Disease relevance of NQO1

• Conversely, the distribution of NQO1 genotypes among patients with treatment-related leukemias with MLL translocations was not statistically different than in the comparison groups [1].
• A small British study suggested that NQO1 C609T was associated with an increased risk of infant leukemias with MLL translocations, especially infant acute lymphoblastic leukemia (ALL) with t(4;11) [1].
• Benzene poisoning, a risk factor for hematological malignancy, is associated with the NQO1 609C-->T mutation and rapid fractional excretion of chlorzoxazone [2].
• These results together suggest that NO signals the transcriptional up-regulation of NQO1 and other detoxifying enzyme and protective genes through Nrf2 via the ARE to counteract NO-induced apoptosis of neuroblastoma cells [3].
• The use of beta-lapachone mono(arylimino) prodrug derivatives, or more specifically a derivative converted in a tumor-specific manner (i.e., in the acidic local environment of the tumor tissue), should reduce normal tissue toxicity while eliciting tumor-selective cell killing by NQO1 bioactivation [4].

Psychiatry related information on NQO1

• Moreover, GSTM1 gene deletion and missense mutation (Pro187Ser) of the NQO1 gene showed no significant association with alcohol withdrawal symptoms [5].
• To test the hypothesis, we have performed an association study between the NQO1 gene polymorphism C609T and late-onset Alzheimer's disease (LOAD) in Chinese population [6].

High impact information on NQO1

• Our findings provide the first evidence for in vivo degradation of p53 and p73 by the 20S proteasomes and its regulation by NQO1 and NADH level [7].
• Results: In general, DT-diaphorase activity levels were higher than those observed for the other two reductases across the entire cell line panel [8].
• The extent of induction of gene expression in colon mucosa reached a peak of 5.75-fold for gamma-GCS, and a peak of 4.14-fold for DT-diaphorase at 250 mg/m2 ; higher doses were not more effective [9].
• Peripheral mononuclear cell and colon mRNA content for gamma-glutamylcysteine synthetase (gamma-GCS) and DT-diaphorase increased after dosing to reach a peak on day 2-4 after treatment, and declined to baseline in the subsequent 7-10 d [9].
• Levels of gamma-GCS and DT-diaphorase correlated closely (P < or = 0.001) between peripheral mononuclear cells and colon mucosa both at baseline and at peak [9].

Chemical compound and disease context of NQO1

• Northern blot analysis shows the presence of one NQO2 mRNA of 1.2 kb in control and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) treated human hepatoblastoma Hep-G2 cells and that TCDD treatment does not lead to enhanced levels of NQO2 mRNA as it does for NQO1 mRNA [10].
• METHODS: NQO1 transcription and DNA hypermethylation in hepatoma cells with or without 5-aza-deoxycytidine (5-Aza-CdR) treatment were investigated by reverse-transcription PCR (RT-PCR), sodium bisulfite sequencing and methylation-specific PCR (MSP) [11].
• NQO1 results suggest that different quinones (possibly estrogenic quinone metabolites) might affect the histological development of breast tumors [12].
• We conclude that up-regulation of QR, either by overexpression or induction by tamoxifen, can protect breast cells against oxidative DNA damage caused by estrogen metabolites, representing a possible novel mechanism of tamoxifen prevention against breast cancer [13].
• Multiple detoxification systems, including NQO1 and glutathione protect against benzene metabolite-induced toxicity [14].

Biological context of NQO1

• The distributions of the XRCC3 Thr241Met and NQO1 Pro187Ser genotypes were not significantly different in patients and controls [15].
• In this report, we have investigated the role of Nrf3 in ARE-mediated gene expression and induction of NQO1 in response to antioxidants [16].
• The antioxidant response element (ARE) and Nrf2 are known to regulate the expression and coordinated induction of genes encoding detoxifying enzymes including NAD(P)H:quinone oxidoreductase1 (NQO1) in response to antioxidants [17].
• These DN-Nrf2 cells exhibited reduced NQO1 enzymatic activity and were sensitized to NO-induced apoptosis [3].
• To further elucidate the role of the association of Hsp70 with the NQO1*1 protein, site-directed mutagenesis was used to modify a proposed Hsp70 binding site near the N terminus of the NQO1 protein [18].

Anatomical context of NQO1

• By comparing 3-NBA-DNA adduct formation in the presence of cofactors of NAD(P)H:quinone oxidoreductase (NQO1) and xanthine oxidase, most of the reductive activation of 3-NBA in human hepatic cytosols was attributed to NQO1 [19].
• Using human tumor cell lines devoid of NQO1 enzymatic activity, we have previously identified a single nucleotide polymorphism (NQO1*2 allele) in the human NQO1 gene [18].
• Exposure of human aortic endothelial cells (HAECs) to L-flow, but not to O-flow, induced the expression of cytoprotective genes, such as NAD(P)H quinone oxidoreductase 1 (NQO1) by 5-fold and heme oxygenase-1 by 8-fold [20].
• The association between p53 and NQO1 was not affected by treatment of HCT-116 cells with ES936, demonstrating that the association was not dependent on the catalytic activity of NQO1 [21].
• An association of p53 and NQO1 was also observed in primary human keratinocytes and mammary epithelial cells [21].

Associations of NQO1 with chemical compounds

• Inhibition of adduct formation by dicoumarol, an NQO1 inhibitor, supported this finding and was confirmed with human recombinant NQO1 [19].
• By contrast, nontoxic doses of SUL, BITC, or PEITC failed to induce expression of CYP1A1 in LS-174 cells, but caused an increase of between 11- and 17-fold in the protein levels of AKR1C1, NQO1, and GCS(h) [22].
• CYP2E1 and NQO1 genotypes were determined by PCR-RFLP, and CYP2E1 enzymatic activity was estimated by the fractional excretion of chlorzoxazone (fe(6-OH)) for 50 cases of BP and 50 controls [2].
• This suggests that a redox mechanism involving NQO1-mediated NAD(P)H oxidation is not responsible for the stabilization of p53 [21].
• Overexpression of Nrf3 in Hep-G2 cells led to a concentration-dependent decrease in transfected and endogenous NQO1 gene expression and induction in response to antioxidant tert-butylhydroquinone (t-BHQ) [16].
• NSCLC cells were killed in an NQO1-dependent manner by beta-lapachone (LD50, approximately 4 microM) with a minimum 2-h exposure [23].

Physical interactions of NQO1

• Deletion mutation analysis revealed that Nrf3 repression of NQO1 gene expression required heterodimerization and DNA binding domains but not transcriptional activation domain of Nrf3 [16].
• The x-ray crystal structure of rat QR1 shows that the 43 amino acid C-terminal tail of QR1 provides the binding site for the hydrophilic portions of NADH and NADPH [24].
• Band and supershift assays with the NQO1 gene ARE and nuclear proteins demonstrate that small MafG and MafK bind to the ARE as Maf-Maf homodimers and Maf-Nrf2 heterodimers [25].
• Folding models suggest that the highly conserved histidine 217 of the cytochrome b subunit from the cytochrome bc1 complex is close to the quinone reductase (Qi) site [26].

Enzymatic interactions of NQO1

• Quinone reductase catalyzed the conversion in the presence of NADH or NADPH of DES Q to 53-65% Z-DES, a marker product of reduction [27].
• NAD(P)H:quinone oxidoreductase (NQO1) is a flavoprotein which catalyzes the two-electron reduction of quinones and azo-dyes and thus prevents the formation of free radicals and toxic oxygen metabolites that may be generated by the one-electron reductions catalyzed by cytochrome P450 reductase [28].

Co-localisations of NQO1

• We conclude that NQO1 activity co-localizes closely with AD pathology supporting a presumed role as an antioxidant system upregulated in response to the oxidative stress of the AD process [29].

Regulatory relationships of NQO1

• In these experiments a full-length p53 coding region was used to express p53 in the presence of recombinant NQO1 protein [21].
• RESULTS: NQO1 transcription was down-regulated and the CpG island DNA was hypermethylated in Hep3B and HuH6 cells [11].
• Dibenzoylmethane treatment at the same concentrations did not induce GSTP1-1 expression and significantly stimulated QR expression only at the 2.0 microM concentration [30].
• Apoptotic responses in beta-lap-exposed NQO1-expressing cells were significantly delayed and survival enhanced by exogenous over-expression of calpastatin, a natural inhibitor of mu- and m-calpains [31].
• Transfection with siRNA specific for NQO1 suppressed NQO1 expression and significantly abrogated MUC5AC mRNA expression [32].

Other interactions of NQO1

• Allelic variation in genes encoding enzymes such as NADP(H) quinone oxidoreductase (NQO1) and glutathione S-transferase T1 (GSTT1) that metabolize environmental toxicants predispose to subtypes of AML, including therapy-related AML [33].
• NQO2 activity appears to be related to expression of NQO1 (DT-diaphorase), an enzyme that is known to have a favorable distribution toward certain human cancers [34].
• The CYP2D6 (-) "poor metabolizer " and the NQO1 (-) "defective" genotypes were not clearly associated with a higher risk of RCC [35].
• The p value for difference in relative risk for NQO1 by GSTM1 genotype = 0.013 [36].
• There were no clear differences in adduct levels in relation to genotypes of NQO1 or GSTP1 [37].

Analytical, diagnostic and therapeutic context of NQO1

• Whereas both L-flow and O-flow induced the nuclear accumulation of Nrf2 to comparable levels, chromatin immunoprecipitation analysis revealed that Nrf2 binding to the NQO1 ARE was significantly diminished in the case of O-flow compared with that of L-flow [20].
• Results from these experiments demonstrated co-immunoprecipitation of NQO1 with p53 and vice versa [21].
• Hsp70, however, was found to associate with NQO1*1 protein in cells when co-IPs were performed with an anti-NQO1 antibody followed by immunoblotting with an anti-Hsp70 antibody or vice versa [18].
• We conducted a hospital based case-control study to evaluate the potential association between genetic polymorphisms of CYP2E1 (C1019T in the 5' flanking region) and NQO1 (C609T in exon 6) and bladder cancer risk in Asian population [38].
• After treatment with 5-Aza-CdR, NQO1 transcription was restored and CpG island DNA was demethylated in these cells [11].

References