Abstract
NAD(P)H:Quinone Oxidoreductase1 (NQO1) also known as DT-diaphorase is a flavoprotein that catalyzes the two-electron reduction of quinones, quinone imines and azo-dyes and thereby protects cells against mutagenicity and carcinogenicity resulting from free radicals and toxic oxygen metabolites generated by the oneelectron reductions catalyzed by cytochromes P450 and other enzymes. High levels of NQO1 gene expression have been observed in liver, lung, colon and breast tumors as compared to normal tissues of the same origin. The transcription of the NQO1 gene is activated in response to exposure to bifunctional (e.g. β-naphthoflavone (β-NF), 2, 3, 7, 8 tetrachorodibenzo-p-dioxin (TCDD)) and monofunctional (phenolic antioxidants/chemoprotectors e.g. 2(3)-tert-butyl-4-hydroxy-anisole (BHA)) inducers. The high level of expression of the NQO1 gene and its induction by β-NF and BHA require the presence of an AP1 binding site contained within the human Antioxidant Response Element (hARE) and are mediated by products of proto-oncogenes, Jun and Fos. Induction of NQO1 gene expression involves transfer of a redox signal from xenobiotics to unknown ‘redox protein(s)’ which in turn, modify the Jun and Fos proteins for greater affinity towards the AP1 site of the NQO1 gene and activates transcription. The expression and regulation of the NQO1 gene is complex as many additional cis-elements have been identified in the promoter region and is a subject of great future interest. In addition to established tumors, NQO1 gene expression is also increased in developing tumors, indicating a role in cellular defense during tumorogenesis. It has been proposed that low molecular weight substance(s) can diffuse from tumor cells into surrounding normal cells and activate the expression of the NQO1 gene. Purification and characterization of such substance(s) may provide important information in regard to the mechanism of activation of NQO1 gene expression and the role of increased NQO1 expression in tumor development. In view of the general consensus that NQO1 is over-expressed in tumor cells and the realization that NQO1 may either activate or detoxify xenobiotics, it is important to establish the role of NQO1 in the activation, and the detoxification of xenobiotics and drugs and in the intrinsic sensitivity of tumors to bioreductive alkylating aziridinyl benzoquinones such as diaziquone (AZQ), mitomycin C (MMC), and indoloquinone EO9, as well as to the dinitrophenyl aziridine, CB1954, and the benzotriazine-di-N-oxide, SR 4233.
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References
Ernster L, Navazio F: Soluble diaphorases in animal tissues. Acta Chem Scand 12: 595, 1958
Ernster L, Ljunggren M, Danielson L: Purification and some properties of a highly dicoumarol-sensitive liver diaphorase. Biochem Biophys Res Commun 2: 88–92, 1960
Ernster L: DT-diaphorase: A historical review. Chem Scripta 27A: 1–13, 1987
Lind C, Hochstein P, Ernster L: DT-diaphorase: Properties, reaction mechanism, metabolic function. A progress report. In: King TE, Mason HS, Morrison M (eds) Oxidases and Related Redox Systems. Pergamon Press, Oxford, 1982, pp 321–347
Talalay P: Mechanisms of induction of enzymes that protect against chemical carcinogenesis. Adv Enzyme Regul 28: 149–159, 1989
Riley RJ, Workman P: DT-diaphorase and cancer chemotherapy. Biochem Pharm 43: 1657–1669, 1992
Prochaska HJ, Talalay P, Sies H: Direct protective effect of NAD(P)H:Quinone Reductase against Menadione-induced chemiluminescence of postmitochondrial fractions of mouse liver. J Biol Chem 262: 1931–1934, 1987
Chesis PL, Levin DE, Smith MT, Ernster L, Ames BN: Mutagenicity of quinones: pathways of metabolic activation and detoxification. Proc Natl Acad Sci 81: 1696–1700, 1984
Lind C: Formation of Benzo(a)pyrene-3,6-quinol monoand diglucuronides in rat liver microsomes. Arch Biochem Biophys 280: 226–235, 1985
Smart RC, Zannoni VG: DT-diaphorase and peroxidase influence the covalent binding of the metabolites of phenol, the major metabolite of benzene. Mol Pharmacol 26: 105–111, 1984
Thor H, Smith MT, Hartzell P, Bellomo G, Jewell S, Orrenius S: The metabolism of menadione (2-methyl-1,4-naphthoquinone) by isolated hepatocytes. J Biol Chem 257: 12419–12425, 1982
De Flora A: Prominent role of DT-diaphorase as a cellular mechanism reducing chromium (VI) and reverting its mutagenicity. Cancer Res 45: 3188–3196, 1985
Talcott RE, Rosenblum M, Levin VA: Possible role of DT-diaphorase in the bioactivation of antitumor quinones. Biochem Biophys Res Commun 111: 346–351, 1983
De Flora S, Bernnicelli C, Camoirano A, Serra D, Hochstein P: Influence of DT-diaphorase on the mutagenicity of organic and inorganic compounds. Carcinogenesis 9: 611–617, 1988
Ernster L: DT-diaphorase. Methods in Enzymology 10: 309–317, 1967
Martin LF, Patrick SD, Wallin R: DT-diaphorase in morbidly obese patients. Cancer Letters 36: 341–347, 1987
Conover TE, Ernster L: DT-diaphorase. IV. Coupling of extramitochondrial reduced pyridine nucleotide oxidation to mitochondrial respiratory chain. Biochim Biophys Acta 67: 268–280, 1963
Danielson L, Ernster L, Ljunggren M: Selective extraction of DT-diaphorase from mitochondria and microsomes. Acta Chem Scand 14: 1837–1838, 1960
Edlund C, Elhrmammer A, Dallner G: Distribution of newly synthesized DT-diaphorase in rat liver. Biosci Rep 2: 861–865, 1982
Amzel LM, Bryant SH, Prochask HJ, Talalay P: Preliminary crystallographic X-ray data for NAD(P)H:quinone reductase from mouse liver. J Biol Chem 261: 1379, 1986
Shaw PM, Reiss A, Adesnik M, Nebert DW, Schembri J, Jaiswal AK: The human dioxin-inducible NAD(P)H:quinone oxidoreductase cDNA-encoded protein expressed in COS-1 cells is identical to diaphorase 4. Eur J Biochem 195: 171–176, 1991
Hojeberg B, Blomberg K, Sternberg S, Lind C: Biospecific adsorption of hepatic DT-diaphorase on immobilized dicoumarol. Arch Biochem Biophys 207: 205–216, 1981
Raftell M, Blomberg K: Immunochemical studies on two DT-diaphorase active antigens isolated from rat liver cytosol by affinity chromatography. Arch Biochem Biophys 199: 165–171, 1980
Segura-Aquilar J, Kaiser R, Lind C: Separation and characterization of isoforms of DT-diaphorase from rat liver cytosol. Biochem Biophys Acta 1120: 33–42, 1992
Prochaska HJ, Talalay P: Purification and characterization of two isofunctional forms of NAD(P)H:quinone reductase from mouse liver. J Biol Chem 261: 1372–1378, 1986
Edwards YH, Potter J, Hopkinson DA: Human FAD-dependent NAD(P)H diaphorase. Biochem J 187: 429–436, 1980
Williams JB, Lu AYH, Cameron RG, Pickett CB: Rat liver NAD(P)H:Quinone reductase. J Biol Chem 261: 5524–5528, 1986
Robertson JA, Chen HC, Nebert DW: NAD(P)H:menadione oxidoreductase: novel purification of enzyme. cDNA and complete aminoacid sequence and gene regulation. J Biol Chem 261: 15794–15799, 1986
Smith D, Martin LF, Wallin R: Human DT-diaphorase, a potential cancer protecting enzyme. Its purification from abdominal adipose tissue. Cancer Letters 42: 103–112, 1988
Jaiswal AK, McBride OW, Adensik M, Nebert DW: Human dioxin-inducible cytosolic NAD(P)H:Quinone Oxidoreductase. J Biol Chem 263: 13572–13578, 1988
Jaiswal AK, Burnett P, Adesnik M, McBride OW: 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, 1990
Segura-Aguilar JE, Lind C: Isolation and characterization of DT-diaphorase enzymes from rat liver. Chem Scripta 27A: 37–41, 1987
Ma Q, Cui K, Xiao F, Lu AYH, Yang CS: Identification of glycine-rich sequence as an NAD(P)H-binding site and tyrosine 128 as a dicoumarol-binding site in Rat Liver NAD (P)H:Quinone Oxidoreductase by site-directed Mutagenesis. J Biol Chem 267: 22298–22304, 1992
Jaiswal AK: Human NAD(P)H:Quinone Oxidoreductase gene structure and induction by dioxin. Biochemistry 30: 10647–10653, 1991
Bayney RM, Morton MR, Favreau LV, Pickett CB: Rat liver NAD(P)H:Quinone Reductase: regulation of quinone reductase gene expression by planar aromatic compounds and determination of the exon structure of the quinone reductase structural gene. J Biol Chem 264: 21793–21797, 1989
Schor NA: The use of DT-diaphorase for the detection of foci of early neoplastic transformation in rat liver. Cancer Lett 5: 167–171, 1978
Schor NA: The activity of the DT-diaphorase in experimental hepatomas Cancer. Biochem Biophys Acta 2: 5–9, 1977
Becker FF, Stout DL: A constitutive deficiency in the monooxygenase system of spontaneous mouse liver tumors. Carcinogenesis 5: 785–788, 1984
Beyer RE, Segura-Aguilar J, Lind C, Castro VM: DT-diaphorase activity in various cells in culture with emphasis on induction in ascites hepatoma cells. Chemica Scripta 27A: 145–150, 1987
Schor NA, Cornelisse CJ: Biochemical and quantitative histochemical study of reduced pyridine nucleotide dehydrogenation by human colon carcinomas. Cancer Res 43: 4850–4855, 1983
Schor NA, Rice BF, Huseby RA: Dehydrogenation of reduced pyridine nucleotides by Leydig cell tumors of the rat testis. Proc Soc Exp Biol Med 151: 418–421, 1976
Koudstaal J, Makkin B, Overdiep SH: Enzyme histochemical pattern in human tumors-II. Oxidoreductases in carcinoma of the colon and the breast. Eur J Cancer 11: 111–115, 1975
Batist K, Cowan KH, Curt G, Katki AG, Mayer CE: Increased glutathioneS-transferase activity (GST) in drug treated human breast cancer cells. Proc Am Assoc Cancer Res 26: 345A, 1985
Schlager JJ, Powis G: Cytosolic NAD(P)H:(Quinone-Acceptor) Oxidoreductase in human normal and tumor tissue: Effects of cigarette smoking and alcohol. Int J Cancer 45: 403–409, 1990
Cresteil T, Jaiswal AK: High levels of expression of the NAD(P)H:Quinone Oxidoreductase (NQO1) gene in tumor cells compared to normal cells of the same origin. Biochem Pharm 42: 1021–1027, 1991
Beyer BE, Segura-Aguilar JE, Ernster L: The anticancer enzyme DT-diaphorase is induced selectively in liver during Ascites Hepatoma Growth. Anticancer Research 8: 233–238, 1988
Richardson HL, Cunningham L: The inhibitory action of methylcholanthrene on rats fed the azo dye 3′-methyl-4-dimethylaminobenzene. Cancer Res 11: 274–278, 1951
Kumaki K, Jensen NM, Shira JGM, Nebert DW: Genetic differences in induction of cytosol reduced-NAD(P):Menadione Oxidoreductase and microsomal aryl hydrocarbon hydroxylase in the mouse. J Biol Chem 252: 157–165, 1977
Beatty P, Neal RA: Induction of DT-diaphorase by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCCD). Biochem Biophys Res Commun 68: 197–204, 1976
Prochaska HJ, De Long MJ, Talalay P: On the mechanism of induction of cancer-protective enzymes: a unifying proposal. Proc Natl Acad Sci 82: 8232–8236, 1985
Whitlock JP: The regulation of gene expression by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Pharmacol Rev 39: 147–161, 1987
Nebert DW, Gonzalez FJ: P450 genes: structure, evolution and regulation. Ann Rev Biochem 56: 945–953, 1987
Gonzalez FJ: The molecular biology of cytochrome P450s. Pharmacol Rev 40: 243–288, 1988
Neuhold LA, Shirayoshi Y, Ozato K, Jones JE, Nebert DW: Regulation of mouse CYP1A1 gene expression by dioxin: requirement for two cis-acting elements during induction. Mol Cell Biol 9: 2378–2386, 1989
Whitlock JP Jr: Genetic and molecular aspects of 2,3,7,8-tetrachlorodibenzo-p-dioxin action. Ann Rev Pharm 30: 251–277, 1990
Henry ECG, Rucci G, Gasiewicz TA: Characterization of multiple forms of the Ah receptor: comparison of species and tissues. Biochemistry 28: 6430–6440, 1989
Perdew GH, Poland A: Purification of the Ah receptor from C57BL/6J mouse liver. J Biol Chem 263: 9848–9852, 1988
Watson AJ, Hankinson O: DNA transfection of a gene repressing aryl hydrocarbon hydroxylase induction. Carcinogenesis 9: 1581–1586, 1988
De Long MJ, Santamaria AB, Talalay P: Role of cytochrome P1-450 in the induction of NAD(P)H:quinone reductase in a murine hepatoma cell line and its mutants. Carcinogenesis 8: 1549–1553, 1987
Talalay P, De Long MJ, Prochaska HJ: Identification of a common chemical signal regulating the induction of enzymes that protect against chemical carcinogenesis. Proc Natl Acad Sci 85: 8261–8265, 1988
Li Y, Jaiswal AK: Regulation of human NAD(P)H:quinone oxidoreductase gene: role of AP1 binding site contained within human antioxidant response element. J Biol Chem 267: 15097–15104, 1992
Li Y, Jaiswal AK: Identification of Jun-B as third member in human antioxidant response element-nuclear protein complex. Biochem Biophys Res Commun 188: 992–996, 1992
Favreau LV, Pickett CB: Transcriptional regulation of the rat NAD(P)H:quinone reductase gene. Identification of regulatory elements controlling basal level expression and inducible expression by planar aromatic compounds and phenolic antioxidants. J Biol Chem 266: 4556–4561, 1991
Rushmore TH, Pickett CB: Transcriptional regulation of the rat glutathioneS-transferase Ya subunit gene: characterization of a xenobiotic-responsive element controlling inducible expression by phenolic antioxidants. J Biol Chem 265: 14648–14653, 1990
Rushmore TH, King RG, Paulson KE, Pickett CB: Regulation of glutathioneS-transferase Ya subunit gene expression: identification of a unique xenobiotic-responsive element controlling inducible expression by planar aromatic compounds. Proc Natl Acad Sci USA 87: 3826–3830, 1990
Rushmore TH, Morton MR, Pickett CB: The antioxidant responsive element. Activation by oxidative stress and identification of the DNA consensus sequence required for functional activity. J Biol Chem 266: 11632–11639, 1991
Friling RS, Bensimon A, Tichauer Y, Daniel V: Xenobioticinducible expression of murine glutathione S-transferase Ya subunit gene is controlled by an electrophile-responsive element. Proc Natl Acad Sci USA 87: 6258–6262, 1990
Friling RS, Bergelson S, Daniel V: Two adjacent AP-1-like binding sites form the electrophile-responsive element of the murine glutathione S-transferase Ya subunit gene. Proc Natl Acad Sci 89: 668–672, 1992
Herschman HR: Primary response genes induced by growth factors and tumor promoters. Ann Rev Biochem 60: 281–319, 1991
Hai T, Curran T: Cross-family dimerization of transcription factors Fos/Jun and ATF/CREB alters DNA binding specificity. Proc Natl Acad Sci USA 88: 3720–3724, 1991
Xanthoudakis S, Miao G, Wang F, Pan YE, Curran T: Redox activation of Fos-Jun DNA binding activity is mediated by a DNA repair enzyme. EMBO 11: 3323–3335, 1992
Demple B, Amabile-Cuevas CF: Redox redux: The control of oxidative stress responses. Cell 67: 837–839, 1991
Traver RD, Horikoshi T, Danenberg KD, Stadlbaur THW, Danenberg PV, Ross D, Gibson NW: 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
Ehlen T, Dubeau L: Loss of heterozygosity on chromosomal segments 3p, 6q and 11p in human ovarian carcinomas. Oncogene 5: 219–223, 1990
Vogelstein B, Fearon ER, Kern SE, Hamilton SR, Preisinger AC, Nakamura Y, White R: Allelotypes of colorectal carcinomas. Science 244: 207–211, 1989
Sato T, Tanigami A, Yamakawa K, Akiyama F, Kasumi F, Sakamoto G, Nakamura Y: Allelotype of breast cancer: Cumulative allele losses promote tumor progression in primary breast cancer. Cancer Res 50: 7184–7189, 1990
Prochaska HJ, Santamaria AB, Talalay P: Rapid detection of inducers of enzymes that protect against carcinogens. Proc Natl Acad Sci USA 89: 2394–2398, 1992
Zhang Y, Talalay P, Cho C, Posner GH: A major inducer of anticarcinogenic protective enzymes from broccoli: Isolation and elucidation. Proc Natl Acad Sci USA 89: 2399–2403, 1992
Smith MT, Eastmond DA, DiMonte D: The activation and detoxification of quinones by DT-diaphorase. Chem Scripta 27A: 105–107, 1987
Ross D, Siegel D, Gibson NW, Pacheco D, Thomas DJ, Reasor M, Weirda D: Activation and deactivation of quinones catalyzed by DT-diaphorase. Evidence for bioreductive activation of diaziquone (AZQ) in human tumor cells and detoxification of benzene metabolites in bone marrow stroma. Free Radic Res Commun 8: 373–381, 1990
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Belinsky, M., Jaiswal, A.K. NAD(P)H:Quinone oxidoreductase1 (DT-diaphorase) expression in normal and tumor tissues. Cancer Metast Rev 12, 103–117 (1993). https://doi.org/10.1007/BF00689804
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DOI: https://doi.org/10.1007/BF00689804