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)

Cruciferous vegetables contain glucosinolates that, after conversion to isothiocyanates (ITC), are capable of inducing cytoprotective genes. We examined whether broccoli seeds can elicit a chemoprotective response in mouse organs and rodent cell lines and investigated whether this response requires nuclear factor-erythroid 2 p45-related factor 2 (Nrf2). The seeds studied contained glucosinolate at 40 mmol/kg, of which 59% comprised glucoiberin, 19% sinigrin, 8% glucoraphanin, and 7% progoitrin. Dietary administration of broccoli seeds to nrf2(+/+) and nrf2(-/-) mice produced a approximately 1.5-fold increase in NAD(P)H:quinone oxidoreductase 1 (NQO1) and glutathione S-transferase (GST) activities in stomach, small intestine, and liver of wild-type mice but not in mutant mice; increased transferase activity was associated with elevated levels of GSTA1/2, GSTA3, and GSTM1/2 subunits. These seeds also increased significantly the level of glutamate cysteine ligase catalytic (GCLC) subunit in the stomach and the small intestine of nrf2(+/+) mice but not nrf2(-/-) mice. An aqueous broccoli seed extract was prepared for treatment of cultured cells that contained ITC at approximately 600 mumol/L, composed of 61% 3-methylsulfinylpropyl ITC, 30% sulforaphane, 4% allyl ITC, and 4% 3-butenyl ITC. This extract induced GSTA1/2, GSTA3, NQO1, and GCLC between 3-fold and 10-fold in mouse Hepa-1c1c7 and rat liver RL-34 cells. The broccoli seed extract affected increases in GSTA3, GSTM1, and NQO1 proteins in nrf2(+/+) mouse embryonic fibroblasts but not in nrf2(-/-) mouse embryonic fibroblasts. These experiments show that broccoli seeds are effective at inducing antioxidant and detoxication proteins, both in vivo and ex vivo, in an Nrf2-dependent manner.
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PMID:Transcription factor Nrf2 is essential for induction of NAD(P)H:quinone oxidoreductase 1, glutathione S-transferases, and glutamate cysteine ligase by broccoli seeds and isothiocyanates. 1557 60

This paper reviews the literature on the influence of metabolic and DNA repair polymorphisms of biological indicators of genotoxic risk commonly used in biomonitoring occupational exposure to carcinogens. Genetic polymorphisms which influence biomarkers (urinary metabolites, protein and DNA adducts), include P450 cytochromes (CYPs) and glutathione S-transferases (GSTs) in exposure to polycyclic aromatic hydrocarbons (PAHs), and acetyltransferases (NATs) in exposure to aromatic amines (AAs). As regards exposure to benzene, also relevant is the influence of epoxydohydrolase (EPHX) and NAD(P)H quinone oxidoreductase (NQO1) on the urinary excretion of t,t-muconic and phenylmercapturic acids. With respect to occupational exposure to styrene, EPHX significantly influences the levels of Chromosome Aberrations (CAs), strongly predictive genotoxic biomarkers of cancer risk. Some recent studies examine the role of polymorphisms linked to DNA repair genes in the modulation of genotoxic risk associated with PAH exposure, both for life-style (dietary and smoking behaviour) and for occupational reasons. In addition, molecular epidemiology studies (case/control studies) of lung cancer in smokers published since 2000 may also be viewed as representing models of effects due to exposure to carcinogenic mixtures, some of which are present in the working environment (e.g., BaP, benzene, AAs). Almost all studies show the clearcut influence (i.e., increased lung cancer risk with OR > or = 2) of genetic polymorphisms linked to PAH metabolism (in particular, CYPIA1, GSTM1 and P1). Among the risk factors are the different mutagen sensitivity towards, for instance, bleomycin and BaP (tested in vitro), the reduced repair capacity to DNA damage induced by BaP, and increases in some biomarkers of early biological effect (DNA adducts and stable CAs). Other risk factors, such as heredity (siblings of cancer patients have a risk factor > or = 3 with respect to the general population), ethnicity (Chileans > Caucasians; Japanese > Americans) and gender (women > men), have still not been clearly characterized and these are also reported in this paper. It is clear from the above that genetic differences underlie individual susceptibility to lung cancer, whether caused by exposure to tobacco smoke or to occupational carcinogens like PAHs. Some of these indicators of exposure/individual susceptibility can be evaluated in groups at high risk of occupational lung cancer, such as coke-oven and aluminium workers and those exposed to coal tar fumes and soot, etc., with the aim of identifying subjects who are susceptible due to the high concentrations of carcinogens found in their working environment.
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PMID:[Individual susceptibility to occupational carcinogens: the evidence from biomonitoring and molecular epidemiology studies]. 1558 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

Lack of functional telomeres can cause chromosomal aberrations. This type of genetic instability may promote tumorigenesis. We have investigated the association between mean telomere length in buccal cells (assessed with quantitative real-time PCR) and bladder cancer risk in a case-control study. Patients with bladder cancer displayed significantly shorter telomeres than control subjects (P = 0.001). Median telomere length ratio was 0.95 (range 0.53-3.2) for cases and 1.1 (0.51-2.4) for controls. Moreover, the adjusted odds ratio (OR) for bladder cancer was significantly increased in the quartile with the shortest telomere length OR = 4.5 [95% confidence interval (CI) 1.7-12]. It is known that oxidative stress, alkylation or UV radiation increases shortening of telomeres. Therefore, we also analyzed whether environmental and genetic factors associated with DNA damage, i.e. smoking and polymorphisms in the genes involved in the metabolism of genotoxic carcinogens (EPHX1, GSTA1, GSTM1, GSTP1, GSTT1, NAT1, NAT2 and NQO1) or DNA repair (APE1, NBS1, XPC, XPD, XRCC1, XRCC3 and XRCC4), could modify the association between telomere length and cancer risk. A clear effect of smoking and telomere length could be observed. Current smokers with short telomeres had more than six times as higher risk as non-smokers/former smokers with long telomeres (OR = 6.3, 95% CI 1.7-23). Lack of the biotransformation gene GSTM1 and short telomeres were associated with OR = 6.5 (95% CI 2.4-18), whereas homozygous carriers of 312Asn in the DNA repair gene XPD, with short telomeres, displayed an OR of 17 (95% CI 1.9-150). However, no significant interaction for cancer risk could be proven for telomere length, smoking and susceptibility genotypes of metabolizing and DNA-repairing genes.
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PMID:Constitutional short telomeres are strong genetic susceptibility markers for bladder cancer. 1574 60

The genetic susceptibility hypothesis has been used to explain why only a minority of smokers develop lung cancer. Only few studies have studied the role of polymorphisms in phase-I and II metabolizing genes, among young lung cancer patients. We have pooled the individual data of three studies from Denmark and Norway, including 320 patients diagnosed with non-small cell lung cancer at age 59 or below, and 618 age and gender matched controls. A questionnaire was used to determine relevant demographic and lifestyle characteristics, and polymorphisms in following genotypes were determined GSTM1, GSTM3, GSTP1, GSTT1, GPX1, MPO, NQO1 and NAT2. Based on the literature, the alleles of the genotypes were categorised as high- or low-risk alleles. No individual effect of the genotypes was found on the risk of lung cancer. Given a smoking exposure, the presence of high-risk alleles (or phenotypes) was generally found to increase the risk of lung cancer, although the effect modification did not reach statistical significance. A pattern of stronger protective effect was observed in carriers of more than one allele associated with lower risk of lung cancer, and a higher risk of lung cancer in carriers of one or more alleles associated with higher risk of lung cancer, but the results did not reach statistical significance. The effect modification was generally strongest at lower levels of smoking.
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PMID:Polymorphisms in genes involved in xenobiotic metabolism and lung cancer risk under the age of 60 years. A pooled study of lung cancer patients in Denmark and Norway. 1582 18

The cytochrome P450 (CYP) superfamily of enzymes catalyse one of the first steps in the metabolism of carcinogens such as polycyclic aromatic hydrocarbons, nitroaromatics and arylamines. Polymorphisms within the CYP1A1 gene have been shown to be associated with lung cancer risk, predominantly among Asian populations. Despite functional evidence of a possible role of CYP1B1 in lung cancer susceptibility, only a few studies have evaluated polymorphisms in this gene in relation to lung cancer susceptibility. This population-based study evaluates polymorphisms in both of these CYP genes within never smokers, most of whom had environmental tobacco smoke (ETS) exposure. Cases (n = 160) were identified through the metropolitan Detroit Surveillance, Epidemiology and End Results program, and age, sex and race-matched population-based controls (n = 181) were identified using random digit dialing. Neither CYP1A1 MspI nor CYP1A1 Ile(462)Val was associated with lung cancer susceptibility among Caucasians or African-Americans. Among Caucasians, however, CYP1B1 Leu(432)Val was significantly associated with lung cancer susceptibility odds ratio (OR) for at least one valine allele = 2.87 [95% confidence interval (CI) 1.63-5.07]. Combinations of this Phase I enzyme polymorphism along with selected Phase II enzyme polymorphisms (GSTM1 null, GSTP1 Ile(105)Val and NQO1 C(609)T) were evaluated. The combination of CYP1B1 Leu(432)Val and NQO1 C(609)T appeared to be associated with the highest risk of lung cancer (OR = 4.14, 95% CI 1.60-10.74), although no combinations differed significantly from the risk associated with CYP1B1 Leu(432)Val alone. When individuals were stratified by household ETS exposure (yes/no), CYP1B1 Leu(432)Val alone and in combination with Phase II enzyme polymorphisms was more strongly associated with increased lung cancer susceptibility among those with at least some household ETS exposure. Additional studies will be required to further validate these findings among never smokers and to evaluate the effects of this polymorphism among smoking populations as well.
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PMID:CYP1A1 and CYP1B1 polymorphisms and risk of lung cancer among never smokers: a population-based study. 1605 42

Polymerase chain reaction with confronting two-pair primers (PCR-CTPP) is an effective genotyping method for single nucleotide polymorphisms (SNPs) in aspects of reducing time and costs for analysis. So far we have established PCR-CTPP conditions for tens of SNPs, including a triplex genotyping (Kawase et al., 2003). In the present study we report a quadruplex PCR-CTPP to genotype simultaneously four functional polymorphisms of carcinogen-metabolizing enzymes, CYP1A1 Ile462Val, GSTM1 null, GSTT1 null and NQO1 C609T, which were reported that they have significant associations with smoking-related cancers. We applied this method for 475 health check-up examinees to demonstrate the performance. Among the subjects, the genotype frequency of CYP1A1 Ile462Val was 56.8% for Ile/Ile, 38.1% for Ile/Val and 5.1% for Val/Val. The null type frequencies of GSTM1 and GSTT1 were 52.8% and 49.9%, respectively. And the genotype frequency of NQO1 C609T was 41.9% for C/C, 41.3% for C/T and 16.8% for T/T. Their distributions were similar to those reported for Japanese by other studies. To the best of our awareness, this is the first paper that reports the success in quadruplex PCR-CTPP. The applied polymorphisms are useful ones, which would be adopted not only for research purposes, but also for risk assessment of individuals exposed to carcinogenic substances. This convenient genotyping would be applied for cancer prevention especially in Asian Pacific regions, where expensive genotyping methods are hardly available.
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PMID:Multiplex PCR with confronting two-pair primers for CYP1A1 Ile462Val, GSTM1, GSTT1, and NQO1 C609T. 1623 98

Metabolic polymorphisms may influence the risk of childhood leukaemia related to maternal tobacco, coffee or alcohol consumption. The data were extracted from a case-control study including 280 cases of acute leukaemia and 288 controls. Blood sampling was obtained for a representative subset of 219 cases and 105 controls. Gene-environment interactions were estimated using both case-control and case-only analyses. The polymorphisms of CYP1A1, GSTM1, GSTP1, GSTT1 and NQO1 were not associated with the risk of leukaemia. The slow EPHX1 allele was negatively associated with childhood leukaemia while an inverse non-significant association was observed with the fast EPHX1 allele. Maternal smoking during pregnancy was not related to leukaemia, but an interaction was observed in the case-only analysis with CYP1A1*2A variant allele (odds ratio (OR) 2.2 [1.0-4.9]) and with GSTM1 deletion (OR 2.3 [1.2-4.4]). Conversely, coffee drinking interacted negatively with NQO1 polymorphism in the case-only analysis (OR 0.6 [0.3-1.2] and 0.4 [0.1-1.0] for light and heavy coffee consumptions, respectively). This study suggests that maternal smoking may be a risk factor for leukaemia in children who carry CYP1A1 or GSTM1 genotypes, which might increase reactive metabolites of polycyclic aromatic hydrocarbons.
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PMID:Childhood leukaemia, polymorphisms of metabolism enzyme genes, and interactions with maternal tobacco, coffee and alcohol consumption during pregnancy. 1628 98

Airborne particulate pollutants, such as diesel exhaust particles, are thought to exacerbate lung and cardiovascular diseases through induction of oxidative stress. Sulforaphane, derived from cruciferous vegetables, is the most potent known inducer of phase II enzymes involved in the detoxification of xenobiotics. We postulated that sulforaphane may be able to ameliorate the adverse effects of pollutants by upregulating expression of endogenous antioxidant enzymes. Stimulation of bronchial epithelial cells with the chemical constituents of diesel particles result in the production of proinflammatory cytokines. We first demonstrated a role for phase II enzymes in regulating diesel effects by transfecting the airway epithelial cell line (BEAS-2B) with the sentinel phase II enzyme NAD(P)H: quinine oxidoreductase 1 (NQO1). IL-8 production in response to diesel extract was significantly reduced in these compared with untransfected cells. We then examined whether sulforaphane would stimulate phase II induction and whether this would thereby ablate the effect of diesel extracts on cytokine production. We verified that sulforaphane significantly augmented expression of the phase II enzyme genes GSTM1 and NQO1 and confirmed that sulforaphane treatment increased glutathione S-transferase activity in epithelial cells without inducing cell death or apoptosis. Sulforaphane pretreatment inhibited IL-8 production by BEAS-2B cells upon stimulation with diesel extract. Similarly, whereas diesel extract stimulated production of IL-8, granulocyte-macrophage colony-stimulating factor, and IL-1beta from primary human bronchial epithelial cells, sulforaphane pretreatment inhibited diesel-induced production of all of these cytokines. Our studies show that sulforaphane can mitigate the effect of diesel in respiratory epithelial cells and demonstrate the chemopreventative potential of phase II enzyme enhancement.
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PMID:Sulforaphane-stimulated phase II enzyme induction inhibits cytokine production by airway epithelial cells stimulated with diesel extract. 1690 40

Functional polymorphisms in the genes encoding detoxification enzymes could modify the response to treatment in acute myeloid leukemia and therefore affect the final clinical outcome. In the present study, we genotyped 153 patients diagnosed with de novo acute myeloid leukemia (AML) to clarify the influence of the genetic polymorphisms CYP1A1*2A, CYP3A4*1B, CYP2E1*5B, del{GSTT1}, del{GSTM1}, and NQO1*2 on disease outcome. The del{GSTM1} showed a higher frequency in females (62%) than in males (41%) (P=0.01). The number of functional NQO1 alleles influenced the response to induction therapy; 81% (55/68) NQO1-negative patients, 69% (28/41) heterozygous patients, and 27% (2/7) homozygous patients achieved complete remission (CR) (P=0.04). The presence of GST deletions was associated with a lower probability of disease-free survival (DFS) and this effect was more relevant in male patients. Males with del{GSTM1} showed a 28% DFS versus 57% DFS for undeleted GSTM1 (P=0.04). Similarly, males with undeleted GSTM1 and GSTT1 showed a 64% DFS versus 34% DFS for males with at least one GST deletion (P=0.05). This study suggests that the NQO1*2 polymorphism is relevant to the patient's response to induction therapy and that GST deletions influence treatment outcome after chemotherapy, especially in male patients.
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PMID:The GST deletions and NQO1*2 polymorphism confers interindividual variability of response to treatment in patients with acute myeloid leukemia. 1711 47


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