Disease relevance of NQO2

• Quantitative triplex reverse transcriptase polymerase chain reaction was employed to analyze NQO1 and NQO2 mRNA expression in normal hepatic and biliary tissue as well as in cholangiocellular carcinomas (CCC), hepatocellular carcinomas (HCC), and focal nodular hyperplasias (FNH) [1].
• 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 [2].
• We conducted a study of the potential association between idiopathic Parkinson's disease and polymorphisms of GSTM1, NQO1, and NQO2 [3].
• We propose that induction of NQO2 may relate to the observed increased expression of p53 that, in turn, contributes to the observed suppression of cell growth in both melanoma cell lines [4].
• Human NAD(P)H:quinone acceptor oxidoreductase-2 (NQO2) has been prepared using an Escherichia coli expression method [5].

Psychiatry related information on NQO2

• CONCLUSION: Present data suggest that an insertion/deletion polymorphism in the promoter region of the NQO2 gene plays an important role in the pathogenesis of alcoholism and alcohol withdrawal symptoms [6].
• In this study, we investigated a possible association between polymorphisms of the GSTM1, NQO1, and NQO2 genes and alcohol withdrawal symptoms such as delirium tremens, hallucination, and seizure [6].

High impact information on NQO2

• Now chloroquine-binding proteins in malaria-infected erythrocytes, surprisingly, have been identified as human aldehyde dehydrogenase 1 and quinone reductase 2, raising the interesting possibility that the target of the anti-malarial activity of chloroquine might be a host enzyme [7].
• In the absence of this binding site in QR2, the enzyme retains the essential catalytic machinery, including affinity for FAD, but cannot bind phosphorylated hydride donors [8].
• Recombinant human QR2: (i) reacts with N-ribosyl- and N-alkyldihydronicotinamides, but not with NADH, NADPH, or NMNH; (ii) is very weakly inhibited by dicumarol or Cibacron blue; (iii) is very potently inhibited by benzo[a]pyrene [8].
• 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 [9].
• In particular, 1-carbamoylmethyl-3-carbamoyl-1,4dihydropyridine was shown to be a co-substrate for NQO2 with greater stability than NRH, with the ability to enter cells and potentiate the cytotoxicity of CB 1954 [9].

Chemical compound and disease context of NQO2

• NQO2-null mice also demonstrated decreased toxicity when exposed to menadione or menadione with NRH [10].
• NQO2 was most abundant in CWR22Rv1, a model for prostate cancer transition from androgen-dependent to the hormone-refractory state, but was marginally expressed in JCA-1 cells as representing more advanced stage prostate cancer [11].
• K562 cells with QR2 expression suppressed by RNAi showed similar properties as resveratrol-treated cells in their resistance to quinone toxicity [12].
• Heterologous expression of TmQR2 in Escherichia coli confirmed that the gene encoded a functional, dicumarol-inhibitable QR2 that could use either NADH or NADPH as an electron donor [13].
• Inhibition of melanoma cell proliferation by resveratrol is correlated with upregulation of quinone reductase 2 and p53 [4].
• The high NQO2 activity of intraperitoneal ovarian metastases relative to other tissues indicates a potential for tretazicar therapy in the treatment of this disease [14].

Biological context of NQO2

• To elucidate their role in carcinogenesis, the gene expression of human NQO1 and NQO2 in paired normal and tumor tissue samples was examined [1].
• Malignant hepatocellular tissue (HCC), however, displayed up-regulation of NQO1 and down-regulation of NQO2 [1].
• 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 [2].
• In the present report we describe the nucleotide sequence and deduced amino acid sequence for a cDNA clone that is likely to encode a second form of NAD(P)H:quinone oxidoreductase (NQO2) which was isolated by screening a human liver cDNA library by hybridization with a NQO1 cDNA probe [2].
• Our data suggested that the deletion of 29-bp nucleotides in the promoter region of the NQO2 gene associates with the development of PD [3].

Anatomical context of NQO2

• In addition, MMC caused an increase in DNA cross-links in a cell line transfected to overexpress NQO2 to an extent comparable to that observed with an isogenic NQO1-expressing cell line [15].
• Northern blot analysis indicates that NQO2 gene is expressed in human heart, brain, lung, liver, and skeletal muscle but does not express in placenta [16].
• Here, we demonstrate that the NQO2 gene is differentially expressed by the polymorphic promoters in human fibroblasts and Hep-G2 cells transfected with NQO2 gene reporter constructs [17].
• Our preliminary data, although sample size was not enough, demonstrated that the RNA concentration of NQO2 in white blood cells isolated from peripheral blood was higher in individuals homozygous (II) for the I allele than in those heterozygous (ID) or homozygous (DD) for the D allele [18].
• Disruption of dihydronicotinamide riboside:quinone oxidoreductase 2 (NQO2) leads to myeloid hyperplasia of bone marrow and decreased sensitivity to menadione toxicity [10].

Associations of NQO2 with chemical compounds

• Thus, the simplest quaternary salt of nicotinamide, 1-methyl-3-carboxamidopyridinium iodide, was a co-substrate for NQO2 when reduced to the corresponding 1,4-dihydropyridine derivative [9].
• A negatively charged substituent at the 3-position of the reduced pyridine ring also negated the ability of these compounds to act as cosubstrates for NQO2 [9].
• COS1 cells transfected with NQO2 cDNA showed a 5-7-fold increase in NAD(P)H:quinone oxidoreductase activity as compared to nontransfected cells when either 2,6-dichlorophenolindophenol or menadione was used as substrate [2].
• NRH:Quinone Oxidoreductase 2 (NQO2) has been described as having no enzymatic activity with nicotinamide adenine dinucleotide (NADH) or NADPH as electron donating cosubstrates [15].
• Chromatography of Line IV clone 3 and clone 1 cell extracts on resveratrol affinity columns revealed that the basal expression of dihydronicotinamide riboside quinone reductase 2 (NQO2) was higher in Line IV clone 1 than clone 3 cells [4].

Regulatory relationships of NQO2

• NQO2 gene expression is induced in response to antioxidant tert-butylhydroquinone (tBHQ) [19].

Other interactions of NQO2

• Nucleotide sequence analysis of the 5'-flanking region of the NQO2 gene revealed presence of four SP1 binding sites at positions -214, -170, -106, and -75, a single copy of the antioxidant response element (ARE) at nucleotide -936, and three copies of xenobiotic response element (XRE) at positions -708, -557, and -51 [16].
• We also determined the expression of cytosolic quinone oxidoreductases NQO1, NQO2 (known as MT3 receptor) and nuclear receptor RORalpha by RT-PCR [20].
• Deletion mutagenesis and transfection studies suggested that the ARE region between nucleotides -1433 and -1424 is essential for basal expression and antioxidant induction of NQO2 gene expression [19].
• No associations between Parkinson's disease and polymorphisms of the quinone oxidoreductase (NQO1, NQO2) genes [21].
• A 22-kDa polypeptide, RTP-22, eluted with resveratrol was identified by MALDI-TOF MS and cloning/expression in Escherichia coli, as dihydronicotinamide riboside quinone reductase 2 (NQO2) [11].

Analytical, diagnostic and therapeutic context of NQO2

• NRH and reduced pyridinium derivatives that, like NRH, act as co-substrates for NQO2, produce a dramatic increase in the cytotoxicity of CB 1954 against human cell lines in vitro and its anti-tumor activity against certain human xenografts in vivo [22].
• METHODS: We analysed the promoter and coding regions of the NQO2 gene for 102 patients with schizophrenia and for 234 controls using single-strand conformational change polymorphism and PCR direct-sequencing analyses and the RNA concentration of NQO2 in white blood cells isolated from peripheral blood was measured [18].
• NQO1-null and NQO2-null mice also showed susceptibility to autoimmune disease as revealed by decreased apoptosis in thymocytes and pre-disposition to collagen-induced arthritis [23].
• Sequence analysis revealed six putative antioxidant response elements (ARE1 through 6) in the human NQO2 gene promoter [19].
• Band shift, supershift, and chromatin immunoprecipitation (ChIP) assays demonstrated binding of nuclear factors Nrf2 and JunD with human NQO2 gene ARE [19].

References