Cardiovascular Toxicology

, Volume 12, Issue 1, pp 39–45 | Cite as

NAD(P)H:Quinone Oxidoreductase 1 and its Potential Protective Role in Cardiovascular Diseases and Related Conditions

  • Hong Zhu
  • Yunbo Li


NAD(P)H:quinone oxidoreductase (NQO) represents a family of flavoproteins that catalyze the two-electron reduction of quinones and their derivatives. In mammalian systems, there are two members of NQO, namely, NQO1 and NQO2. NQO1 utilizes NAD(P)H, whereas NQO2 employs dihydronicotinamide riboside (NRH) as the electron donors. In addition to the well-documented action in reducing quinone compounds and preventing the formation of reactive oxygen species, NQO enzymes, especially NQO1 also possess other important biological activities. These include anti-inflammatory effects, direct scavenging of superoxide anion radicals, and stabilization of p53 and other tumor suppressors. Recently, multiple studies in animal models demonstrated a potential role for NQO1 in protecting against cardiovascular injury and related conditions, including atherogenesis, dyslipidemia, and insulin resistance. Functional gene polymorphisms have been identified in human NQO1 gene. Studies on the association between NQO1 gene polymorphisms and susceptibility to disease development also suggested a possible involvement of NQO1 in human cardiovascular diseases and metabolic syndrome. This review is intended to summarize the recent development regarding the biochemical properties and molecular regulation of NQO1 and its potential beneficial role in cardiovascular diseases and related conditions, including metabolic syndrome.


NQO1 Cardiovascular diseases Gene polymorphisms Metabolic syndrome Inflammation Oxidative stress 



This work is supported in part by NIH grants DK81905 (HZ) and HL93557 (YL).


  1. 1.
    Ernster, L., & Lindberg, O. (1958). Animal mitochondria. Annual Review of Physiology, 20, 13–42.PubMedCrossRefGoogle Scholar
  2. 2.
    Jaiswal, A. K., Burnett, P., Adesnik, M., & McBride, O. W. (1990). 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. Biochemistry, 29, 1899–1906.PubMedCrossRefGoogle Scholar
  3. 3.
    Jaiswal, A. K. (1994). Human NAD(P)H:quinone oxidoreductase2. Gene structure, activity, and tissue-specific expression. J Biol Chem, 269, 14502–14508.PubMedGoogle Scholar
  4. 4.
    Zhao, Q., Yang, X. L., Holtzclaw, W. D., & Talalay, P. (1997). Unexpected genetic and structural relationships of a long-forgotten flavoenzyme to NAD(P)H:quinone reductase (DT-diaphorase). Proceedings of the National Academy of Sciences of the United States of America, 94, 1669–1674.PubMedCrossRefGoogle Scholar
  5. 5.
    Liao, S., & Williams-Ashman, H. G. (1961). Enzymatic oxidation of some non-phosphorylated derivatives of dihydronicotinamide. Biochemical and Biophysical Research Communications, 4, 208–213.PubMedCrossRefGoogle Scholar
  6. 6.
    Dinkova-Kostova, A. T., & Talalay, P. (2010). NAD(P)H:quinone acceptor oxidoreductase 1 (NQO1), a multifunctional antioxidant enzyme and exceptionally versatile cytoprotector. Archives of Biochemistry and Biophysics, 501, 116–123.PubMedCrossRefGoogle Scholar
  7. 7.
    Ross, D. (2004). Quinone reductases multitasking in the metabolic world. Drug Metabolism Reviews, 36, 639–654.PubMedCrossRefGoogle Scholar
  8. 8.
    Seow, H. A., Penketh, P. G., Belcourt, M. F., Tomasz, M., Rockwell, S., & Sartorelli, A. C. (2004). Nuclear overexpression of NAD(P)H:quinone oxidoreductase 1 in Chinese hamster ovary cells increases the cytotoxicity of mitomycin C under aerobic and hypoxic conditions. J Biol Chem, 279, 31606–31612.PubMedCrossRefGoogle Scholar
  9. 9.
    Adikesavan, A. K., Barrios, R., & Jaiswal, A. K. (2007). In vivo role of NAD(P)H:quinone oxidoreductase 1 in metabolic activation of mitomycin C and bone marrow cytotoxicity. Cancer Research, 67, 7966–7971.PubMedCrossRefGoogle Scholar
  10. 10.
    Siegel, D., Gustafson, D. L., Dehn, D. L., Han, J. Y., Boonchoong, P., Berliner, L. J., et al. (2004). NAD(P)H:quinone oxidoreductase 1: role as a superoxide scavenger. Molecular Pharmacology, 65, 1238–1247.PubMedCrossRefGoogle Scholar
  11. 11.
    Zhu, H., Jia, Z., Mahaney, J. E., Ross, D., Misra, H. P., Trush, M. A., et al. (2007). The highly expressed and inducible endogenous NAD(P)H:quinone oxidoreductase 1 in cardiovascular cells acts as a potential superoxide scavenger. Cardiovascular Toxicology, 7, 202–211.PubMedCrossRefGoogle Scholar
  12. 12.
    Cao, Z., & Li, Y. (2004). The chemical inducibility of mouse cardiac antioxidants and phase 2 enzymes in vivo. Biochemical and Biophysical Research Communications, 317, 1080–1088.PubMedCrossRefGoogle Scholar
  13. 13.
    Siegel, D., & Ross, D. (2000). Immunodetection of NAD(P)H:quinone oxidoreductase 1 (NQO1) in human tissues. Free Radical Biology and Medicine, 29, 246–253.PubMedCrossRefGoogle Scholar
  14. 14.
    Griendling, K. K., & FitzGerald, G. A. (2003). Oxidative stress and cardiovascular injury: Part I: Basic mechanisms and in vivo monitoring of ROS. Circulation, 108, 1912–1916.PubMedCrossRefGoogle Scholar
  15. 15.
    Griendling, K. K., & FitzGerald, G. A. (2003). Oxidative stress and cardiovascular injury: Part II: Animal and human studies. Circulation, 108, 2034–2040.PubMedCrossRefGoogle Scholar
  16. 16.
    Asher, G., Lotem, J., Cohen, B., Sachs, L., & Shaul, Y. (2001). Regulation of p53 stability and p53-dependent apoptosis by NADH quinone oxidoreductase 1. Proceedings of the National Academy of Sciences of the United States of America, 98, 1188–1193.PubMedCrossRefGoogle Scholar
  17. 17.
    Anwar, A., Dehn, D., Siegel, D., Kepa, J. K., Tang, L. J., Pietenpol, J. A., et al. (2003). Interaction of human NAD(P)H:quinone oxidoreductase 1 (NQO1) with the tumor suppressor protein p53 in cells and cell-free systems. Journal of Biological Chemistry, 278, 10368–10373.PubMedCrossRefGoogle Scholar
  18. 18.
    Asher, G., Tsvetkov, P., Kahana, C., & Shaul, Y. (2005). A mechanism of ubiquitin-independent proteasomal degradation of the tumor suppressors p53 and p73. Genes and Development, 19, 316–321.PubMedCrossRefGoogle Scholar
  19. 19.
    Garate, M., Wong, R. P., Campos, E. I., Wang, Y., & Li, G. (2008). NAD(P)H quinone oxidoreductase 1 inhibits the proteasomal degradation of the tumour suppressor p33(ING1b). EMBO Rep, 9, 576–581.PubMedCrossRefGoogle Scholar
  20. 20.
    Alard, A., Fabre, B., Anesia, R., Marboeuf, C., Pierre, P., Susini, C., et al. (2010). NAD(P)H quinone-oxydoreductase 1 protects eukaryotic translation initiation factor 4GI from degradation by the proteasome. Molecular and Cellular Biology, 30, 1097–1105.PubMedCrossRefGoogle Scholar
  21. 21.
    Nioi, P., & Hayes, J. D. (2004). Contribution of NAD(P)H:quinone oxidoreductase 1 to protection against carcinogenesis, and regulation of its gene by the Nrf2 basic-region leucine zipper and the arylhydrocarbon receptor basic helix-loop-helix transcription factors. Mutation Research, 555, 149–171.PubMedCrossRefGoogle Scholar
  22. 22.
    Chen, X. L., Varner, S. E., Rao, A. S., Grey, J. Y., Thomas, S., Cook, C. K., et al. (2003). Laminar flow induction of antioxidant response element-mediated genes in endothelial cells. A novel anti-inflammatory mechanism. Journal of Biological Chemistry, 278, 703–711.PubMedCrossRefGoogle Scholar
  23. 23.
    Lee, S. O., Chang, Y. C., Whang, K., Kim, C. H., & Lee, I. S. (2007). Role of NAD(P)H:quinone oxidoreductase 1 on tumor necrosis factor-alpha-induced migration of human vascular smooth muscle cells. Cardiovascular Research, 76, 331–339.PubMedCrossRefGoogle Scholar
  24. 24.
    Kim, S. Y., Jeoung, N. H., Oh, C. J., Choi, Y. K., Lee, H. J., Kim, H. J., et al. (2009). Activation of NAD(P)H:quinone oxidoreductase 1 prevents arterial restenosis by suppressing vascular smooth muscle cell proliferation. Circulation Research, 104, 842–850.PubMedCrossRefGoogle Scholar
  25. 25.
    Hur, K. Y., Kim, S. H., Choi, M. A., Williams, D. R., Lee, Y. H., Kang, S. W., et al. (2010). Protective effects of magnesium lithospermate B against diabetic atherosclerosis via Nrf2-ARE-NQO1 transcriptional pathway. Atherosclerosis, 211, 69–76.PubMedCrossRefGoogle Scholar
  26. 26.
    Gaikwad, A., Long, D. J., 2nd, Stringer, J. L., & Jaiswal, A. K. (2001). In vivo role of NAD(P)H:quinone oxidoreductase 1 (NQO1) in the regulation of intracellular redox state and accumulation of abdominal adipose tissue. Journal of Biological Chemistry, 276, 22559–22564.PubMedCrossRefGoogle Scholar
  27. 27.
    Hwang, J. H., Kim, D. W., Jo, E. J., Kim, Y. K., Jo, Y. S., Park, J. H., et al. (2009). Pharmacological stimulation of NADH oxidation ameliorates obesity and related phenotypes in mice. Diabetes, 58, 965–974.PubMedCrossRefGoogle Scholar
  28. 28.
    Pink, J. J., Planchon, S. M., Tagliarino, C., Varnes, M. E., Siegel, D., & Boothman, D. A. (2000). NAD(P)H:Quinone oxidoreductase activity is the principal determinant of beta-lapachone cytotoxicity. Journal of Biological Chemistry, 275, 5416–5424.PubMedCrossRefGoogle Scholar
  29. 29.
    Bey, E. A., Bentle, M. S., Reinicke, K. E., Dong, Y., Yang, C. R., Girard, L., et al. (2007). An NQO1- and PARP-1-mediated cell death pathway induced in non-small-cell lung cancer cells by beta-lapachone. Proceedings of the National Academy of Sciences of the United States of America, 104, 11832–11837.PubMedCrossRefGoogle Scholar
  30. 30.
    Kelsey, K. T., Ross, D., Traver, R. D., Christiani, D. C., Zuo, Z. F., Spitz, M. R., et al. (1997). Ethnic variation in the prevalence of a common NAD(P)H quinone oxidoreductase polymorphism and its implications for anti-cancer chemotherapy. British Journal of Cancer, 76, 852–854.PubMedCrossRefGoogle Scholar
  31. 31.
    Gaedigk, A., Tyndale, R. F., Jurima-Romet, M., Sellers, E. M., Grant, D. M., & Leeder, J. S. (1998). NAD(P)H:quinone oxidoreductase: polymorphisms and allele frequencies in Caucasian, Chinese and Canadian Native Indian and Inuit populations. Pharmacogenetics, 8, 305–313.PubMedCrossRefGoogle Scholar
  32. 32.
    Traver, R. D., Siegel, D., Beall, H. D., Phillips, R. M., Gibson, N. W., Franklin, W. A., et al. (1997). Characterization of a polymorphism in NAD(P)H:quinone oxidoreductase (DT-diaphorase). British Journal of Cancer, 75, 69–75.PubMedCrossRefGoogle Scholar
  33. 33.
    Han, S. J., Kang, E. S., Kim, H. J., Kim, S. H., Chun, S. W., Ahn, C. W., et al. (2009). The C609T variant of NQO1 is associated with carotid artery plaques in patients with type 2 diabetes. Molecular Genetics and Metabolism, 97, 85–90.PubMedCrossRefGoogle Scholar
  34. 34.
    Isbir, C. S., Ergen, A., Tekeli, A., Zeybek, U., Gormus, U., & Arsan, S. (2008). The effect of NQO1 polymorphism on the inflammatory response in cardiopulmonary bypass. Cell Biochemistry and Function, 26, 534–538.PubMedCrossRefGoogle Scholar
  35. 35.
    Martin, N. J., Collier, A. C., Bowen, L. D., Pritsos, K. L., Goodrich, G. G., Arger, K., et al. (2009). Polymorphisms in the NQO1, GSTT and GSTM genes are associated with coronary heart disease and biomarkers of oxidative stress. Mutation Research, 674, 93–100.PubMedGoogle Scholar
  36. 36.
    Shyu, H. Y., Fong, C. S., Fu, Y. P., Shieh, J. C., Yin, J. H., Chang, C. Y., et al. (2010). Genotype polymorphisms of GGCX, NQO1, and VKORC1 genes associated with risk susceptibility in patients with large-artery atherosclerotic stroke. Clinical Chemistry of Acta, 411, 840–845.CrossRefGoogle Scholar
  37. 37.
    Palming, J., Sjoholm, K., Jernas, M., Lystig, T. C., Gummesson, A., Romeo, S., et al. (2007). The expression of NAD(P)H:quinone oxidoreductase 1 is high in human adipose tissue, reduced by weight loss, and correlates with adiposity, insulin sensitivity, and markers of liver dysfunction. Journal of Clinical Endocrinology and Metabolism, 92, 2346–2352.PubMedCrossRefGoogle Scholar
  38. 38.
    Wang, G., Zhang, L., & Li, Q. (2006). Genetic polymorphisms of GSTT1, GSTM1, and NQO1 genes and diabetes mellitus risk in Chinese population. Biochemical and Biophysical Research Communications, 341, 310–313.PubMedCrossRefGoogle Scholar
  39. 39.
    Kristiansen, O. P., Larsen, Z. M., Johannesen, J., Nerup, J., Mandrup-Poulsen, T., & Pociot, F. (1999). No linkage of P187S polymorphism in NAD(P)H: quinone oxidoreductase (NQO1/DIA4) and type 1 diabetes in the Danish population. DIEGG and DSGD. Danish IDDM epidemiology and genetics group and the Danish study group of diabetes in childhood. Human Mutation, 14, 67–70.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Division of Biomedical SciencesEdward via College of Osteopathic Medicine, Virginia Tech Corporate Research CenterBlacksburgUSA
  2. 2.Department of Biomedical Sciences and PathobiologyVirginia Polytechnic Institute and State UniversityBlacksburgUSA
  3. 3.Virginia Tech-Wake Forest University School of Biomedical Engineering and SciencesBlacksburgUSA

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