activates RH1 to a potent cross-linking species. Further studies using streptonigrin, ES921, and RH1 were undertaken to analyze the relationship between NQO1 activity and quinone toxicity. Toxicity of these compounds was measured in a panel of BE-NQ cells expressing a range of NQO1 activity (23-433 nmol/min/mg). Data obtained suggest a threshold for NQO1-induced toxicity above 23 nmol/min/mg and a sharp dose-response curve between the no effect level of NQO1 (23 nmol/min/mg) and the maximal effect level (>77 nmol/min/mg). These data provide evidence that NQO1 can bioactivate antitumor quinones in this system and suggest that a threshold level of NQO1 activity is required to initiate toxic events.
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PMID:Relationship between NAD(P)H:quinone oxidoreductase 1 (NQO1) levels in a series of stably transfected cell lines and susceptibility to antitumor quinones. 1137 80

The natural indoles 3,3'-diindolylmethane (DIM), ascorbigen (ASG), indole-3-carbinol (I3C), and indolo[3,2-b]carbazole (ICZ), as well as the natural isothiocyanates sulforaphane (SUL), benzyl isothiocyanate (BITC) and phenethyl isothiocyanate (PEITC), all possess cancer chemopreventive properties. It is now shown that DIM, ICZ, SUL, and BITC can each stimulate apoptosis in human colon adenocarcinoma LS-174 and Caco-2 cells. Treatment of LS-174 cells with nontoxic doses of DIM, ASG, I3C, or ICZ affected an increase of up to 21-fold in cytochrome P450 1A1 (CYP1A1). None of these indoles caused an elevation in either aldo-keto reductase 1C1 (AKR1C1) or the gamma-glutamylcysteine synthetase heavy subunit (GCS(h)), but DIM, I3C, and ICZ produced a very modest increase in NAD(P)H:quinone oxidoreductase 1 (NQO1). By contrast, nontoxic doses of SUL, BITC, or PEITC failed to induce expression of CYP1A1 in LS-174 cells, but caused an increase of between 11- and 17-fold in the protein levels of AKR1C1, NQO1, and GCS(h). Treatment of the colon cell line with ICZ or SUL caused increases in the levels of mRNA for CYP1A1, AKR1C1, and NQO1 that were consistent with the enzyme data. Exposure of Caco-2 cells to media containing indoles or isothiocyanates gave similar results to those obtained using LS-174 cells. Evidence is presented that the ability of indoles and isothiocyanates to stimulate either xenobiotic response element- or antioxidant response element-driven gene expression accounts for the two groups of phytochemicals inducing different gene batteries. Pretreatment of LS-174 cells for 24 h with ICZ and SUL before exposure for 24 h to benzo(a)pyrene (BaP) reduced to <20% the number of single-strand DNA breaks produced by the carcinogen. Neither ICZ alone nor SUL alone were able to confer the same degree of protection against DNA damage produced by BaP as they achieved in combination. Similar results were obtained with H(2)O(2) as the genotoxic agent. Together, these phytochemicals may prevent colon tumorigenesis by both stimulating apoptosis and enhancing intracellular defenses against genotoxic agents.
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PMID:Dietary indoles and isothiocyanates that are generated from cruciferous vegetables can both stimulate apoptosis and confer protection against DNA damage in human colon cell lines. 1150 62

The modifying effects of dietary administration of capsaicin, which is the principal pungent capsicum fruit, and rotenone, which is a naturally occurring pesticide derived from Derris and Lonchorcarpus species, on azoxymethane (AOM)-induced colon tumorigenesis were investigated in male F344 rats. Gavage with capsaicin and rotenone significantly elevated phase II enzymes, glutathione S-transferase (GST) and quinone reductase (QR), in the liver and colon. In an aberrant crypt foci (ACF) bioassay, feeding of capsaicin and rotenone at a dose of 500 ppm for 4 weeks significantly inhibited ACF formation induced by AOM (20 mg/kg body weight, once a week for 2 weeks). In a subsequent long-term study designed to confirm the protective effects of both compounds on ACF development, one group was treated with AOM alone and four other groups received the carcinogen treatment plus diets containing 500 ppm test compounds for 4 weeks (initiation phase) and for 34 weeks (post-initiation phase). Two groups were treated with capsaicin or rotenone alone (500 ppm in diet) and one group was maintained on the basal diet. At the termination of the study, dietary exposure of capsaicin during the initiation phase was found to significantly reduce the incidence of colonic adenocarcinoma (60% vs. 24%, 60% reduction, P=0.0407). Rotenone feeding during the post-initiation phase also reduced the frequency of colonic adenocarcinoma (60% vs. 19%, 68% reduction, P=0.0226). Our results suggest that two natural compounds, capsaicin and rotenone, might be useful for the prevention of human colon cancers.
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PMID:Chemoprevention of azoxymethane-induced rat colon carcinogenesis by dietary capsaicin and rotenone. 1160 90

Lung adenocarcinoma has replaced squamous cell lung carcinoma as the most frequent histological subtype in lung cancers. However, genetic factors that affect cancer susceptibility are much less understood in adenocarcinoma than in squamous cell carcinoma. In this study, polymorphisms in five genes involved in the metabolism of carcinogens or in the repair of damaged DNA in lung cells, NQO1-Pro187Ser, GSTT1-positive/null, GSTM1-positive/null, CYP1A1-Ile462Val, and OGG1-Ser326Cys, were examined for association with lung adenocarcinoma risk in a case-control study of 198 patients and 152 control subjects. The NQO1 and GSTT1 polymorphisms were associated with lung adenocarcinoma risk with adjusted odds ratio of 2.15 for the NQO1-Pro/Pro genotype versus the Ser/Ser genotype and adjusted odds ratio of 1.61 for the GSTT1-null genotype versus the positive genotype, respectively. Furthermore, individuals with the combined genotype of NQO1-Pro/Pro and GSTT1-null showed greater risk compared with those of NQO1-Ser/Ser and GSTT1-positive. In contrast, significant association was not observed for the GSTM1, CYP1A1, and OGG1 polymorphisms with lung adenocarcinoma risk, although several studies have shown their implication in the risk for squamous cell lung carcinoma. The result indicates that the NQO1-Pro/Pro and GSTT1-null genotypes are risk factors for lung adenocarcinoma development, and that the genetic factors for susceptibility to adenocarcinoma are different from those to squamous cell carcinoma. The enhanced risk of the NQO1-Pro/Pro genotype combined with the GSTT1-null genotype was more evident in smokers than in nonsmokers. Therefore, carcinogens in tobacco smoke, which are activated by NQO1 and detoxified by GSTT1, could have a role in lung adenocarcinoma development.
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PMID:Contribution of the NQO1 and GSTT1 polymorphisms to lung adenocarcinoma susceptibility. 1216 26

We assessed the association of three genetic polymorphisms, NAD(P)H quinone oxidoreductase (NQO1), Glutathione-S-transferase P1 (GSTP1), and manganese superoxide dismutase (MnSOD), with lung cancer risk in 198 cases and 332 controls in Taiwan. Overall, NQO1 and MnSOD polymorphisms were not associated with an increased risk of lung cancer. Individuals carrying variant alleles of GSTP1 were at higher risk of squamous cell lung carcinoma (odds ratio, 1.63; 95% confidence interval, 0.96-2.74). When the groups were further stratified by smoking status following gender and histological type, the wild-type NQO1 was associated with lung adenocarcinoma among smokers but not among nonsmokers (odds ratio, 2.49; 95% confidence interval, 1.17-5.32). These results suggest that NQO1 plays a role in the development of cigarette smoking-associated lung adenocarcinoma. In addition, GSTP1 polymorphism was associated with the risk of squamous cell lung carcinoma in Taiwan.
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PMID:Analysis of NQO1, GSTP1, and MnSOD genetic polymorphisms on lung cancer risk in Taiwan. 1271 Nov 12

The dithiolethione oltipraz is a potent chemopreventive agent in preclinical models, and induces the expression of protective enzymes in the colon mucosa and peripheral mononuclear cells of treated human subjects. We investigated the effects of oltipraz on DT-diaphorase expression in HT29 colon adenocarcinoma cells. Following a 24-hr exposure to 100 microM oltipraz, elevated steady-state levels of mRNA for Jun and Fos family members were observed. A nuclear run-on assay showed induction of c-fos and c-jun transcripts at the end of the exposure, peaking at 12 hr after resuspension of cells in drug-free medium. Gel mobility shift analysis revealed a similar time-course of induced nuclear factor binding to an AP-1 probe. Supershift analysis verified the participation of Jun and Fos in the complexes. The redox coactivator Ref-1, a function of which is to enhance AP-1 binding, was induced 5-fold by oltipraz. Immunodepletion of Ref-1 partially inhibited factor binding to the AP-1 probe. Deletion analysis of the DT-diaphorase promoter in a CAT reporter construct revealed that loss of the AP-1 site accounted for approximately 65% of the induction by oltipraz. Mutation of the AP-1 element in a full-length promoter construct yielded similar results. These data suggest the importance of transcriptional activation mediated by AP-1 in the chemopreventive activity of oltipraz, and indicate that novel chemoprevention structures may be selected based upon agonist activity at this locus.
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PMID:Role of the AP-1 element and redox factor-1 (Ref-1) in mediating transcriptional induction of DT-diaphorase gene expression by oltipraz: a target for chemoprevention. 1281 61

NQO1 is an antioxidant enzyme, important in the detoxification of environmental carcinogens. A single nucleotide polymorphism (C-->T) at position 609 of the NQO1 cDNA has been associated with susceptibility to tumours induced by chemical carcinogens. In our case-control study, we determined the prevalence of the C609T NQO1 polymorphism by PCR-RFLP analysis in Caucasian patients with oesophageal adenocarcinoma (OAC; n=61), cardiac adenocarcinoma (CAC; n=120) or gastric adenocarcinoma (GAC; n=203) vs. a control group that consisted of 252 healthy blood donors. Additionally, NQO1 mRNA expression and NQO1 protein expression were determined by RT-PCR and immunohistochemistry in a subset of cases. The NQO1 C609T genotype distribution was significantly different among controls (C/C, 73.4%; C/T, 25.0%; T/T, 1.6%) as compared to OAC patients (C/C, 49.2%; C/T, 47.5%; T/T, 3.3%; p=0.0004), CAC patients (C/C, 55.8%; C/T, 40.0%; T/T, 4.2%; p=0.0005) and with GAC patients (C/C, 65.5%; C/T; 30.6%, T/T; 3.9%; p=0.0377). The 609T allele overall frequency was 0.141 in controls, 0.270 in OAC patients, 0.241 in CAC patients and 0.192 in GAC patients. Individuals carrying 1 or 2 609T alleles had a 2.85-fold higher risk (95% CI: 1.61-5.07; p=0.0003) for the development of OAC and a 2.18-fold higher risk (95% CI: 1.38-3.44; p=0.0007) for the development of CAC than wild-type gene homozygotes. Immunohistochemical analysis showed NQO1 protein expression in 133 carcinomas, whereas 17 carcinomas were negative. Negativity for NQO1 protein expression correlated strongly with the NQO1 genotype being present in 3.9% of cases with C/C, 13.9% of cases with C/T and 62.5% of cases with T/T genotype (p<0.001). In contrast, NQO1 mRNA expression was detectable irrespective of underlying genotype. In conclusion, determination of the NQO1 genotype may gain importance as a stratification marker in future prevention trials for adenocarcinoma of upper gastrointestinal tract.
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PMID:Association between NAD(P)H: quinone oxidoreductase 1 (NQ01) inactivating C609T polymorphism and adenocarcinoma of the upper gastrointestinal tract. 1450 37

Caco-2 cells are a widely used model in drug development to study intestinal drug transport and metabolism. Recently, serotonin (5-hydroxytryptamine, 5-HT) has been characterized as a highly selective substrate of human UDP-glucuronosyltransferase UGT1A6 [Krishnaswamy S, Duan SX, von Moltke LL, Greenblatt DJ, Court MH. Validation of serotonin (5-hydroxytryptamine) as an in vitro substrate probe for human UDP-glucuronosyltransferase (UGT) 1A6. Drug Metab Disp 2003; 31:133-9], an isoform which conjugates planar phenols and is inducible by Ah receptor agonists and by oxidative/electrophile stress. To gain more insight into intestinal 5-HT disposition, uptake and metabolism of this neurotransmitter was studied in Caco-2 cell monolayers. It was found that 5-HT was taken up from the basolateral and to a lesser extent from the apical surface. It was mainly excreted basolaterally as 5-HT glucuronide. 5-HT UGT activity and UGT1A6 mRNA were induced by Ah receptor agonists and by oxidative stress generated by tert-butylhydroquinone and by isomeric thymoquinone, a potential antitumor agent and constituent of Nigella sativa seeds, commonly used as a condiment in the Middle East. While UGT1A6 induction was clearly detectable in NAD(P)H:quinone oxidoreductase 1 (NQO1)-deficient Caco-2 cells, it was not induced in NQO1-efficient HT-29 colon adenocarcinoma cells. The results suggest that--in addition to its detoxification function--intestinal UGT1A6 contributes to intestinal homeostasis of 5-HT from dietary sources and from release by enterochromaffin cells.
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PMID:Serotonin glucuronidation by Ah receptor- and oxidative stress-inducible human UDP-glucuronosyltransferase (UGT) 1A6 in Caco-2 cells. 1582 10


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