NQO1 (NAD (P)H dehydrogenase, quinone 1)

2004-06-01   David Ross 

School of Pharmacy, University of Colorado Health Sciences Center, Denver 80262, USA


Atlas Image
NQO1 (16q22) - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics.



Spans approximately 20 kb consisting of 6 exons and 5 introns. Highly inducible protein and the 5 flanking region contains an AP2, ARE or EpRE(antioxidant or electrophile responsive element) and an XRE (xenobiotic responsive element).


Three mRNA sizes (1.2, 1.7 and 2.7 kb) have been observed due to multiple polyadenylation sites. An alternatively spliced form of NQO1 mRNA lacking exon 4 is also possible although the corresponding truncated protein has not been detected.



NQO1 is a flavoprotein which functions as a homodimer. The physiological dimer has one catalytic site per monomer. Each monomer consists of 273 amino acids.
For structures of human recombinant NQO1 with quinones complexed in the active site see Structures of recombinant human and mouse NAD(P)H:quinone oxidoreductases: species comparison and structural changes with substrate binding and release (Structure Explorer - 1D4A) and. Structure-based development of antitumor quinones. Complexes of NQO1 with three potential chemotherapeutic quinones (Structure Explorer - 1H66).


NQO1 is expressed in human epithelial and endothelial tissues and at high levels throughout many human solid tumors.


NQO1 is a mainly cytosolic enzyme (approx. 90%) although it has also been localized in smaller amounts to mitochondria, endoplasmic reticulum and nucleus.


NQO1 catalyzes obligate two electron reduction of a wide variety of substrates. The most efficient substrates are quinones but the enzyme will also reduce quinone-imines, nitro and azo compounds. The enzyme functions via a hydride transfer mechanism and requires a pyridine nucleotide cofactor. Reduction proceeds with equal facility with both NADH and NADPH. NQO1 can generate antioxidant forms of both vitamin E and ubiquinone after free radical attack. The capability to protect cells from oxidative challenge and the ability to reduce quinones via an obligate two electron mechanism, which precludes generation of reactive oxygen radicals, demonstrates that NQO1 is a chemoprotective enzyme. NQO1 knockout mice demonstrated increased susceptibility to benzo(a)pyrene and 7,12-dimethylbenz(a) anthracene induced skin carcinogenesis. NQO1 has been proposed to stabilize the tumor suppressor gene p53 and has been shown to interact with p53 in a protein-protein interaction.

Certain compounds such as antitumor quinones, however, can be bioactivated by two electron reduction and in these cases NQO1 serves as an activating enzyme. Because of the high levels of NQO1 in certain tumors, this has led to an interest in designing compounds which can be efficiently bioactivated by NQO1 as antitumor agents.


Amino acid homology across species is high (mouse/human 86%, mouse/rat -94%, human/rat 86%). NQO2 is a separate gene product demonstrating 49% and 54% similarity at the amino acid and nucleotide levels respectively.



Two polymorphisms have been characterized. The NQO1 *2 allele represents a C609T change in the cDNA coding for a Pro187Ser change in the enzyme. The NQO1 *3 allele is a C465T change in the cDNA coding for an Arg139Trp change. The NQO1 * 2 allele is much more frequent than the *3 allele and has profound consequences for phenotype. The NQO1 *2 protein has diminished catalytic activity and the protein is rapidly degraded by the ubiquitin-proteasomal system. As a result, cells and tissues carrying the homozygous NQO1 *2 allele have no detectable NQO1 activity and at best, trace levels of NQO1 protein. The NQO1 *2/*2 genotype is effectively a null polymorphism. NQO1 is highly inducible and although NQO1 levels can vary considerably among individuals with the same genotype, the NQO1 *2 allele has been reported to show a gene dose effect since heterozygotes (NQO1 *1/*2) contained significantly less NQO1 protein than wild type (NQO1 *1/*1) samples.

Implicated in

Entity name
Increased risk of leukemia has been associated with the NQO1 *2 allele and diminished NQO1 activity. Childhood leukemia (particularly with MLL fusions) , adult leukemia (ALL, AML particularly with translocations or inversions) and secondary leukemias and myelodysplasias as a result of chemotherapy have been associated with the NQO1 *2 polymorphism.
Increased benzene induced myelotoxicity in occupationally exposed individuals has also been linked to the NQO1 *2 polymorphism.
Entity name
Solid tumors
Increased risk of renal and urothelial cell carcinomas and cutaneous basal cell carcinomas have also been associated with the NQO1 *2 polymorphism but conflicting results have been obtained in colon cancer and lung cancer. A number of epidemiological studies have investigated the possible link between NQO1 and cancer and have been recently summarized [6].DISEASE


Pubmed IDLast YearTitleAuthors
125293182003Interaction of human NAD(P)H:quinone oxidoreductase 1 (NQO1) with the tumor suppressor protein p53 in cells and cell-free systems.Anwar A et al
118677462002NQO1 stabilizes p53 through a distinct pathway.Asher G et al
75656311995Nicotinamide adenine dinucleotide (phosphate): quinone oxidoreductase (DT-diaphorase) as a target for bioreductive antitumor quinones: quinone cytotoxicity and selectivity in human lung and breast cancer cell lines.Beall HD et al
86379081996The role of DT-diaphorase in the maintenance of the reduced antioxidant form of coenzyme Q in membrane systems.Beyer RE et al
115876402001Structure-based development of anticancer drugs: complexes of NAD(P)H:quinone oxidoreductase 1 with chemotherapeutic quinones.Faig M et al
97317171998NAD(P)H:quinone oxidoreductase: polymorphisms and allele frequencies in Caucasian, Chinese and Canadian Native Indian and Inuit populations.Gaedigk A et al
77809661995An alternatively spliced form of NQO1 (DT-diaphorase) messenger RNA lacking the putative quinone substrate binding site is present in human normal and tumor tissues.Gasdaska PY et al
89128651996The NAD(P)H:quinone oxidoreductase locus in human colon carcinoma HCT 116 cells resistant to mitomycin C.Hu LT et al
16571511991Human NAD(P)H:quinone oxidoreductase (NQO1) gene structure and induction by dioxin.Jaiswal AK et al
28435251988Human dioxin-inducible cytosolic NAD(P)H:menadione oxidoreductase. cDNA sequence and localization of gene to chromosome 16.Jaiswal AK et al
93281421997Ethnic variation in the prevalence of a common NAD(P)H quinone oxidoreductase polymorphism and its implications for anti-cancer chemotherapy.Kelsey KT et al
103977481999Prevalence of the inactivating 609C-->T polymorphism in the NAD(P)H:quinone oxidoreductase (NQO1) gene in patients with primary and therapy-related myeloid leukemia.Larson RA et al
75680291995The three-dimensional structure of NAD(P)H:quinone reductase, a flavoprotein involved in cancer chemoprotection and chemotherapy: mechanism of the two-electron reduction.Li R et al
22333011990DT-diaphorase: purification, properties, and function.Lind C et al
114813892001NAD(P)H:quinone oxidoreductase 1 deficiency and increased susceptibility to 7,12-dimethylbenz[a]-anthracene-induced carcinogenesis in mouse skin.Long DJ 2nd et al
103939631999A potential mechanism underlying the increased susceptibility of individuals with a polymorphism in NAD(P)H:quinone oxidoreductase 1 (NQO1) to benzene toxicity.Moran JL et al
110512612000Analysis of genetic polymorphism in NQO1, GST-M1, GST-T1, and CYP3A4 in 469 Japanese patients with therapy-related leukemia/ myelodysplastic syndrome and de novo acute myeloid leukemia.Naoe T et al
78129661995NAD(P)H:quinone oxidoreductase expression and mitomycin C resistance developed by human colon cancer HCT 116 cells.Pan SS et al
95164351998Disruption of the DT diaphorase (NQO1) gene in mice leads to increased menadione toxicity.Radjendirane V et al
76202171994Bioactivation of quinones by DT-diaphorase, molecular, biochemical, and chemical studies.Ross D et al
111547362000NAD(P)H:quinone oxidoreductase 1 (NQO1): chemoprotection, bioactivation, gene regulation and genetic polymorphisms.Ross D et al
150471002004NAD(P)H:quinone oxidoreductase 1 (NQO1, DT-diaphorase), functions and pharmacogenetics.Ross D et al
111608622001Rapid polyubiquitination and proteasomal degradation of a mutant form of NAD(P)H:quinone oxidoreductase 1.Siegel D et al
92713531997The reduction of alpha-tocopherolquinone by human NAD(P)H: quinone oxidoreductase: the role of alpha-tocopherolhydroquinone as a cellular antioxidant.Siegel D et al
102086501999Genotype-phenotype relationships in studies of a polymorphism in NAD(P)H:quinone oxidoreductase 1.Siegel D et al
110352532000Immunodetection of NAD(P)H:quinone oxidoreductase 1 (NQO1) in human tissues.Siegel D et al
112223892001Low NAD(P)H:quinone oxidoreductase 1 activity is associated with increased risk of acute leukemia in adults.Smith MT et al
17373391992NAD(P)H:quinone oxidoreductase gene expression in human colon carcinoma cells: characterization of a mutation which modulates DT-diaphorase activity and mitomycin sensitivity.Traver RD et al
90006001997Characterization of a polymorphism in NAD(P)H: quinone oxidoreductase (DT-diaphorase).Traver RD et al
104636131999A lack of a functional NAD(P)H:quinone oxidoreductase allele is selectively associated with pediatric leukemias that have MLL fusions. United Kingdom Childhood Cancer Study Investigators.Wiemels JL et al
98659241998A new screening system for NAD(P)H:quinone oxidoreductase (NQO1)-directed antitumor quinones: identification of a new aziridinylbenzoquinone, RH1, as a NQO1-directed antitumor agent.Winski SL et al

Other Information

Locus ID:

NCBI: 1728
MIM: 125860
HGNC: 2874
Ensembl: ENSG00000181019


dbSNP: 1728
ClinVar: 1728
TCGA: ENSG00000181019


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Ubiquinone and other terpenoid-quinone biosynthesisKEGGko00130
Ubiquinone and other terpenoid-quinone biosynthesisKEGGhsa00130
Metabolism of amino acids and derivativesREACTOMER-HSA-71291
Metabolism of polyaminesREACTOMER-HSA-351202
Regulation of ornithine decarboxylase (ODC)REACTOMER-HSA-350562
Fluid shear stress and atherosclerosisKEGGko05418
Fluid shear stress and atherosclerosisKEGGhsa05418

Protein levels (Protein atlas)

Not detected


Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA128406956fluorouracilChemicalClinicalAnnotationassociatedPD10208650, 11160862, 18511948, 21479364, 21946896, 24533712, 25545243
PA130620651anthracyclines and related substancesChemicalClinicalAnnotationassociatedPD10208650, 11160862, 18511948, 21479364, 21946896, 24533712, 25545243
PA131285527oxaliplatinChemicalLiterature, MultilinkAnnotationassociated24924344
PA151958383Gastrointestinal Stromal TumorsDiseaseClinicalAnnotationassociatedPD30237583
PA164712331Alkylating AgentsChemicalClinicalAnnotationassociatedPD10208650, 11160862, 18511948, 21479364, 21946896, 24533712, 25545243
PA164713176Platinum compoundsChemicalClinicalAnnotationassociatedPD10208650, 11160862, 18511948, 21479364, 21946896, 24533712, 25545243
PA166155017rs1800566VariantVipGeneassociated12370763, 11821413
PA443560Breast NeoplasmsDiseaseClinicalAnnotationassociatedPD10208650, 11160862, 18511948, 21479364, 21946896, 24533712, 25545243
PA443622Carcinoma, Non-Small-Cell LungDiseaseClinicalAnnotationassociatedPD10208650, 11160862, 18511948, 21479364, 21946896, 24533712, 25545243
PA444818Lung NeoplasmsDiseaseVipGeneassociated16170238
PA445062NeoplasmsDiseaseClinicalAnnotationassociatedPD10208650, 11160862, 18511948, 21479364, 21946896, 24533712, 25545243
PA445204Ovarian NeoplasmsDiseaseClinicalAnnotationassociatedPD10208650, 11160862, 18511948, 21479364, 21946896, 24533712, 25545243
PA445742Stomach NeoplasmsDiseaseClinicalAnnotationassociatedPD10208650, 11160862, 18511948, 21479364, 21946896, 24533712, 25545243
PA449412doxorubicinChemicalVipGeneassociated9333325, 10954045
PA451906warfarinChemicalClinicalAnnotationassociatedPD21923605, 26257249, 27581200, 27740732
PA451991benzeneChemicalVariantAnnotation, VipGeneassociatedPD15935810


Pubmed IDYearTitleCitations
128674922003Comparison of primary human hepatocytes and hepatoma cell line Hepg2 with regard to their biotransformation properties.133
157347322005Bach1 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.124
199131212009Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.85
185119482008NAD(P)H:quinone oxidoreductase 1 NQO1*2 genotype (P187S) is a strong prognostic and predictive factor in breast cancer.84
185119482008NAD(P)H:quinone oxidoreductase 1 NQO1*2 genotype (P187S) is a strong prognostic and predictive factor in breast cancer.84
157461602005Constitutional short telomeres are strong genetic susceptibility markers for bladder cancer.83
163854462006A testing framework for identifying susceptibility genes in the presence of epistasis.81
189810902008Lipopolysaccharide-induced expression of NAD(P)H:quinone oxidoreductase 1 and heme oxygenase-1 protects against excessive inflammatory responses in human monocytes.76
123701942003Laminar flow induction of antioxidant response element-mediated genes in endothelial cells. A novel anti-inflammatory mechanism.71
198086632009Nrf2-dependent and -independent responses to nitro-fatty acids in human endothelial cells: identification of heat shock response as the major pathway activated by nitro-oleic acid.71


David Ross

NQO1 (NAD (P)H dehydrogenase, quinone 1)

Atlas Genet Cytogenet Oncol Haematol. 2004-06-01

Online version: http://atlasgeneticsoncology.org/gene/375/nqo1-(nad-(p)h-dehydrogenase-quinone-1)

Historical Card

2001-12-01 NQO1 (NAD (P)H dehydrogenase, quinone 1) by  David Ross 

School of Pharmacy, University of Colorado Health Sciences Center, Denver 80262, USA