Disease relevance of Nqo1

• Quinone reductase promoter-chlor-amphenicol acetyltransferase fusion genes containing different lengths of the 5'-flanking region were transfected into rat and human hepatoma cells [1].
• N,N,N', N'-Tetrakis-(2-pyridylmethyl)ethylenediamine (TPEN) and other cell-permeant metal chelators also effectively blocked DTDP-induced toxicity in neurons [2].
• Expression of mammalian DT-diaphorase in Escherichia coli: purification and characterization of the expressed protein [3].
• Rat liver NAD(P)H:quinone oxidoreductase cDNA was cloned and expressed in a eukaryotic cell expression plasmid containing a cytomegalovirus (CMV) promoter [4].
• Nuclear localization of transfected NQO1 activity increased the cytotoxicity of MC over that produced by overexpression in the cytosol under both aerobic and hypoxic conditions, with greater cytotoxicity being produced under hypoxia [5].

High impact information on Nqo1

• When microsomes were exposed to a concentration of deoxycholate which makes them permeable to macromolecules but does not disrupt the membrane, the detergent alone was sufficient to release four enzymes: nucleoside diphosphatase, esterase, beta-glucuronidase, and a portion of the DT-diaphorase [6].
• Induction of phase 2 detoxication enzymes [e.g., glutathione transferases, epoxide hydrolase, NAD(P)H: quinone reductase, and glucuronosyltransferases] is a powerful strategy for achieving protection against carcinogenesis, mutagenesis, and other forms of toxicity of electrophiles and reactive forms of oxygen [7].
• The incorporation of dicoumarol, a potent inhibitor of DT-diaphorase, interfered with the protection provided by CoQ [8].
• The interaction between DT-diaphorase and CoQ was also demonstrated in an isolated rat liver hepatocyte system [8].
• DT-diaphorase was isolated and purified from rat liver cytosol, and its ability to reduce several CoQ homologs incorporated into large unilamellar vesicles was demonstrated [8].

Chemical compound and disease context of Nqo1

• We have determined the effect of beta-naphthoflavone and the azo dye, sudan III, on the level of quinone reductase mRNA in a responsive rat hepatoma cell line [1].
• Nicotinamide 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 [9].
• It is concluded that, similar to glutathione, the oxidative stress limiting NQO is likely to contribute to the capacity of astroglial cells to protect dopaminergic neurons against L-Dopa, and, hence, may be considered as a potential target for the development of neuroprotective strategies for Parkinson's disease [10].
• NADH consumption was accompanied by dicumarol-sensitive oxygen uptake both with the purified enzyme and with cytosol from human melanoma cells with high levels of DT-diaphorase activity [11].
• The neuroprotective action of norepinephrine can be explained by (1) its ability to form complexes with Fe3+, (2) the uptake of Fe-norepinephrine complex via the norepinephrine transporter and (3) lack of toxicity of the Fe-norepinephrine complex even when DT-diaphorase is inhibited [12].

Biological context of Nqo1

• We have determined the nucleotide sequence of a cDNA clone, pDTD55, complementary to rat liver quinone reductase mRNA (Williams, J.B., Lu, A.Y.H., Cameron, R.G., and Pickett, C.B. (1986) J. Biol. Chem. 261, 5524-5528) [13].
• A comparison of the quinone reductase sequence with other known flavoenzymes did not reveal a significant degree of amino acid sequence homology [13].
• 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 [1].
• These results indicate that 5'-FSBA inactivated DT-diaphorase by occupying its NAD(P)H binding site [14].
• Rat liver DT-diaphorase is inactivated by 5'-[p-(fluorosulfonyl)benzoyl]adenosine (5'-FSBA), following pseudo-first-order kinetics [14].

Anatomical context of Nqo1

• Treatment with EK significantly lowered PCNA index in ACF and reduced PGE2 content in the colonic mucosa, while EK elevated liver GST and QR activities [15].
• The membrane-permeant oxidizing agent 2,2'-dithiodipyridine (DTDP) can induce Zn(2+) release from metalloproteins in cell-free systems [2].
• The remaining 19 amino acid residues at the NH2 terminus were identical with those of the DT-diaphorase purified from rat liver cytosol [3].
• NQO1, GST, and SULT1A1 activities in other brain regions including the cortex, cerebellum, and hippocampus were less sensitive to chronic E(2) treatment [16].
• NQO1 was primarily localized in vascular elements and neurons and SULT1A1 primarily in neurons and neuropil of control and E(2)-treated rats [16].

Associations of Nqo1 with chemical compounds

• The crystal structure of NAD(P)H quinone oxidoreductase 1 in complex with its potent inhibitor dicoumarol [17].
• DENA treatment alone also brought about a sharp decrease in cytosolic UDP-glucose dehydrogenase (EC 1.1.1.22), DT-diaphorase (EC 1.6.99.2), and glutathione S-transferase (EC 2.5.1.18) activities in HNs and NNSP compared to normal liver [18].
• These findings suggest that EK may be effective for inhibiting colonic ACF, through induction of liver GST and QR and possibly alteration of PGE2 production [15].
• DT-diaphorase which was increased 2-3-fold in RH nodules was unaltered in CP nodules [19].
• Rat liver NAD(P)H: quinone reductase nucleotide sequence analysis of a quinone reductase cDNA clone and prediction of the amino acid sequence of the corresponding protein [13].

Regulatory relationships of Nqo1

• The effect of dicoumarol on glucuronidation of 3-OH-benzo(a)pyrene (BP) appears to be due to inhibition of UDPglucuronosyltransferase (UDPGT) and not to an inhibited DT-diaphorase (NAD(P)H:quinone oxidoreductase); to date the only enzyme known to be inhibited by dicoumarol [20].
• Three of four regimens increased epoxide hydrolase activity (150-600% of control) and DT-diaphorase activity (150-200% of control) [21].
• This azoreductase activity was inhibited by cyanide and cytochrome b5 antibody, but was resistant to carbon monoxide and SKF-525A (beta-diethylaminoethyl-diphenylpropylacetate) [22].

Other interactions of Nqo1

• We administered these agrochemicals to the male rat and examined their effects on cytochrome P450 (P450), glutathione S-transferase (GST), UDP-glucuronosyltransferase (UDPGT), and NAD(P)H-quinone oxidoreductase 1 (NQO1)-related metabolism in the liver [23].
• Significant dose-dependent restoration was recorded in renal glutathione content, its dependent enzymes and other phase II metabolizing enzymes viz., catalase, glutathione-S-transferase and quinone reductase (P < 0.001) with prophylactic treatment of FL [24].
• Activation of ERK 1/2 was demonstrated to be independent of NAD(P)H:quinone oxidoreductase using the inhibitor dicoumarol, thus excluding redox cycling as the major mechanism causing these menadione effects [25].
• DL-alpha-Lipoic acid prevented changes in superoxide dismutase and quinone reductase activities induced by diabetes without affecting the enzymes of glutathione metabolism [26].
• Hepatic cytochrome P450 1A1 (EROD) activity, DT-diaphorase activity, AP-1 DNA-binding activity, conjugated dienes, and alpha-tocopherol (vitamin E) as well as alpha-tocopheryl quinone (oxidized vitamin E) were determined [27].

Analytical, diagnostic and therapeutic context of Nqo1

• On Southern blot analysis a total of 14-16 kilobases of rat genomic DNA fragments hybridize to the cDNA probe, indicating one or a small number of menadione reductase genes in this family [28].
• Reverse phase high pressure liquid chromatography of tryptic digests of [14C]5'-FSBA-labeled DT-diaphorase revealed one radioactive peak containing two comigrating peptides [14].
• Western blot analysis revealed that the changes in these activities were caused by increases in the amounts of DT-diaphorase and GST Ya subunit [29].
• After purification by Cibacron Blue affinity chromatography, the expressed enzyme migrated as a single band on 12.5% sodium dodecyl sulfate-polyacrylamide gel with a molecular weight equivalent to that of the purified rat liver cytosolic DT-diaphorase [3].
• Rat liver NAD(P)H:quinone oxidoreductase: cDNA expression and site-directed mutagenesis [4].

References