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HGNC Approved Gene Symbol: NQO1
Cytogenetic location: 16q22.1 Genomic coordinates (GRCh38) : 16:69,709,401-69,726,560 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16q22.1 | {Benzene toxicity, susceptibility to} | 3 | ||
| {Breast cancer, poor survival after chemotherapy for} | 3 | |||
| {Leukemia, post-chemotherapy, susceptibility to} | 3 |
NQO1 (EC 1.6.5.2) is a flavoprotein that catalyzes the 2-electron reduction of various quinones and redox dyes, such as phyloquinone and the vitamin K menadione (Jaiswal et al., 1988).
Using rat Nmor1 to probe a liver cDNA library, Jaiswal et al. (1988) cloned human NMOR1. The deduced 274-amino acid protein has a calculated molecular mass of 30.9 kD and shares 85% identity with rat cytosolic Nmor1. Northern blot analysis of normal human liver and HepG2 human hepatoblastoma cells revealed transcripts of 1.2, 1.7, and 2.7 kb that appeared to differ only in the lengths of their 3-prime UTRs.
Using Northern blot analysis, Jaiswal (1994) detected variable expression of 1.2- and 2.7-kb NQO1 transcripts in all human tissues examined. Both transcripts showed highest expression in kidney, followed by skeletal muscle and lung. Lowest expression was detected in pancreas.
Jaiswal et al. (1988) showed that tetrachlorodibenzo-p-dioxin (TCDD) treatment of HepG2 cells produced a 5-fold induction of NMOR1 activity. TCDD predominantly induced transcription of the 2.7-kb NMOR mRNA.
Edwards et al. (1983) showed that the quantitative polymorphism of DIA4 can be attributed to the segregation of a 'low activity' allele. In 4 to 6% of persons there is a DIA4-absent phenotype. In a series of human/hamster hybrids, made using a human parental cell heterozygous for both phosphoglycolate phosphatase (PGP; 172280) and DIA4, the low activity allele and the PGP(2) allele cosegregated except in 2 of 16 discordant hybrids. DIA4 is presumably the same as NAD(P)H:menadione oxidoreductase (NMOR1).
Jaiswal et al. (1988) determined that the 3-prime end of the NQO1 gene contains 4 polyadenylation signal sequences, with an Alu repetitive sequence between polyadenylation sites 2 and 3.
Jaiswal (1991) determined that the NQO1 gene contains 6 coding exons and spans about 20 kb.
By study of man-mouse somatic cell hybrids, Grzeschik (1980) and Povey et al. (1980) identified a fourth diaphorase locus (DIA4) which segregates with chromosome 16. The regional assignment was 16q12-q22 (smallest region of overlap, SRO).
By Southern blot analysis of genomic DNA from human/rodent somatic cell hybrids, Jaiswal et al. (1988) demonstrated that the single-copy NMOR1 gene maps to chromosome 16, consistent with the assignment of DIA4 to that chromosome.
Using mouse/human somatic cell hybrids containing rearranged chromosome 16 together with multiple probes, Chen et al. (1991) assigned the NMOR1 locus to 16q22.1.
NQO1 is a 2-electron reductase that detoxifies quinones derived from the oxidation of phenolic metabolites of benzene. Individuals homozygous for the T/T form of the 609C-T polymorphism (125860.0001) have an increased risk of benzene hematotoxicity. Moran et al. (1999) used a human promyeloblastic cell line to investigate the ability of the benzene metabolite hydroquinone (HQ) to induce NQO1. The concentration-dependent induction of NQO1 protein and activity was observed in these cells when cultured with HQ. Multiple detoxification systems, including NQO1 and glutathione, protect against benzene metabolite-induced toxicity. Indeed, exposure to a noncytotoxic concentration of HQ induced both NQO1 and soluble thiols and protected against HQ-induced apoptosis. Wildtype human bone marrow cells (homozygous for 609C), when exposed to HQ, showed an increase in NQO1 protein and activity, whereas no NQO1 was induced by HQ in bone marrow cells with the T/T genotype. Intermediate induction of NQO1 by HQ was observed in heterozygous bone marrow cells (C/T). nQO1 also was induced by HQ in wildtype (C/C) human bone marrow CD34(+) progenitor cells. The data suggested that failure to induce functional NQO1 may contribute to the increased risk of benzene poisoning in individuals homozygous for the 609C-T substitution.
Millstein et al. (2006) developed an efficient testing strategy called the 'focused interaction testing framework' (FITF) to identify susceptibility genes involved in epistatic interactions useful in case-control studies of candidate genes. In an application to asthma (see 600807) case-control data from the Children's Health Study, FITF identified a significant multilocus effect between the NQO1 gene, the myeloperoxidase gene (MPO; 606989), and the catalase gene (CAT; 115500), 3 genes that are involved in the oxidative stress pathway. In an independent dataset consisting primarily of African American and Asian American children, these 3 genes also showed a significant association with asthma status (P = 0.0008).
Fagerholm et al. (2008) found that the common NQO1 missense variant P187S (125860.0001) (rs1800566) in homozygosity disables NQO1 and strongly predicted poor survival among 2 independent series of women with breast cancer (P = 0.002, N = 1,005; P = 0.005, N = 1,162), an effect particularly evident after anthracycline-based adjuvant chemotherapy with epirubicin (P = 7.52 x 10(-6)) and in p53-aberrant tumors (P = 6.15 x 10(-5)). Survival after metastasis was reduced among NQO1*2 homozygotes, further implicating NQO1 deficiency in cancer progression and treatment resistance. Consistently, response to epirubicin was impaired in NQO1*2-homozygous breast carcinoma cells, in vitro, reflecting both p53-linked and p53-independent roles of NQO1. Fagerholm et al. (2008) proposed a model of defective anthracycline response in NQO1-deficient breast tumors, along with increased genomic instability promoted by elevated reactive oxygen species (ROS), and suggested that the NQO1 genotype is a prognostic and predictive marker for breast cancer.
Data on gene frequencies of allelic variants were tabulated by Roychoudhury and Nei (1988).
Radjendirane et al. (1998) generated Nqo1-null mice by targeted disruption. Mice lacking NQO1 gene expression were indistinguishable from wildtype mice. However, Nqo1-null mice exhibited increased toxicity when administered menadione compared with wildtype mice. These results established a role for NQO1 in protection against quinone toxicity.
Traver et al. (1992, 1997) characterized a polymorphism in NQO1, a C-to-T substitution at position 609 of NQO1 cDNA, which codes for a proline-to-serine change at residue 187 (P187S). In cells with a T/T genotype, NQO1 activity was not detected, and lack of activity corresponded to a lack of NQO1 protein.
Kelsey et al. (1997) found that the prevalence of the T/T genotype varied among ethnic groups from 4 to 20%, with the highest prevalence occurring in Asian populations.
Rothman et al. (1997) reported a case-control study of benzene-exposed workers in China showing an increased risk of hematotoxicity in individuals with the T/T NQO1 genotype. A protective role for NQO1 against benzene-derived quinones in bone marrow in situ required reconciling with the observation that freshly isolated bone marrow mononuclear and progenitor cells failed to express NQO1. Moran et al. (1999) showed that exposure to benzene metabolites does not induce NQO1 in individuals of the T/T genotype as it does in persons with the C/C genotype, and induces NQO1 to an intermediate degree in persons with the T/C genotype.
Synthetic antioxidants and extracts of cruciferous vegetables, including broccoli (Benson et al., 1980), are potent inducers of NQO1. Given the association between lack of NQO1 activity, benzene toxicity, and subsequent risk of benzene-induced leukemia, Smith (1999) decided to investigate the role of the 609C-to-T polymorphism in leukemia in general. With colleagues, he studied a series of 104 leukemia cases from the Chicago area, more than half of which represented myeloid leukemia secondary to chemotherapy. The mutant allele frequency was 1.4-fold higher than expected in the post-therapy AML cases and was 1.6-fold higher among patients with abnormalities in chromosomes 5 and/or 7. Zhang et al. (1998) had shown that benzene increases abnormalities in chromosomes 5 and 7 in exposed workers, and hydroquinone produces similar changes in cultured human cells (Zhang et al., 1998). Thus, lack of or lowered NQO1 activity may make individuals vulnerable to leukemia secondary to chemical exposure.
Fagerholm et al. (2008) found that homozygosity for the T/T genotype of NQO1 (NQO1*2, rs1800566T) strongly predicted poor survival among 2 independent series of women with breast cancer (114480) (P = 0.002, N = 1,005; P = 0.005, N = 1,162), an effect particularly evident after anthracycline-based adjuvant chemotherapy with epirubicin (P = 7.52 x 10(-6)) and in p53 (191170)-aberrant tumors (P = 6.15 x 10(-5)).
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Fagerholm, R., Hofstetter, B., Tommiska, J., Aaltonen, K., Vrtel, R., Syrjakoski, K., Kallioniemi, A., Kilpivaara, O., Mannermaa, A., Kosma, V.-M., Uusitupa, M., Eskelinen, M., Kataja, V., Aittomaki, K., von Smitten, K., Heikkila, P., Lukas, J., Holli, K., Bartkova, J., Blomqvist, C., Bartek, J., Nevanlinna, H. NAD(P)H:quinone oxidoreductase 1 NQO1*2 genotype (P187S) is a strong prognostic and predictive factor in breast cancer. Nature Genet. 40: 844-853, 2008. [PubMed: 18511948] [Full Text: https://doi.org/10.1038/ng.155]
Grzeschik, K.-H. Assignment of a structural gene for a fourth human diaphorase (DIA-4) to chromosome 16 in man-mouse somatic cell hybrids. Hum. Genet. 53: 189-193, 1980. [PubMed: 6928411] [Full Text: https://doi.org/10.1007/BF00273494]
Jaiswal, A. K., McBride, O. W., Adesnik, M., Nebert, D. W. Human dioxin-inducible cytosolic NAD(P)H:Menadione oxidoreductase: cDNA sequence and localization of gene to chromosome 16. J. Biol. Chem. 263: 13572-13578, 1988. [PubMed: 2843525]
Jaiswal, A. K. Human NAD(P)H:quinone oxidoreductase (NQO1) gene structure and induction by dioxin. Biochemistry 30: 10647-10653, 1991. [PubMed: 1657151] [Full Text: https://doi.org/10.1021/bi00108a007]
Jaiswal, A. K. Human NAD(P)H:quinone oxidoreductase-2: gene structure, activity, and tissue-specific expression. J. Biol. Chem. 269: 14502-14508, 1994. [PubMed: 8182056]
Kelsey, K. T., Ross, D., Traver, R. D., Christiani, D. C., Zuo, Z. F., Spitz, M. R., Wang, M., Xu, X., Lee, B. K., Schwartz, B. S., Wiencke, J. K. Ethnic variation in the prevalence of a common NAD(P)H quinone oxidoreductase polymorphism and its implications for anti-cancer chemotherapy. Brit. J. Cancer 76: 852-854, 1997. [PubMed: 9328142] [Full Text: https://doi.org/10.1038/bjc.1997.474]
Millstein, J., Conti, D. V., Gilliland, F. D., Gauderman, W. J. A testing framework for identifying susceptibility genes in the presence of epistasis. Am. J. Hum. Genet. 78: 15-27, 2006. Note: Erratum: Am. J. Hum. Genet. 84: 301 only, 2009. [PubMed: 16385446] [Full Text: https://doi.org/10.1086/498850]
Moran, J. L., Siegel, D., Ross, D. A potential mechanism underlying the increased susceptibility of individuals with a polymorphism in NAD(P)H:quinone oxidoreductase 1 (NQO1) to benzene toxicity. Proc. Nat. Acad. Sci. 96: 8150-8155, 1999. [PubMed: 10393963] [Full Text: https://doi.org/10.1073/pnas.96.14.8150]
Povey, S., Wilson, D., Edwards, Y. H. Assignment of a human diaphorase (DIA-4) to chromosome 16. Ann. Hum. Genet. 43: 349-353, 1980. [PubMed: 6893112] [Full Text: https://doi.org/10.1111/j.1469-1809.1980.tb01569.x]
Radjendirane, V., Joseph, P., Lee, Y.-H., Kimura, S., Klein-Szanto, A. J. P., Gonzalez, F. J., Jaiswal, A. K. Disruption of the DT diaphorase (NQO1) gene in mice leads to increased menadione toxicity. J. Biol. Chem. 273: 7382-7389, 1998. [PubMed: 9516435] [Full Text: https://doi.org/10.1074/jbc.273.13.7382]
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. Benzene poisoning, a risk factor for hematological malignancy, is associated with the NQO1 609C-T mutation and rapid fractional excretion of chlorzoxazone. Cancer Res. 57: 2839-2842, 1997. [PubMed: 9230185]
Roychoudhury, A. K., Nei, M. Human Polymorphic Genes: World Distribution. New York: Oxford Univ. Press (pub.) 1988.
Smith, M. T. Benzene, NQO1, and genetic susceptibility to cancer. (Commentary) Proc. Nat. Acad. Sci. 96: 7624-7626, 1999. [PubMed: 10393869] [Full Text: https://doi.org/10.1073/pnas.96.14.7624]
Traver, R. D., Horikoshi, T., Danenberg, K. D., Stadlbauer, T. H., Danenberg, P. V., Ross, D., Gibson, N. W. NAD(P)H:quinone oxidoreductase gene expression in human colon carcinoma cells: characterization of a mutation which modulates DT-diaphorase activity and mitomycin sensitivity. Cancer Res. 52: 797-802, 1992. [PubMed: 1737339]
Traver, R. D., Siegel, D., Beall, H. D., Phillips, R. M., Gibson, N. W., Franklin, W. A., Ross, D. Characterization of a polymorphism in NAD(P)H: quinone oxidoreductase (DT-diaphorase). Brit. J. Cancer 75: 69-75, 1997. [PubMed: 9000600] [Full Text: https://doi.org/10.1038/bjc.1997.11]
Zhang, L., Rothman, N., Wang, Y., Hayes, R. B., Li, G., Dosemeci, M., Yin, S., Kolachana, P., Titenko-Holland, N., Smith, M. T. Increased aneusomy and long arm deletion of chromosomes 5 and 7 in the lymphocytes of Chinese workers exposed to benzene. Carcinogenesis 19: 1955-1961, 1998. [PubMed: 9855009] [Full Text: https://doi.org/10.1093/carcin/19.11.1955]
Zhang, L., Wang, Y., Shang, N., Smith, M. T. Benzene metabolites induce the loss of long arm deletion of chromosomes 5 and 7 in human lymphocytes. Leukemia Res. 22: 105-113, 1998. [PubMed: 9593466] [Full Text: https://doi.org/10.1016/s0145-2126(97)00157-4]