Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.6.5.2 (NQO1)
 6,196 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

We present an oligonucleotide microarray ("MetaboChip") based on the arrayed primer extension (APEX) technique, allowing genotyping of single nucleotide polymorphisms (SNPs) in genes of interest for cancer susceptibility and pharmacogenetics. APEX consists of a sequencing reaction primed by an oligonucleotide anchored with its 5' end to a glass slide and terminating one nucleotide before the polymorphic site. The extension with one fluorescently labeled dideoxynucleotide complementary to the template reveals the polymorphism. Ninety-three SNPs in 42 genes were selected among those resequenced in the context of the SNP500 project, using a set of 102 reference DNA samples from the Coriell Biorepository. Selected SNPs belong to the following genes: ADH1B, ALDH2, APEX, CDKN2A, COMT, CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2C19, CYP2C9, CYP2E1, CYP3A4, DRD2, DRD4, EPHX1, ERCC1, ERCC2, ERCC4, ERCC5, GRPR, GSTA4, GSTM3, GSTP1, GSTT2, LIG3, MDM2, MGMT, MPO, NAT1, NAT2, NQO1, OGG1, PCNA, POLB, SLC6A3, SOD2, TP53, XRCC1, XRCC2, XRCC3, and XRCC9. We assessed the performance of APEX by comparing the results obtained with MetaboChip against those reported by the SNP500. Among 88 SNPs that yielded signals, 6 showed less than 99% of concordance, whereas 82 performed accurately, showing that APEX is a reliable and sensitive genotyping method.
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PMID:Evaluation of a microarray for genotyping polymorphisms related to xenobiotic metabolism and DNA repair. 1457 48

Knowledge of genetic polymorphisms in gene-environment studies may contribute to more accurate identification of avoidable risks and to developing tailor-made preventative measures. The aim of this study was to describe the allele frequencies of single nucleotide polymorphisms (SNPs) of select genes, which may be included in future gene-environment studies on cancer in Japan. SNP typing was performed on middle-aged Japanese men randomly selected from the general population in five areas of Japan. We genotyped and calculated allele frequencies of 153 SNPs located on 40 genes: CYP1A1, CYP1B1, CYP2C9, CYP2C19, CYP2E1, CYP17A1, CYP19A1, AHR, ESR1, ESR2, ERRRG, PGR, EPHX1, EPHX2, HSD17B2, HSD17B3, GSTM2, GSTM3, GSTT2, GSTP1, NAT1, NAT2, COMT, ADH1A, ADH1B, ADH1C, ALDH2, NOS2A, NOS3, IL1A, IL1B, OGG1, NUDT1 [MTH1], DRD2, DRD3, DRD4, SLC6A4, NR3C1 [GCCR], MTHFR, and NQO1. In the present study, the Japanese allele frequencies were verified by using nationwide population samples.
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PMID:Allele frequencies of single nucleotide polymorphisms (SNPs) in 40 candidate genes for gene-environment studies on cancer: data from population-based Japanese random samples. 1463 38

Asphalt fumes are complex mixtures of aerosols and vapors containing various organic compounds, including polycyclic aromatic hydrocarbons (PAHs). Previously, we have demonstrated that inhalation exposure of rats to asphalt fumes resulted in dose-dependent induction of CYP1A1 with concomitant down-regulation of CYP2B1 and increased phase II enzyme quinone reductase activity in the rat lung. In the present study, the potential genotoxic effects of asphalt fume exposure due to altered lung microsomal enzymes were studied. Rats were exposed to air or asphalt fume generated under road paving conditions at various concentrations and sacrificed the next day. Alveolar macrophages (AM) were obtained by bronchoalveolar lavage and examined for DNA damage using the comet assay. To evaluate the systemic genotoxic effect of asphalt fume, micronuclei formation in bone marrow polychromatic erythrocytes (PCEs) was monitored. Lung S9 from various exposure groups was isolated from tissue homogenates and characterized for metabolic activity in activating 2-aminoanthracene (2-AA) and benzo[a]pyrene (BaP) mutagenicity using the Ames test with Salmonella typhimurium YG1024 and YG1029. This study showed that the paving asphalt fumes significantly induced DNA damage in AM, as revealed by DNA migration in the comet assay, in a dose-dependent manner, whereas the micronuclei formation in bone marrow PCEs was not detected even at a very high exposure level (1733 mg h/m3). The conversion of 2-AA to mutagens in the Ames test required lung S9-mediated metabolic activation in a dose-dependent manner. In comparison to the controls, lung S9 from rats exposed to asphalt fume at a total exposure level of 479+/-33 mg h/m3 did not significantly enhance 2-AA mutagenicity with either S. typhimurium YG1024 or YG1029. At a higher total asphalt fume exposure level (1150+/-63 mg h/m3), S9 significantly increased the mutagenicity of 2-AA as compared to the control. However, S9 from asphalt fume-exposed rats did not significantly activate the mutagenicity of BaP in the Ames test. These results show that asphalt fume exposure, which significantly altered both phases I and II metabolic enzymes in lung microsomes, is genotoxic to AM and enhances the metabolic activation of certain mutagens through altered S9 content.
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PMID:Effects of paving asphalt fume exposure on genotoxic and mutagenic activities in the rat lung. 1472 68

The accumulation of basic drugs (cationic amphiphilic), such as beta-adrenergic antagonists, by pulmonary tissue is well known. Ring hydroxylation of nonselective beta-adrenergic blocking agent propranolol is mediated mainly by cytochrome P450 (CYP) 2D6 and N-desisopropylation by CYP1A2 in human and rat liver microsomes. In this study, the repeated administration of propranolol resulted in a marked inhibition of hepatic metabolism and an increase in its systemic availability, due to covalent binding of reactive metabolites (formed from 4-OH-propranolol) to liver microsomal P4502D enzymes. The absence of CYP1A2 and the presence of CYP2D in the lung suggest a different pulmonary metabolism of propranolol in comparison with those in the liver. In this study, we investigated its effects in vivo on some xenobiotic-metabolizing enzymes in rat type II pneumocytes (RTII) and rat alveolar macrophages (RAM). Twenty hours after the last multiple (7 days) oral administration, propranolol (100 mg/kg b.w.) decreased NADPH cytochrome c reductase activity and cytochrome P-450-dependent dealkylation of 7-benzyloxyresorufin (BROD) (CYP1A1, 2A1, 3A1) and 7-ethoxyresorufin (EROD) (CYP1A1) in RTII, while glutathione-S-transferase (GST), DT-diaphorase (QR), gamma-glutamyl transferase (gamma-GT) activities, intracellular reduced glutathione level and dealkylation of 7-pentoxyresorufin (PROD) (CYP2B1) were not changed. It was found that propranolol significantly increased NADPH cytochrome c reductase and BROD activities in RAM. The results suggest a different susceptibility of RTII and RAM to propranolol and its contrary effects on lung xenobiotic-metabolizing enzyme activities in both types of cells.
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PMID:Effects of propranolol on xenobiotic enzyme activities in rat type II pneumocytes and alveolar macrophages in vivo. 1473 27

Allyl sulfides, e.g., diallyl sulfide (DAS), diallyl disulfide (DADS), and diallyl trisulfide (DATS), are principal constituents of garlic oil. In the present study, we investigated the in vivo effect of these sulfides on the phase I and phase II drug-metabolizing enzymes, and elucidated their structure-function relationship. A highly purified form of each sulfide (more than 99% purity) was administered i.p. as a bolus to rats at a concentration of 10 or 100 micromol/kg body weight for 14 consecutive days. As to the phase I enzymes, DAS (100 micromol/kg) slightly but significantly increased cytochrome P-450 (CYP) 2E1 activity (1.6-fold vs. control), whereas DADS and DATS did not affect it or the hepatic total CYP level or CYP1A1/2 activity. With respect to the phase II enzymes, DATS (10 micromol/kg) and DADS at a 10-fold higher dose (100 micromol/kg) significantly increased the activities of glutathione S-transferase, quinone reductase, and antioxidative enzyme glutathione peroxidase; whereas DAS did not. In the carbon tetrachloride (CCl4)-induced acute liver injury model of rats, either DATS (10 micromol/kg) or DADS (100 micromol/kg) significantly reduced the injury caused by the induction of phase II enzymes with CCl4. In conclusion, the sulfides affected both phase I and phase II enzymes, the former being stimulated by the monosulfide only and the latter, strongly by the trisulfide and weakly by the disulfide. Therefore, the polysulfide DATS may be one of the important factors in garlic oil that protects our body against the injury caused by radical molecules encountered in daily life.
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PMID:The effects of allyl sulfides on the induction of phase II detoxification enzymes and liver injury by carbon tetrachloride. 1504 20

The major identified risk factor for lung cancer is tobacco smoking. We identified previously the possible modifying influence of CYP1A1 and GSTM1 polymorphisms on lung cancer risk in a Swedish population. The present study, extended by several study subjects and with analyses for polymorphisms in GSTT1 and NQO1, includes 524 lung cancer cases and 530 control subjects. No evidence for an influence of genetic polymorphisms in CYP1A1, GSTM1, GSTT1, and NQO1 on lung cancer risk overall was found. In smokers, there was, however, a suggestion that the variant CYP1A1 and NQO1 genotypes may confer an increased risk for squamous cell carcinoma. In ever smokers, the homozygously deleted GSTM1 (GSTM1*O/*O) genotype was significantly associated with increased risk of small cell carcinoma (adjusted odds ratio 2.72, 95% confidence interval 1.32-5.90). The risks noted for the variant CYP1A1 genotypes and the GSTM1*O/*O genotype seemed to be restricted to light smokers. The GSTT1*O/*O genotype also appeared to be a possible risk factor in light smokers, whereas, in heavy smokers, this genotype was associated with decreased risk for lung cancer overall (odds ratio 0.36, 95% confidence interval 0.13-0.99). Due to the multiple comparisons made, we cannot exclude the possibility that some of these associations may represent chance findings.
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PMID:Influence of CYP1A1, GSTM1, GSTT1, and NQO1 genotypes and cumulative smoking dose on lung cancer risk in a Swedish population. 1518 45

Naturally occurring phenolics, protocatechuic and tannic acids have been reported to be inhibitors of chemical mutagenesis and carcinogenesis in experimental models. Here, we have studied the effect of pretreatment with these compounds on MC-induced cytochrome P450 and phase II enzymes in rats. The male Wistar rats were treated intraperitoneally with protocatechuic acid and tannic acid in the dose of 50mg/kg every 3 days for 2 weeks. MC was administered at the 12th day of phenolics treatment. The activities of EROD (CYP1A1), MROD (CYP1A2), PROD (CYP2B), PNPH (CYP2E1), GST, UDPGT, NQO1 were measured in the liver and kidney. Protocatechuic acid treatment minimally reduced the MC-induced EROD and MROD, but the observed differences were statistically significant. This compound was also a weak inhibitor of hepatic PNPH. Moreover, Western blot analysis with CYP1A1/1A2- and CYP2E1-specific antibodies showed the same effect in the levels of hepatic CYP1A1/1A2 and CYP2E1. Minimal decrease of renal constitutive (by 23%) and more significant reduction of induced form (by 66%) of PNPH was found as result of treatment with protocatechuic acid. Tannic acid alone had no effect on cytochrome P450 enzymes while in combination with MC this polyphenol minimally enhanced the MC induction of MROD and in greater extent PNPH in liver. The treatment with protocatechuic acid alone enhanced slightly the activities of all three phase II enzymes in liver. The pretreatment with this phenolic of the MC-induced rats however significantly increased the activities of hepatic GST and NQO1 in comparison with MC-treated group. In kidney MC-induced activity of NQO1 was reduced (about 43%) to the control level by tannic acid pretreatment. The results of our present study indicate that in rat the prolonged treatment with protocatechuic acid affects differently the activities of CYP and phase II enzyme when compared to tannic acid. Moreover, the effect of this polyphenols significantly depends on the method of treatment.
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PMID:Modulation of 3-methylcholanthrene-induced rat hepatic and renal cytochrome P450 and phase II enzymes by plant phenols: protocatechuic and tannic acids. 1530 93

Epidemiological evidence shows high red meat consumption to increase the risk of colorectal cancer, while the consumption of fruit and vegetables has been shown to be protective. Many genes have been identified that encode for enzymes involved in the metabolism of dietary carcinogens or anti-carcinogens. A study of 500 incident colorectal cancer cases and population controls, matched for age, sex and general practitioner, was conducted in the United Kingdom to investigate whether 6 such genes (CYP1A1, GSTT1, GSTM1, GSTP1, EPHX1 and NQO1) modify the relationship between diet and disease risk. Usual diet was estimated using a detailed questionnaire administered by interview. Fruit and vegetable consumption were both found to protect against colorectal cancer, while overall meat and red meat consumption were found to increase risk. There was some evidence of interaction between GSTT1 and vegetable consumption (p=0.006, not adjusted for multiple tests) but no evidence of interaction with GSTM1. The protective effect of vegetables was only seen in those with deficient or intermediate GSTT1 predicted phenotype [OR 0.3, 95% confidence interval (0.1, 0.6), and OR 0.6 (0.4, 0.96), OR 1.4 (0.3, 2.4) for those with fast phenotype], and a similar result was observed for cruciferous vegetables. There was also weak evidence of interaction between red meat intake and GSTT1 (p=0.06), GSTP1 (p=0.16, with p=0.02 after adjustment for potential confounders) and NQO1 predicted phenotype (p=0.01). Because of the multiple hypotheses tested in our study, these findings require independent confirmation.
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PMID:Vegetable, fruit and meat consumption and potential risk modifying genes in relation to colorectal cancer. 1535 38

To investigate the genes related to lung cancer susceptibility in Nanjing Han population, China, a 1:1 matched case-control study was performed in which 152 hospital controls were matched to the 152 original lung cancer cases. The polymorphisms of CYP1A1, CYP2E1, GSTM1, GSTT1, GSTP1, mEH and NQO1 genes were analyzed by PCRjRFLP assay. The results showed that the heterozygote and mutation homozygote genotypes of CYP1A1 were related to the risk of squamous cell carcinoma (OR=2.31, 95%CI=1.23-4.36). The risk of suffering from lung cancer was increased 2.06-fold in the individuals with GSTT1 (-) genotype (95%CI= 1.30-3.24). The genotype of NQO1 wt/mt and mt/mt was found also to be associated with the risk of lung cancer (OR=1.66i95%CI=1.01-2.74). It was shown that there was no difference in the genotype distribution of CYP2E1, GSTM1, GSTP1 or mEH between cases and controls. Furthermore, stratified analysis suggested that the combination of genotypes of both CYP1A1 and GSTT1 enzymes had a synergistic action in risk of lung cancer (OR=3.41, 95%CI =1.77-6.55). Similarly, there was a cooperation between CYP1A1 mutation genotype and NQO1 mutation genotype (OR=2.45, 95%CI=1.13-5.31). This study suggested that CYP1A1, GSTT1 and gene NQO1 polymorphisms might be associated with the susceptibility to lung cancer in Nanjing Han population. Analysis of gene-gene interactions was helpful to identification of susceptible individuals and screening high-risk population to lung cancer.
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PMID:[Studies of the genes related to lung cancer susceptibility in Nanjing Han population, China]. 1564 66


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