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Gene Review

NQO1  -  NAD(P)H dehydrogenase, quinone 1

Homo sapiens

Synonyms: Azoreductase, DHQU, DIA4, DT-diaphorase, DTD, ...
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Disease relevance of NQO1

  • Conversely, the distribution of NQO1 genotypes among patients with treatment-related leukemias with MLL translocations was not statistically different than in the comparison groups [1].
  • A small British study suggested that NQO1 C609T was associated with an increased risk of infant leukemias with MLL translocations, especially infant acute lymphoblastic leukemia (ALL) with t(4;11) [1].
  • Benzene poisoning, a risk factor for hematological malignancy, is associated with the NQO1 609C-->T mutation and rapid fractional excretion of chlorzoxazone [2].
  • These results together suggest that NO signals the transcriptional up-regulation of NQO1 and other detoxifying enzyme and protective genes through Nrf2 via the ARE to counteract NO-induced apoptosis of neuroblastoma cells [3].
  • The use of beta-lapachone mono(arylimino) prodrug derivatives, or more specifically a derivative converted in a tumor-specific manner (i.e., in the acidic local environment of the tumor tissue), should reduce normal tissue toxicity while eliciting tumor-selective cell killing by NQO1 bioactivation [4].

Psychiatry related information on NQO1


High impact information on NQO1

  • Our findings provide the first evidence for in vivo degradation of p53 and p73 by the 20S proteasomes and its regulation by NQO1 and NADH level [7].
  • Results: In general, DT-diaphorase activity levels were higher than those observed for the other two reductases across the entire cell line panel [8].
  • The extent of induction of gene expression in colon mucosa reached a peak of 5.75-fold for gamma-GCS, and a peak of 4.14-fold for DT-diaphorase at 250 mg/m2 ; higher doses were not more effective [9].
  • Peripheral mononuclear cell and colon mRNA content for gamma-glutamylcysteine synthetase (gamma-GCS) and DT-diaphorase increased after dosing to reach a peak on day 2-4 after treatment, and declined to baseline in the subsequent 7-10 d [9].
  • Levels of gamma-GCS and DT-diaphorase correlated closely (P < or = 0.001) between peripheral mononuclear cells and colon mucosa both at baseline and at peak [9].

Chemical compound and disease context of NQO1


Biological context of NQO1

  • The distributions of the XRCC3 Thr241Met and NQO1 Pro187Ser genotypes were not significantly different in patients and controls [15].
  • In this report, we have investigated the role of Nrf3 in ARE-mediated gene expression and induction of NQO1 in response to antioxidants [16].
  • The antioxidant response element (ARE) and Nrf2 are known to regulate the expression and coordinated induction of genes encoding detoxifying enzymes including NAD(P)H:quinone oxidoreductase1 (NQO1) in response to antioxidants [17].
  • These DN-Nrf2 cells exhibited reduced NQO1 enzymatic activity and were sensitized to NO-induced apoptosis [3].
  • To further elucidate the role of the association of Hsp70 with the NQO1*1 protein, site-directed mutagenesis was used to modify a proposed Hsp70 binding site near the N terminus of the NQO1 protein [18].

Anatomical context of NQO1


Associations of NQO1 with chemical compounds


Physical interactions of NQO1

  • Deletion mutation analysis revealed that Nrf3 repression of NQO1 gene expression required heterodimerization and DNA binding domains but not transcriptional activation domain of Nrf3 [16].
  • The x-ray crystal structure of rat QR1 shows that the 43 amino acid C-terminal tail of QR1 provides the binding site for the hydrophilic portions of NADH and NADPH [24].
  • Band and supershift assays with the NQO1 gene ARE and nuclear proteins demonstrate that small MafG and MafK bind to the ARE as Maf-Maf homodimers and Maf-Nrf2 heterodimers [25].
  • Folding models suggest that the highly conserved histidine 217 of the cytochrome b subunit from the cytochrome bc1 complex is close to the quinone reductase (Qi) site [26].

Enzymatic interactions of NQO1

  • Quinone reductase catalyzed the conversion in the presence of NADH or NADPH of DES Q to 53-65% Z-DES, a marker product of reduction [27].
  • NAD(P)H:quinone oxidoreductase (NQO1) is a flavoprotein which catalyzes the two-electron reduction of quinones and azo-dyes and thus prevents the formation of free radicals and toxic oxygen metabolites that may be generated by the one-electron reductions catalyzed by cytochrome P450 reductase [28].

Co-localisations of NQO1

  • We conclude that NQO1 activity co-localizes closely with AD pathology supporting a presumed role as an antioxidant system upregulated in response to the oxidative stress of the AD process [29].

Regulatory relationships of NQO1

  • In these experiments a full-length p53 coding region was used to express p53 in the presence of recombinant NQO1 protein [21].
  • RESULTS: NQO1 transcription was down-regulated and the CpG island DNA was hypermethylated in Hep3B and HuH6 cells [11].
  • Dibenzoylmethane treatment at the same concentrations did not induce GSTP1-1 expression and significantly stimulated QR expression only at the 2.0 microM concentration [30].
  • Apoptotic responses in beta-lap-exposed NQO1-expressing cells were significantly delayed and survival enhanced by exogenous over-expression of calpastatin, a natural inhibitor of mu- and m-calpains [31].
  • Transfection with siRNA specific for NQO1 suppressed NQO1 expression and significantly abrogated MUC5AC mRNA expression [32].

Other interactions of NQO1

  • Allelic variation in genes encoding enzymes such as NADP(H) quinone oxidoreductase (NQO1) and glutathione S-transferase T1 (GSTT1) that metabolize environmental toxicants predispose to subtypes of AML, including therapy-related AML [33].
  • NQO2 activity appears to be related to expression of NQO1 (DT-diaphorase), an enzyme that is known to have a favorable distribution toward certain human cancers [34].
  • The CYP2D6 (-) "poor metabolizer " and the NQO1 (-) "defective" genotypes were not clearly associated with a higher risk of RCC [35].
  • The p value for difference in relative risk for NQO1 by GSTM1 genotype = 0.013 [36].
  • There were no clear differences in adduct levels in relation to genotypes of NQO1 or GSTP1 [37].

Analytical, diagnostic and therapeutic context of NQO1


  1. Low NAD(P)H:quinone oxidoreductase activity is associated with increased risk of leukemia with MLL translocations in infants and children. Smith, M.T., Wang, Y., Skibola, C.F., Slater, D.J., Lo Nigro, L., Nowell, P.C., Lange, B.J., Felix, C.A. Blood (2002) [Pubmed]
  2. Benzene poisoning, a risk factor for hematological malignancy, is associated with the NQO1 609C-->T mutation and rapid fractional excretion of chlorzoxazone. Rothman, N., Smith, M.T., Hayes, R.B., Traver, R.D., Hoener, B., Campleman, S., Li, G.L., Dosemeci, M., Linet, M., Zhang, L., Xi, L., Wacholder, S., Lu, W., Meyer, K.B., Titenko-Holland, N., Stewart, J.T., Yin, S., Ross, D. Cancer Res. (1997) [Pubmed]
  3. Nitric oxide-induced transcriptional up-regulation of protective genes by Nrf2 via the antioxidant response element counteracts apoptosis of neuroblastoma cells. Dhakshinamoorthy, S., Porter, A.G. J. Biol. Chem. (2004) [Pubmed]
  4. Development of beta-lapachone prodrugs for therapy against human cancer cells with elevated NAD(P)H:quinone oxidoreductase 1 levels. Reinicke, K.E., Bey, E.A., Bentle, M.S., Pink, J.J., Ingalls, S.T., Hoppel, C.L., Misico, R.I., Arzac, G.M., Burton, G., Bornmann, W.G., Sutton, D., Gao, J., Boothman, D.A. Clin. Cancer Res. (2005) [Pubmed]
  5. Association analyses between polymorphisms of the phase II detoxification enzymes (GSTM1, NQO1, NQO2) and alcohol withdrawal symptoms. Okubo, T., Harada, S., Higuchi, S., Matsushita, S. Alcohol. Clin. Exp. Res. (2003) [Pubmed]
  6. Association analysis of NAD(P)H:quinone oxidoreductase gene 609 C/T polymorphism with Alzheimer's disease. Wang, B., Jin, F., Xie, Y., Tang, Y., Kan, R., Zheng, C., Yang, Z., Wang, L. Neurosci. Lett. (2006) [Pubmed]
  7. A mechanism of ubiquitin-independent proteasomal degradation of the tumor suppressors p53 and p73. Asher, G., Tsvetkov, P., Kahana, C., Shaul, Y. Genes Dev. (2005) [Pubmed]
  8. Reductase enzyme expression across the National Cancer Institute Tumor cell line panel: correlation with sensitivity to mitomycin C and EO9. Fitzsimmons, S.A., Workman, P., Grever, M., Paull, K., Camalier, R., Lewis, A.D. J. Natl. Cancer Inst. (1996) [Pubmed]
  9. Modulation of gene expression in subjects at risk for colorectal cancer by the chemopreventive dithiolethione oltipraz. O'Dwyer, P.J., Szarka, C.E., Yao, K.S., Halbherr, T.C., Pfeiffer, G.R., Green, F., Gallo, J.M., Brennan, J., Frucht, H., Goosenberg, E.B., Hamilton, T.C., Litwin, S., Balshem, A.M., Engstrom, P.F., Clapper, M.L. J. Clin. Invest. (1996) [Pubmed]
  10. Nucleotide and deduced amino acid sequence of a human cDNA (NQO2) corresponding to a second member of the NAD(P)H:quinone oxidoreductase gene family. Extensive polymorphism at the NQO2 gene locus on chromosome 6. Jaiswal, A.K., Burnett, P., Adesnik, M., McBride, O.W. Biochemistry (1990) [Pubmed]
  11. Hypermethylation of NAD(P)H: quinone oxidoreductase 1 (NQO1) gene in human hepatocellular carcinoma. Tada, M., Yokosuka, O., Fukai, K., Chiba, T., Imazeki, F., Tokuhisa, T., Saisho, H. J. Hepatol. (2005) [Pubmed]
  12. Significance of genetic variation at the glutathione S-transferase M1 and NAD(P)H:quinone oxidoreductase 1 detoxification genes in breast cancer development. Siegelmann-Danieli, N., Buetow, K.H. Oncology (2002) [Pubmed]
  13. Functional implications of antiestrogen induction of quinone reductase: inhibition of estrogen-induced deoxyribonucleic acid damage. Bianco, N.R., Perry, G., Smith, M.A., Templeton, D.J., Montano, M.M. Mol. Endocrinol. (2003) [Pubmed]
  14. A potential mechanism underlying the increased susceptibility of individuals with a polymorphism in NAD(P)H:quinone oxidoreductase 1 (NQO1) to benzene toxicity. Moran, J.L., Siegel, D., Ross, D. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  15. The genotype distribution of the XRCC1 gene indicates a role for base excision repair in the development of therapy-related acute myeloblastic leukemia. Seedhouse, C., Bainton, R., Lewis, M., Harding, A., Russell, N., Das-Gupta, E. Blood (2002) [Pubmed]
  16. Nrf3 negatively regulates antioxidant-response element-mediated expression and antioxidant induction of NAD(P)H:quinone oxidoreductase1 gene. Sankaranarayanan, K., Jaiswal, A.K. J. Biol. Chem. (2004) [Pubmed]
  17. Bach1 competes with Nrf2 leading to negative regulation of the antioxidant response element (ARE)-mediated NAD(P)H:quinone oxidoreductase 1 gene expression and induction in response to antioxidants. Dhakshinamoorthy, S., Jain, A.K., Bloom, D.A., Jaiswal, A.K. J. Biol. Chem. (2005) [Pubmed]
  18. Interaction of the molecular chaperone Hsp70 with human NAD(P)H:quinone oxidoreductase 1. Anwar, A., Siegel, D., Kepa, J.K., Ross, D. J. Biol. Chem. (2002) [Pubmed]
  19. Environmental pollutant and potent mutagen 3-nitrobenzanthrone forms DNA adducts after reduction by NAD(P)H:quinone oxidoreductase and conjugation by acetyltransferases and sulfotransferases in human hepatic cytosols. Arlt, V.M., Stiborova, M., Henderson, C.J., Osborne, M.R., Bieler, C.A., Frei, E., Martinek, V., Sopko, B., Wolf, C.R., Schmeiser, H.H., Phillips, D.H. Cancer Res. (2005) [Pubmed]
  20. Differential responses of the Nrf2-Keap1 system to laminar and oscillatory shear stresses in endothelial cells. Hosoya, T., Maruyama, A., Kang, M.I., Kawatani, Y., Shibata, T., Uchida, K., Warabi, E., Noguchi, N., Itoh, K., Yamamoto, M. J. Biol. Chem. (2005) [Pubmed]
  21. Interaction of human NAD(P)H:quinone oxidoreductase 1 (NQO1) with the tumor suppressor protein p53 in cells and cell-free systems. Anwar, A., Dehn, D., Siegel, D., Kepa, J.K., Tang, L.J., Pietenpol, J.A., Ross, D. J. Biol. Chem. (2003) [Pubmed]
  22. 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. Bonnesen, C., Eggleston, I.M., Hayes, J.D. Cancer Res. (2001) [Pubmed]
  23. An NQO1- and PARP-1-mediated cell death pathway induced in non-small-cell lung cancer cells by beta-lapachone. Bey, E.A., Bentle, M.S., Reinicke, K.E., Dong, Y., Yang, C.R., Girard, L., Minna, J.D., Bornmann, W.G., Gao, J., Boothman, D.A. Proc. Natl. Acad. Sci. U.S.A. (2007) [Pubmed]
  24. Unexpected genetic and structural relationships of a long-forgotten flavoenzyme to NAD(P)H:quinone reductase (DT-diaphorase). Zhao, Q., Yang, X.L., Holtzclaw, W.D., Talalay, P. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  25. Small maf (MafG and MafK) proteins negatively regulate antioxidant response element-mediated expression and antioxidant induction of the NAD(P)H:Quinone oxidoreductase1 gene. Dhakshinamoorthy, S., Jaiswal, A.K. J. Biol. Chem. (2000) [Pubmed]
  26. Requirement of histidine 217 for ubiquinone reductase activity (Qi site) in the cytochrome bc1 complex. Gray, K.A., Dutton, P.L., Daldal, F. Biochemistry (1994) [Pubmed]
  27. Temporary decrease in renal quinone reductase activity induced by chronic administration of estradiol to male Syrian hamsters. Increased superoxide formation by redox cycling of estrogen. Roy, D., Liehr, J.G. J. Biol. Chem. (1988) [Pubmed]
  28. High levels of expression of the NAD(P)H:quinone oxidoreductase (NQO1) gene in tumor cells compared to normal cells of the same origin. Cresteil, T., Jaiswal, A.K. Biochem. Pharmacol. (1991) [Pubmed]
  29. Regional NAD(P)H:quinone oxidoreductase activity in Alzheimer's disease. SantaCruz, K.S., Yazlovitskaya, E., Collins, J., Johnson, J., DeCarli, C. Neurobiol. Aging (2004) [Pubmed]
  30. Inhibition of benzo[a]pyrene- and 1,6-dinitropyrene-DNA adduct formation in human mammary epithelial cells bydibenzoylmethane and sulforaphane. Singletary, K., MacDonald, C. Cancer Lett. (2000) [Pubmed]
  31. Mu-calpain activation in beta-lapachone-mediated apoptosis. Tagliarino, C., Pink, J.J., Reinicke, K.E., Simmers, S.M., Wuerzberger-Davis, S.M., Boothman, D.A. Cancer Biol. Ther. (2003) [Pubmed]
  32. Regulation of MUC5AC expression by NAD(P)H:quinone oxidoreductase 1. Zheng, S., Byrd, A.S., Fischer, B.M., Grover, A.R., Ghio, A.J., Voynow, J.A. Free Radic. Biol. Med. (2007) [Pubmed]
  33. CYP1A1*2B (Val) allele is overrepresented in a subgroup of acute myeloid leukemia patients with poor-risk karyotype associated with NRAS mutation, but not associated with FLT3 internal tandem duplication. Bowen, D.T., Frew, M.E., Rollinson, S., Roddam, P.L., Dring, A., Smith, M.T., Langabeer, S.E., Morgan, G.J. Blood (2003) [Pubmed]
  34. Bioactivation of 5-(aziridin-1-yl)-2,4-dinitrobenzamide (CB 1954) by human NAD(P)H quinone oxidoreductase 2: a novel co-substrate-mediated antitumor prodrug therapy. Knox, R.J., Jenkins, T.C., Hobbs, S.M., Chen, S., Melton, R.G., Burke, P.J. Cancer Res. (2000) [Pubmed]
  35. Candidate genetic modifiers of individual susceptibility to renal cell carcinoma: a study of polymorphic human xenobiotic-metabolizing enzymes. Longuemaux, S., Deloménie, C., Gallou, C., Méjean, A., Vincent-Viry, M., Bouvier, R., Droz, D., Krishnamoorthy, R., Galteau, M.M., Junien, C., Béroud, C., Dupret, J.M. Cancer Res. (1999) [Pubmed]
  36. Nicotinamide adenine dinucleotide (phosphate) reduced:quinone oxidoreductase and glutathione S-transferase M1 polymorphisms and childhood asthma. David, G.L., Romieu, I., Sienra-Monge, J.J., Collins, W.J., Ramirez-Aguilar, M., del Rio-Navarro, B.E., Reyes-Ruiz, N.I., Morris, R.W., Marzec, J.M., London, S.J. Am. J. Respir. Crit. Care Med. (2003) [Pubmed]
  37. Analyses of bronchial bulky DNA adduct levels and CYP2C9, GSTP1 and NQO1 genotypes in a Hungarian study population with pulmonary diseases. Ozawa, S., Schoket, B., McDaniel, L.P., Tang, Y.M., Ambrosone, C.B., Kostic, S., Vincze, I., Kadlubar, F.F. Carcinogenesis (1999) [Pubmed]
  38. CYP2E1 and NQO1 genotypes, smoking and bladder cancer. Choi, J.Y., Lee, K.M., Cho, S.H., Kim, S.W., Choi, H.Y., Lee, S.Y., Im, H.J., Yoon, K.J., Choi, H., Choi, I., Hirvonen, A., Hayes, R.B., Kang, D. Pharmacogenetics (2003) [Pubmed]
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