Disease relevance of Nqo1

• We have shown previously that exposure of mouse hepatoma Hepa-1 cells to chromate inhibits the induction of the Cyp1a1 and Nqo1 genes by dioxin [1].
• CDDO-Im induces Nqo1 RNA transcripts in some organs at doses as low as 0.3 mumol/kg body weight (orally) [2].
• Role of NAD(P)H:quinone oxidoreductase 1 (DT diaphorase) in protection against quinone toxicity [3].
• NMO1 mRNA content in acetone-treated papillomas approached the levels detected in TCDD-treated normal skin [4].
• Disruption of the NAD(P)H:quinone oxidoreductase 1 (NQO1) gene in mice causes myelogenous hyperplasia [5].

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

• On the other hand, all three metals, alone or in the presence of TCDD, enhanced Nqo1 and Gst ya mRNA levels and Nqo1 activity [15].
• The RNA synthesis inhibitor actinomycin D significantly inhibited the Nqo1 and Gst ya mRNA induction in response to metals, indicating a requirement of de novo RNA synthesis [23].
• The various results from CHO cells and NQO1-/- mice indicated that NQO1 protects against quinone-induced cytotoxicity, as well as DNA and membrane damage [3].
• Transcriptional regulation of the NAD(P)H:quinone oxidoreductase 1 and glutathione S-transferase ya genes by mercury, lead, and copper [23].
• A modulatory effect of two doses and BHA was also observed for the activities of glutathione S-transferase, DT-diaphorase, superoxide dismutase and catalase in the kidney, lung and forestomach, as compared with the control group [24].
• These data show a major in vivo role of NQO1 in metabolic activation of mitomycin C with implications in mitomycin C chemotherapy [25].

Regulatory relationships of Nqo1

• Our data clearly show that As(3+)-, Cd(2+)-, and Cr(6+)-induced oxidative stress modulates Cyp1a1 at transcriptional and posttranscriptional levels but induces Nqo1 and Gst ya at the transcriptional level [15].
• BHA-treated Swiss albino mice induced DTD, GST and all antioxidative parameters in the kidney, lung and forestomach [24].
• Catalase activity in the cytosol was induced 5.2-fold and DT-diaphorase activity was increased 3.5- and 3.2-fold in the cytosol and mitochondria, respectively [26].
• Studies in rodents indicate that certain enzymes of this battery, namely cytochrome P4501A1 (CYP1A1), UDP-glucuronosyltransferase (UGT1*06) and NAD(P)H: quinone acceptor oxidoreductase (NMO1) are induced by the synthetic antioxidant 5,10-dihydroindeno[1,2-b]indole (DHII) [27].
• 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 [28].

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

• Analyses of CYP1A1, CYP1B1, cytosolic aldehyde dehydrogenase class 3, and NAD(P)H:menadione oxidoreductase (NMO1) mRNA content by RT-PCR revealed significant increases in all four mRNAs in the normal tissue adjacent to papillomas after exposure to 4 nmol of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) but no increases in the tumors [4].
• Xenografts established from the clonal lines exhibited significant tumor control following MMC treatment (treated/control [T/C] 17% and 51% for DTD and P450R xenografts, respectively) that was not seen in wild-type tumors (T/C 102%) [22].
• Immunoblotting confirmed that in the small intestine, the constitutive level of NQO1 is lower in the Nrf2-/- mouse, and it also showed that induction of the oxidoreductase was substantially diminished in the mutant mouse [31].
• Immunohistochemistry revealed that induction of NQO1, class-alpha GST, and GCS(h) occurs primarily in epithelial cells of the small intestine [31].
• This structural information is very important for designing suitable drugs and approaches for human cancer chemotherapy mediated by DT-diaphorase [32].

References