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Gene Review

Nqo1  -  NAD(P)H dehydrogenase, quinone 1

Mus musculus

Synonyms: AV001255, Azoreductase, DT-diaphorase, DTD, Dia4, ...
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Disease relevance of Nqo1


High impact information on Nqo1

  • Finally, we show that the regulation of ODC stability by NQO1 is especially prominent under oxidative stress [6].
  • Antibodies to hapten 2-phenyloxazolone (phOx) of all BALB/c and DBA/2 mice have the same idiotype and the same major (public) isoelectric focusing pattern whose main spectrotype is called Ox-1 [7].
  • CONCLUSIONS: NQO1(-/-) mice are more susceptible to DMBA-induced skin cancer than are their wild-type littermates, suggesting that NQO1 may protect cells from DMBA carcinogenesis [8].
  • Herein, we used NQO1(-/-) mice to investigate whether NQO1 also protects them against 7,12-dimethylbenz[a]anthracene (DMBA), where methyl substituents diminish primary quinone formation [8].
  • Stable, high-level expression of the active NQO1 gene transfected into the DT-diaphorase-deficient (by NQO1 mutation) BE human colon carcinoma cell line resulted in a 32-fold increase in 17AAG growth-inhibition activity [9].

Chemical compound and disease context of Nqo1

  • By monitoring quinone reductase induction in cultured murine hepatoma cells as the biological assay, we have isolated and identified (-)-1-isothiocyanato-(4R)-(methylsulfinyl)butane [CH3-SO-(CH2)4-NCS, sulforaphane] as a major and very potent phase II enzyme inducer in SAGA broccoli (Brassica oleracea italica) [10].
  • However, NQO1-null mice exhibited increased toxicity when administered menadione compared with wild-type mice [11].
  • Elevations of hepatic quinone reductase, glutathione, and alpha- and mu-class glutathione S-transferase isoforms in mice with chronic hepatitis: a compensatory response to injury [12].
  • We studied the antitumor effects of KW-2149 in MMC-resistant variants of human colon carcinoma HT-29 (HT-29/MMC) and mouse hepatoma Hepa-I (C4, B13NBii1) cells, which are deficient in DT-diaphorase and cytochrome P450 reductase, respectively [13].
  • Overall, our results indicate that NQO1 plays a pivotal role in signaling activated by TNF and other inflammatory stimuli and that its suppression is a potential therapeutic strategy to inhibit the proliferation, survival, invasion, and metastasis of tumor cells [14].

Biological context of Nqo1

  • In the present study, we evaluated the role of As(3+)-, Cd(2+)-, and Cr(6+)-induced oxidative stress on the expression of Cyp1a1, Nqo1, and Gst ya in Hepa 1c1c7 cells [15].
  • Cadmium or arsenic did not change Cyp1a1 mRNA levels but did enhance TCDD-inducible levels of Nqo1 mRNA, an effect that paralleled the ability of these metals to activate a beta-galactosidase gene reporter system regulated by an electrophile response promoter element [16].
  • These data suggest that a gene located on chromosome 7 encodes a trans-acting regulatory factor that might be a negative effector of the Nmo-1 gene, which we show here is located on chromosome 8 approximately 1.4 centimorgans (about 1000 kilobase pairs) from the Es-2 gene [17].
  • Wild-type (NQO1+/+) and knockout (NQO1-/-) mice were given i.p. injections of menadione and BPQ, followed by analysis of membrane damage and DNA damage [3].
  • Lower induction of p53 and decreased apoptosis in NQO1-null mice lead to increased sensitivity to chemical-induced skin carcinogenesis [18].

Anatomical context of Nqo1

  • In a similar experiment, overexpression of NQO1 significantly protected CHO cells against the cytotoxicity of these quinones [3].
  • Quinone reductase can be induced in murine Hepa 1c1c7 hepatoma cells and 3T3 embryo fibroblasts by compounds that are chemoprotectors in vivo, including some phenolic antioxidants, azo dyes, aromatic diamines, and aminophenols [19].
  • RNA and protein-free pSP189 DNA was incubated in a cell-free system with benzo(a)pyrene-3,6-quinone and purified NQO1 or with benzoquinone hydroquinone to generate adducted pSP189 DNA [20].
  • The activities of NAD(P)H-dependent quinone reductase (QR) and the cytochrome P-450 monooxygenases 7-ethoxycoumarin O-deethylase (7-ECD) and 7-ethoxyresorufin O-deethylase (7-ERD) were measured in four subpopulations of murine epidermal keratinocytes (MKs) that differed in their stages of differentiation [21].
  • The most profound effect was seen in the MDA468 cells, where a 27-fold increase in potency was observed for MMC in the DTD-overexpressing cell line [22].

Associations of Nqo1 with chemical compounds


Regulatory relationships of Nqo1


Other interactions of Nqo1

  • Moreover, the Cyp1a1 and Cyp1a2 genes and the Nmo-1 gene are induced by tetrachlorodibenzo-p-dioxin in the cch/cch, cch/c14CoS, and c14CoS/c14CoS mice [17].
  • The absence of BPQ-induced skin carcinogenicity in NQO1-/- mice may be related to the strain (C57BL/6) of mice used in the present study and/or due to poor BPQ absorption into the skin and/or due to detoxification of BPQ by cytosolic NRH:quinone oxidoreductase 2 (NQO2) [3].
  • Two genes are members of the [Ah] battery and induced by ROM-mediated oxidative stress: NAD(P)H:menadione oxidoreductase (Nmo1) and UDP glucuronosyltransferase-1A6 (Ugt1a6) [29].
  • Examining mRNA, protein, and enzyme activity, we demonstrate that the absence of CYP1A1 has no effect on the hepatic constitutive expression of Cyp1a2 or Nqo1 [30].
  • The extract was effective in inducing GST, DTD, SOD and CAT activity in the forestomach and SOD and CAT activity in the lung at both dose levels [24].

Analytical, diagnostic and therapeutic context of Nqo1


  1. Chromium inhibits transcription from polycyclic aromatic hydrocarbon-inducible promoters by blocking the release of histone deacetylase and preventing the binding of p300 to chromatin. Wei, Y.D., Tepperman, K., Huang, M.Y., Sartor, M.A., Puga, A. J. Biol. Chem. (2004) [Pubmed]
  2. Pharmacodynamic characterization of chemopreventive triterpenoids as exceptionally potent inducers of Nrf2-regulated genes. Yates, M.S., Tauchi, M., Katsuoka, F., Flanders, K.C., Liby, K.T., Honda, T., Gribble, G.W., Johnson, D.A., Johnson, J.A., Burton, N.C., Guilarte, T.R., Yamamoto, M., Sporn, M.B., Kensler, T.W. Mol. Cancer Ther. (2007) [Pubmed]
  3. Role of NAD(P)H:quinone oxidoreductase 1 (DT diaphorase) in protection against quinone toxicity. Joseph, P., Long, D.J., Klein-Szanto, A.J., Jaiswal, A.K. Biochem. Pharmacol. (2000) [Pubmed]
  4. Differential induction of Cyp1a1, Cyp1b1, Ahd4, and Nmo1 in murine skin tumors and adjacent normal epidermis by ligands of the aryl hydrocarbon receptor. Reiners, J.J., Jones, C.L., Hong, N., Myrand, S.P. Mol. Carcinog. (1998) [Pubmed]
  5. Disruption of the NAD(P)H:quinone oxidoreductase 1 (NQO1) gene in mice causes myelogenous hyperplasia. Long, D.J., Gaikwad, A., Multani, A., Pathak, S., Montgomery, C.A., Gonzalez, F.J., Jaiswal, A.K. Cancer Res. (2002) [Pubmed]
  6. 20S proteasomal degradation of ornithine decarboxylase is regulated by NQO1. Asher, G., Bercovich, Z., Tsvetkov, P., Shaul, Y., Kahana, C. Mol. Cell (2005) [Pubmed]
  7. Inheritance of antibody specificity V. Anti-2-phenyloxazolone in the mouse. Näkelä, O., Kaartinen, M., Pelkonen, J.L., Karjalainen, K. J. Exp. Med. (1978) [Pubmed]
  8. NAD(P)H:quinone oxidoreductase 1 deficiency and increased susceptibility to 7,12-dimethylbenz[a]-anthracene-induced carcinogenesis in mouse skin. Long, D.J., Waikel, R.L., Wang, X.J., Roop, D.R., Jaiswal, A.K. J. Natl. Cancer Inst. (2001) [Pubmed]
  9. DT-Diaphorase expression and tumor cell sensitivity to 17-allylamino, 17-demethoxygeldanamycin, an inhibitor of heat shock protein 90. Kelland, L.R., Sharp, S.Y., Rogers, P.M., Myers, T.G., Workman, P. J. Natl. Cancer Inst. (1999) [Pubmed]
  10. A major inducer of anticarcinogenic protective enzymes from broccoli: isolation and elucidation of structure. Zhang, Y., Talalay, P., Cho, C.G., Posner, G.H. Proc. Natl. Acad. Sci. U.S.A. (1992) [Pubmed]
  11. Disruption of the DT diaphorase (NQO1) gene in mice leads to increased menadione toxicity. Radjendirane, V., Joseph, P., Lee, Y.H., Kimura, S., Klein-Szanto, A.J., Gonzalez, F.J., Jaiswal, A.K. J. Biol. Chem. (1998) [Pubmed]
  12. Elevations of hepatic quinone reductase, glutathione, and alpha- and mu-class glutathione S-transferase isoforms in mice with chronic hepatitis: a compensatory response to injury. Fernandes, C.L., Dong, J.H., Roebuck, B.D., Chisari, F.V., Montali, J.A., Schmidt, D.E., Prochaska, H.J. Arch. Biochem. Biophys. (1996) [Pubmed]
  13. Nonenzymatic reductive activation of 7-N-((2-([2-(gamma-L-glutamylamino)ethyl]dithio)ethyl))mitomycin C by thiol molecules: a novel mitomycin C derivative effective on mitomycin C-resistant tumor cells. Lee, J.H., Naito, M., Tsuruo, T. Cancer Res. (1994) [Pubmed]
  14. Genetic deletion of NAD(P)H:quinone oxidoreductase 1 abrogates activation of nuclear factor-kappaB, IkappaBalpha kinase, c-Jun N-terminal kinase, Akt, p38, and p44/42 mitogen-activated protein kinases and potentiates apoptosis. Ahn, K.S., Sethi, G., Jain, A.K., Jaiswal, A.K., Aggarwal, B.B. J. Biol. Chem. (2006) [Pubmed]
  15. The role of oxidative stress in the modulation of aryl hydrocarbon receptor-regulated genes by As3+, Cd2+, and Cr6+. Elbekai, R.H., El-Kadi, A.O. Free Radic. Biol. Med. (2005) [Pubmed]
  16. Disruption of dioxin-inducible phase I and phase II gene expression patterns by cadmium, chromium, and arsenic. Maier, A., Dalton, T.P., Puga, A. Mol. Carcinog. (2000) [Pubmed]
  17. Marked increases in hepatic NAD(P)H:oxidoreductase gene transcription and mRNA levels correlated with a mouse chromosome 7 deletion. Petersen, D.D., Gonzalez, F.J., Rapic, V., Kozak, C.A., Lee, J.Y., Jones, J.E., Nebert, D.W. Proc. Natl. Acad. Sci. U.S.A. (1989) [Pubmed]
  18. Lower induction of p53 and decreased apoptosis in NQO1-null mice lead to increased sensitivity to chemical-induced skin carcinogenesis. Iskander, K., Gaikwad, A., Paquet, M., Long, D.J., Brayton, C., Barrios, R., Jaiswal, A.K. Cancer Res. (2005) [Pubmed]
  19. On the mechanisms of induction of cancer-protective enzymes: a unifying proposal. Prochaska, H.J., De Long, M.J., Talalay, P. Proc. Natl. Acad. Sci. U.S.A. (1985) [Pubmed]
  20. Hydroquinones cause specific mutations and lead to cellular transformation and in vivo tumorigenesis. Joseph, P., Klein-Szanto, A.J., Jaiswal, A.K. Br. J. Cancer (1998) [Pubmed]
  21. Differential expression of basal and hydrocarbon-induced cytochrome P-450 monooxygenase and quinone reductase activities in subpopulations of murine epidermal cells differing in their stages of differentiation. Reiners, J.J., Cantu, A.R., Thai, G., Schöller, A. Drug Metab. Dispos. (1992) [Pubmed]
  22. Viral delivery of P450 reductase recapitulates the ability of constitutive overexpression of reductase enzymes to potentiate the activity of mitomycin C in human breast cancer xenografts. Cowen, R.L., Patterson, A.V., Telfer, B.A., Airley, R.E., Hobbs, S., Phillips, R.M., Jaffar, M., Stratford, I.J., Williams, K.J. Mol. Cancer Ther. (2003) [Pubmed]
  23. Transcriptional regulation of the NAD(P)H:quinone oxidoreductase 1 and glutathione S-transferase ya genes by mercury, lead, and copper. Korashy, H.M., El-Kadi, A.O. Drug Metab. Dispos. (2006) [Pubmed]
  24. Modulatory effect of Urtica dioica L. (Urticaceae) leaf extract on biotransformation enzyme systems, antioxidant enzymes, lactate dehydrogenase and lipid peroxidation in mice. Ozen, T., Korkmaz, H. Phytomedicine (2003) [Pubmed]
  25. In vivo role of NAD(P)H:quinone oxidoreductase 1 in metabolic activation of mitomycin C and bone marrow cytotoxicity. Adikesavan, A.K., Barrios, R., Jaiswal, A.K. Cancer Res. (2007) [Pubmed]
  26. Effects of acetylsalicylic acid on parameters related to peroxisome proliferation in mouse liver. Cai, Y., Sohlenius, A.K., Andersson, K., Sundberg, C., DePierre, J.W. Biochem. Pharmacol. (1994) [Pubmed]
  27. Regulation of [Ah] gene battery enzymes and glutathione levels by 5,10-dihydroindeno[1,2-b]indole in mouse hepatoma cell lines. Liu, R.M., Vasiliou, V., Zhu, H., Duh, J.L., Tabor, M.W., Puga, A., Nebert, D.W., Sainsbury, M., Shertzer, H.G. Carcinogenesis (1994) [Pubmed]
  28. Identification of a novel Nrf2-regulated antioxidant response element (ARE) in the mouse NAD(P)H:quinone oxidoreductase 1 gene: reassessment of the ARE consensus sequence. Nioi, P., McMahon, M., Itoh, K., Yamamoto, M., Hayes, J.D. Biochem. J. (2003) [Pubmed]
  29. Extrahepatic expression of NAD(P)H:menadione oxidoreductase, UDP glucuronosyltransferase-1A6, microsomal aldehyde dehydrogenase, and hepatic nuclear factor-1 alpha mRNAs in ch/ch and 14CoS/14CoS mice. Vasiliou, V., Reuter, S.F., Nebert, D.W. Biochem. Biophys. Res. Commun. (1997) [Pubmed]
  30. Targeted knockout of Cyp1a1 gene does not alter hepatic constitutive expression of other genes in the mouse [Ah] battery. Dalton, T.P., Dieter, M.Z., Matlib, R.S., Childs, N.L., Shertzer, H.G., Genter, M.B., Nebert, D.W. Biochem. Biophys. Res. Commun. (2000) [Pubmed]
  31. The Cap'n'Collar basic leucine zipper transcription factor Nrf2 (NF-E2 p45-related factor 2) controls both constitutive and inducible expression of intestinal detoxification and glutathione biosynthetic enzymes. McMahon, M., Itoh, K., Yamamoto, M., Chanas, S.A., Henderson, C.J., McLellan, L.I., Wolf, C.R., Cavin, C., Hayes, J.D. Cancer Res. (2001) [Pubmed]
  32. Molecular basis of the catalytic differences among DT-diaphorase of human, rat, and mouse. Chen, S., Knox, R., Wu, K., Deng, P.S., Zhou, D., Bianchet, M.A., Amzel, L.M. J. Biol. Chem. (1997) [Pubmed]
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