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)

NQO1 gene expression was evaluated by RT-PCR and SNP status by RFLP in matched samples of lung tumors and adjacent normal tissue. NQO1 was found to be overexpressed in lung tumors when compared to matched normal lung tissue. The mean expression in normal lung tissue was 28.26 x 10(-14) ng/microl +/- 44.9 SD and 61.46 x 10(-14) ng/microl +/- 103.2 SD in lung tumors. NQO1 gene expression was higher in the tumor than in the matched normal lung tissue in 27/50 (59%) patients (p=0.014). In the normal samples, 25 (50%) were wild-type, 16 were heterozygotes (32%) and 8 had the SNP (16%). In the matched tumor samples 14 were wild-type (28%), 16 were heterozygous (32%) and 19 (38%) had the SNP (p=0.0043). The genomic NQO1 mutation was associated with survival in a pilot study of stage II/III NSCLC patients. Patients with a homozygous SNP genotype had a significantly shorter survival (median 12 months), than heterozygous or homozygous wild-type patients (median 41 months) (p=0.007), suggesting NQO1 may be important in chemosensitivity as well as the pathogenesis of lung cancer and NQO1 genotyping may be a useful component of pharmacogenetic strategies for the treatment of NSCLC.
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PMID:Evaluation of NQO1 gene expression and variant allele in human NSCLC tumors and matched normal lung tissue. 1237 Jul 63

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.
Lung Cancer 2003 May
PMID:Analysis of NQO1, GSTP1, and MnSOD genetic polymorphisms on lung cancer risk in Taiwan. 1271 Nov 12

The synthesis and biological evaluation of a homologous series of conjugates (9-13) of 2,5-diaziridinylbenzoquinone (DZQ) and 9-carbonylacridine, a DNA intercalating moiety, via a polymethylene unit (n=2-6) are described. In addition, the non-acridine compound 14, analogous to compound 12, and the 5-methyl-DZQ derivatized conjugate 15, an analog of compound 10, were also prepared. Through a Comet assay, compounds 9-13 were shown to produce DNA interstrand cross-links at submicromolar concentrations, consistent with K562 leukemia cells accumulating in the G2/M stage in the cell cycle. The cytotoxicity of compounds 9-15 was examined using a MTT assay on several human cancer cell lines, including chronic myeloid leukemia K562, the non-small cell lung cancers H596 and H460, and colon carcinoma cells BE and HT29. H460 and HT29 are rich in DT-diaphorase (DTD), and H596 and BE cells have negligible amounts of functional DTD. Under continuous exposure of drugs, except to the non-aziridine compound 19b, the IC50 values of all other compounds were determined to be in the range of 0.3-11.3 nM. Compound 10, which has a propyl linker group, was subjected to in vivo studies. When BDF1 mice with established mouse mammary carcinoma were treated with compound 10 (2 mg/kg at day 1 and 5 mg/kg at day 7), a significant delay (9-10 days) in cancer growth was recorded when compared to untreated controls. Furthermore, administration of compound 10 to nu/nu BDF1 mice bearing human lung cancer H460 xenograft (1.5 mg/kg for 10 for five consecutive days from day 13 and 17) also showed a significant reduction in tumor growth compared to untreated controls. The half-life of compound 10 in the presence of five different peptidases (porcine esterase, carboxypeptidase A, B and Y, and pepsin) was determined to be between 30 and 60 h.
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PMID:Synthesis and biological evaluation of novel diaziridinylquinone-acridine conjugates. 1450 82

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

Lung cancer rates among men and particularly among women, almost all of whom are non-smokers, in Xuan Wei County, China are among the highest in China and have been causally associated with exposure to indoor smoky coal emissions that contain very high levels of polycyclic aromatic hydrocarbons (PAHs). As such, this population provides a unique opportunity to study the pathogenesis of PAH-induced lung cancer that is not substantially influenced by the large number of other carcinogenic constituents of tobacco smoke. Aldo-keto reductases (AKRs) activate PAH dihydrodiols to yield their corresponding reactive and redox-active o-quinones, which can then generate reactive oxygen species that cause oxidative DNA damage. We therefore examined the association between single nucleotide polymorphisms (SNPs) in four genes (AKR1C3-Gln5His, NQO1-Pro187Ser, MnSOD-Val16Ala and OGG1-Ser326Cys) that play a role in the generation, prevention or repair of oxidative damage and lung cancer risk in a population-based, case-control study of 119 cases and 113 controls in Xuan Wei, China. The AKR1C3-Gln/Gln genotype was associated with a 1.84-fold [95% confidence interval (CI) = 0.98-3.45] increased risk and the combined OGG1-Cys/Cys and Ser/Cys genotypes were associated with a 1.93-fold (95% CI = 1.12-3.34) increased risk of lung cancer. Subgroup analysis revealed that the effects were particularly elevated among women who had relatively high cumulative exposure to smoky coal. SNPs in MnSOD and NQO1 were not associated with lung cancer risk. These results suggest that SNPs in the oxidative stress related-genes AKR1C3 and OGG1 may play a role in the pathogenesis of lung cancer in this population, particularly among heavily exposed women. However, due to the small sample size, additional studies are needed to evaluate these associations within Xuan Wei and other populations with substantial exposure to PAHs.
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PMID:Oxidative damage-related genes AKR1C3 and OGG1 modulate risks for lung cancer due to exposure to PAH-rich coal combustion emissions. 1528 79

Loss of antioxidant/oxidant homeostasis perpetuates inflammation in the lungs and may contribute to the development of COPD and lung cancer. Cigarette smoke (CS) is a primary source of airway oxidative stress and recruits inflammatory cells into smokers' lungs. However, whether these consequences are attributable to a specific or the collective fraction of CS is unknown. We investigated whether the particulate or the gas phase of CS would alter expression of the antioxidant enzymes MnSOD and NQO1 or CINC-1. Sprague Dawley rats were exposed to sham (n = 10) or the particulate phase (PP; n = 10) or gas phase (n = 10) of a Kentucky reference cigarette (1R4F) for 2 h/d for 28 d, after which animals were sacrificed and the lower left lobe of the lung was removed. Immunoblots for SOD and NQO1 revealed that lungs exposed to PP had higher MnSOD/actin and NQO1/actin ratios than either sham-or gas phase-treated animals. In contrast, CuZnSOD remained unchanged. In PP-exposed animals, CINC-1 was 3-fold higher than in sham-exposed animals. The increases in MnSOD and NQO1 protein were associated with increases in total SOD, NQO1, and MPO activities. These data provide evidence that the PP of CS alters oxidant/antioxidant homeostasis in the lungs and participates in the pathogenesis of CS-induced lung diseases such as COPD and cancer.
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PMID:Particulate phase cigarette smoke increases MnSOD, NQO1, and CINC-1 in rat lungs. 1547 4

The NAD(P)H:quinone oxidoreductase 1 gene, NQO1, contains a C to T transition at amino acid codon 187, which results in very low enzymatic activity. Previous studies of the association between NQO1 genotype and lung cancer have had mixed findings. This population-based case control study examines the association between NQO1 genotype and lung cancer in the largest sample of never smokers (<100 cigarettes, lifetime) to date. Cases (n = 161) were identified through the metropolitan Detroit Surveillance, Epidemiology and End Results (SEER) program, and 5-year age- and race-matched population-based controls (n = 173) were identified using random digit dialing. Allele frequencies of C and T, respectively, were 0.79 and 0.21 in Caucasians, and 0.84 and 0.16 in African Americans. Among those diagnosed aged >/=50 years, C/T and T/T genotyped individuals had 0.48 times lower lung cancer risk than individuals with C/C genotype (95% CI: 0.27-0.87). There was a non-significant suggestion of a protective effect associated with the T allele among those with a history of environmental tobacco smoke exposure (OR = 0.57, 95% CI: 0.32-1.03) but not among those without (OR = 0.98, 95% CI: 0.41-2.38). Sex, race, family history of lung cancer and histologic type did not modify the effect of NQO1 genotype on lung cancer risk. The observed risk reductions may be attributable to the greatly reduced procarcinogen activating of NAD(P)H:quinone oxidoreductase 1 in individuals with at least one copy of the T allele.
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PMID:NQO1 T allele associated with decreased risk of later age at diagnosis lung cancer among never smokers: results from a population-based study. 1549 87

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

We compared the cytotoxicity of the bioreductive antitumor agents mitomycin C (MMC) and streptonigrin (SN) with or without the DT-diaphorase (DTD) inducer dimethyl fumarate (DMF) in four human glioblastoma cell lines with the conventional chemotherapeutic agent, 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). We also examined four other types of cancer cells to compare with glioblastoma cells. Cytotoxicity was measured with the sulforhodamine B (SRB) assay and was represented by 50% inhibition concentration (IC50). Enzymatic activities of DTD, cytochrome b5 reductase and glutathione-S-transferase (GST) in cells were measured spectrophotometrically. IC50 for BCNU was in a range of 28-300 microM in the glioblastoma cell lines. Glioblastoma cells were more sensitive to MMC or SN than to BCNU. Pretreatment with DMF significantly increased cytotoxicity of MMC and SN in glioblastoma cell lines and the NCI-H1299 lung cancer cell line, but had no effect on BCNU cytotoxicity. DMF significantly increased DTD and cytochrome b5 reductase activity, and decreased GST in three of four glioblastoma cell lines. Addition of the DTD inhibitor, dicumarol, significantly inhibited cytotoxicity of MMC and SN, and reversed the increased cytotoxicity seen when DMF was combined with either MMC or SN in all glioblastoma cell lines. Combining inducers of DTD and cytochrome b5 reductase with bioreductive agents may be a potential therapeutic strategy for glioblastoma.
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PMID:Enhanced cytotoxicity of bioreductive antitumor agents with dimethyl fumarate in human glioblastoma cells. 1565 14


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