Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.6.5.2 (NQO1)
 6,196 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The stimulation of reduced-NAD(P):menadione oxidoreductase (EC 1.6.99.2) activity in liver cytosol is highly correlated with the stimulation of hepatic microsomal aryl hydrocarbon (benzo[a]pyrene) hydroxylase (EC 1.14.14.2) activity in 3-methylcholanthrene-, beta-naphthoflavone-, phenobarbital-, or pregnenolone-16alpha-carbonitrile-treated inbred C57BL/6N and DBA/2N mice and in eight other inbred strains treated with 3-methylcholanthrene. No oxidoreductase activity is detectable in mouse liver microsomes. Cytochrome c and 2,6-dichlorophenolindophenol are equally good electron acceptors for the oxidoreductase. There is no preferential in vitro inhibition of induced versus control oxidoreductase activities by either alpha-naphthoflavone or metyrapone. In 3-methylcholanthrene-treated F1 and F2 progeny and offspring from backcrosses between the F1 and either C57BL/6N or DBA/2N parent, however, there is not a strict correlation between induced or noninducible aryl hydrocarbon hydroxylase and oxidoreductase activities. 2,3,7,8-Tetrachlorodibenzo-p-dioxin, at doses (80 mug kg-1) sufficiently high to induce the hydroxylase almost as well in DBA/2N as in C57BL/6N mice, induces the oxidoreductase about 3-fold in C57BL/6N and less than 50% in DBA/2N mice. All the data are consistent with an hypothesis that two loci (Ox-1 and Ox-2) regulate oxidoreductase induction by 3-methylcholanthrene, that one of the genes is linked to the Ah locus (with an estimated recombination frequency between 2% and 23%), and that the other gene is not linked to the Ah locus. These experimental data might be useful in the protein activator hypothesis of the Britten-Davidson model for gene regulation.
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PMID:Genetic differences in induction of cytosol reduced-NAD(P):menadione oxidoreductase and microsomal aryl hydrocarbon hydroxylase in the mouse. 83 15

Stromal cells from bone marrow are susceptible to toxicity induced by several redox-active metabolites of benzene, including hydroquinone (HQ). We have previously shown that tert-butyl-hydroquinone (tBHQ) can induce quinone reductase (QR) in bone marrow stroma as well as protect stromal cells against HQ-induced toxicity. Current studies investigate the underlining mechanisms of chemoprotection against HQ in DBA/2- and C57Bl/6-derived bone marrow stromal cells. The chemoprotector 1,2-dithiole-3-thione (DTT) has been used in these studies due to tBHQ toxicity to stromal cells at higher concentrations. Pretreatment of cells with DTT prior to HQ administration protected cells against HQ-induced toxicity. DTT induced QR activity in a dose-dependent manner in stromal cells from both strains of mice. However, there were no corresponding changes in glutathione transferase activity. DTT also increased cytosolic glutathione (GSH) concentrations by approximately 85% in both strains. Since bone marrow stroma consists primarily of fibroblasts and macrophages, we also evaluated QR activity in the separate cell types from the two strains of mice. There were differences in basal and DTT-induced QR activity between fibroblasts and macrophage cells derived from the same strain of mice, as well as the expected differences between strains. Additionally, dicoumarol, an inhibitor of QR activity, potentiated HQ-induced toxicity in both strains of bone marrow stromal cells. Thus, cellular glutathione, QR activity, and their inducibility by chemoprotective agents such as DTT may prove to be important factors in chemically induced bone marrow toxicity and carcinogenicity.
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PMID:Induction of quinone reductase and glutathione in bone marrow cells by 1,2-dithiole-3-thione: effect on hydroquinone-induced cytotoxicity. 137 15

DBA/2 mice have been reported to be more susceptible than C57BL/6 mice to the bone marrow toxic effects of two quinone-generating chemicals, benzo[a]pyrene and benzene. In this study we have investigated the activity of quinone reductase (QR) (NADPH:DT diaphorase), a quinone detoxifying enzyme, in whole bone marrow and bone marrow-derived stromal cells from these two strains of mice. The sensitivity of bone marrow-derived stromal cells to toxicity induced by several metabolites of benzene was also investigated. Whole bone marrow and primary cultures of stromal cells cultured from DBA/2 mice had a lower basal level of QR activity compared to those of C57Bl/6 mice and as such exhibited a greater sensitivity to the toxic effects of hydroquinone (HQ), a metabolite of benzene. However, there was no difference between the two strains of mice to benzoquinone- or phenol-induced toxicity. Increased QR activity in DBA/2 and C57Bl/6 stromal cells could be induced by prior stromal cell treatment with tert-butylhydroquinone which resulted in protection against subsequent hydroquinone treatment. Thus, differences in target organ QR activity may contribute to differential susceptibility to quinone-generating bone marrow toxins.
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PMID:Differences in quinone reductase activity in primary bone marrow stromal cells derived from C57BL/6 and DBA/2 mice. 234 85

Anticarcinogenic enzyme inducers are of two types: (a) bifunctional inducers [2,3,7,8-tetrachlorodibenzo-p-dioxin, polycyclic aromatics, azo dyes, beta-naphthoflavone] that elevate both Phase II enzymes [e.g., glutathione S-transferases, UDP-glucuronosyltransferases, and NAD(P)H:(quinone-acceptor) oxidoreductase] and certain Phase I enzymes [e.g., aryl hydrocarbon hydroxylase (AHH)]; and (b) monofunctional inducers [e.g., diphenols, thiocarbamates, 1,2-dithiol-3-thiones, isothiocyanates] that elevate primarily Phase II enzymes without significantly affecting AHH. Since Phase I enzymes such as AHH may activate precarcinogens to ultimate carcinogens whereas Phase II enzyme induction suffices to achieve chemoprotection, an understanding of the molecular mechanisms that regulate these enzymes is critical for devising methods for chemoprotection. We report a systematic analysis of the inductions of aryl hydrocarbon hydroxylase (AHH) and NAD(P)H:quinone reductase (QR) by seven monofunctional and eight bifunctional inducers, singly or in combination, in a murine hepatoma cell line (Hepa 1c1c7) and two mutants defective in either Ah (Aryl hydrocarbon) receptor function (BPrc1) or in AHH expression (c1). We have also examined such inductions in genetically defined mouse strains with high affinity (C57BL/6J) and low affinity (DBA/2J) Ah receptors. The combination of our earlier model for the induction of Phase I and Phase II enzymes (H. J. Prochaska, M. J. De Long, and P. Talalay, Proc. Natl. Acad. Sci. USA, 82: 8232, 1985) with mechanism(s) for autoregulation of AHH (O. Hankinson, R. D. Anderson, B. W. Birren, F. Sander, M. Negishi, and D. W. Nebert, J. Biol. Chem., 260: 1790, 1985) is compatible with our results. Thus, induction of QR by monofunctional inducers does not depend on a competent Ah receptor or AHH activity and appears to involve an electrophilic chemical signal. In contrast, bifunctional inducers require competent Ah receptors to induce both AHH and QR, although the latter process appears to be regulated by more than one mechanism. It is our view that bifunctional inducers bind to the Ah receptor thereby enhancing transcription of genes encoding both AHH and QR. Metabolizable bifunctional inducers are then converted by the induced AHH to products that resemble monofunctional inducers and are capable of generating the aforementioned chemical signal. The existence of mechanism(s) for AHH autoregulation that also affect Phase II enzyme expression would account for the high basal activities of QR in the AHH-defective mutant (c1).
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PMID:Regulatory mechanisms of monofunctional and bifunctional anticarcinogenic enzyme inducers in murine liver. 340 19

NAD(P)H:menadione oxidoreductase induction by polycyclic hydrocarbons is known to be governed by the aromatic hydrocarbon-responsive (Ah) locus. This cytosolic enzyme was isolated from 3-methylcholanthrene-treated rat liver by a rapid two-step procedure with the use of affinity gel purification and fast-protein liquid chromatography. Polyclonal antiserum to menadione reductase was raised in rabbits. On Western (immuno) blot analysis, large increases in this hepatic menadione reductase protein (NMOR1) of 3-methylcholanthrene-treated C57BL/6N but not DBA/2N mice confirmed that induction of this enzyme by 3-methyl-cholanthrene is regulated by the Ah receptor. A cDNA expression library was constructed in lambda gt11 and screened with antiserum. Positive cDNA clones were plaque purified and further characterized by showing enhanced hybridization to 3-methylcholanthrene-induced poly(A+) RNA from rats; the longest cDNA clone (1,501 base pairs) has an open reading frame (bases 75-899) and a nucleotide sequence consistent with a new gene family. On Northern blot analysis, a single 3-methylcholanthrene-inducible rat liver mRNA (approximately 1.6 kilobases) hybridizes to the cDNA probe. 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. The amino acid sequence (274 residues) and Mr of 30,946 compare well with the size of the rat enzyme (32 kDa) estimated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The amino acid sequence of two internal fragments of the trypsin-digested purified NMOR1 protein is in complete agreement with that deduced from the cDNA nucleotide sequence. This study represents the first cloning and sequencing of a cDNA encoding a Phase II drug-metabolizing enzyme under control of the Ah locus.
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PMID:NAD(P)H:menadione oxidoreductase. Novel purification of enzyme cDNA and complete amino acid sequence, and gene regulation. 353 15

Oral exposure of DBA/2 mice to benzo[a]pyrene (BP) has been shown to result in hematotoxicity which is manifested as aplastic anemia and leukemia. Since normal hematopoiesis is regulated by bone marrow stromal cells, in this study we have characterized the bone marrow stromal toxicity induced by BP and BP-derived metabolites, particularly quinones. Incubation of stromal cells with various concentrations of BP-1,6-, 3,6-, 6,12-, or 7,8-quinone for 24 hr resulted in a significant decrease of cell survival in a concentration-dependent manner, while cells treated with BP or BP-7,8-dihydrodiol did not exhibit any significant loss of cell survival. Among the BP quinones examined, BP-1,6-quinone was the most cytotoxic to stromal cells. The cytotoxicity induced by BP-1,6-quinone also exhibited a time-dependent relationship. Pretreatment of stromal cells with 1,2-dithiole-3-thione (D3T) resulted in a significant induction of both cellular reduced glutathione (GSH) content and quinone reductase (QR) activity in a concentration-dependent manner. However, D3T pretreatment did not offer any protection against BP-1,6-quinone-induced toxicity. Furthermore, dicumarol, a potent inhibitor of QR, or buthionine sulfoximine, a specific inhibitor of GSH biosynthesis, did not potentiate BP-1,6-quinone-induced cytotoxicity was not altered. However, incubation of stromal cells with BP-1,6-quinone resulted in a significant depletion of cellular ATP content and mitochondrial morphological changes, which preceded the loss of cell survival. In addition to BP-1,6-quinone, other cytotoxic BP quinones also exhibited a capacity to deplete cellular ATP level in stromal cells, while BP, which was not cytotoxic to stromal cells, did not elicit any significant decrease in cellular ATP level. These observations suggest that mitochondria may be a potential target of BP quinones. Overall, the above results indicate that neither cellular GSH and QR nor reactive oxygen species appear to be involved in BP quinone-induced stromal cell injury and that BP quinones may elicit cytotoxicity to stromal cells through directly disrupting mitochondrial energy metabolism.
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PMID:Characterization of benzo[a]pyrene quinone-induced toxicity to primary cultured bone marrow stromal cells from DBA/2 mice: potential role of mitochondrial dysfunction. 753 Aug 64

Stromal cells from DBA/2 mouse bone marrow have been shown to be susceptible to cytotoxicity induced by several redox-active metabolites of benzene, including hydroquinone (HQ). Treatment with HQ also alters the composition of stromal cell populations by preferentially killing stromal macrophages compared to stromal fibroblasts. This cytotoxicity can be prevented by 1,2-dithiole-3-thione (DTT) as a result of the induction of quinone reductase (QR), a quinone-processing enzyme, and glutathione. The inductive activities of DTT protected stromal cells against HQ-induced cytotoxicity and against HQ-induced impairment of stromal cell ability to support myelopoiesis. In vivo feeding of DTT to DBA/2 mice increased QR activity within the bone marrow compartment and protected bone marrow stromal cells isolated from the DTT-fed animals from ex vivo HQ challenge. Thus, the inducibility of cellular defense mechanisms and xenobiotic-processing enzymes by chemoprotective agents such as DTT may be a useful strategy for protecting against chemically induced bone marrow toxicities.
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PMID:Studies with 1,2-dithiole-3-thione as a chemoprotector of hydroquinone-induced toxicity to DBA/2-derived bone marrow stromal cells. 835 4

Mechanistic toxicology has predominantly been focused on adverse effects that are caused by reactive metabolites or by reactive oxygen species. However, many important xenobiotics exert their toxicity, not by generating reactive products, but rather by altering expression of specific genes. In particular, some environmental contaminants target nuclear receptors that function as regulators of transcription. For example, binding of xenobiotic chemicals to steroid receptors is a principle mechanism of endocrine disruption. The aryl hydrocarbon receptor (AHR) mediates toxicity of dioxin-like compounds. In mice, a polymorphism in the AHR ligand-binding domain reduces binding affinity by about 10-fold in the DBA/2 strain compared with the C57BL/6 strain; consequently, dose-response curves for numerous biochemical and toxic effects are shifted about one log to the right in DBA/2 mice. In the Han/Wistar (Kuopio) (H/W) rat strain, a polymorphism causes a deletion of 38 or 43 amino acids from the AHR transactivation domain. This deletion is associated with a greater than 1000-fold resistance to lethality from 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Genes in the conventional AH gene battery (e.g. CYP1A1, CYP1A2, CYP1B1, ALDH3A1, NQO1 and UGT1A1) remain responsive to TCDD in H/W rats despite the large deletion. However, the deletion may selectively alter the receptor's ability to dysregulate specific genes that are key to dioxin toxicity. We are identifying these genes using an expression array approach in dioxin-sensitive vs. dioxin-resistant rat strains and lines. Polymorphisms exist in the human AH receptor, but thus far they have not been shown to have any substantial effect on human responses to AHR-ligands.
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PMID:Toxicological implications of polymorphisms in receptors for xenobiotic chemicals: the case of the aryl hydrocarbon receptor. 1599 9

Previous studies indicate that 1-bromopropane (1BP) has neurotoxicity and reproductive toxicity both in humans and animals. The present study investigated strain differences in susceptibility to 1BP and identified possible biological factors that determine such susceptibility. Twenty-four male mice of each of the three strains (C57BL/6J, DBA/2J, and BALB/cA) were divided into four groups of six each and exposed to 1BP at 0, 50, 110, and 250 ppm for 8 h/day for 28 days by inhalation. At the end of exposure period, the relative susceptibilities of each strain to 1BP-mediated hepatotoxicity and male reproductive toxicity were evaluated. The contributing factors to strain-dependent susceptibility were assessed by determination of hepatic CYP2E1 levels, glutathione-S-transferase (GST) activity, glutathione (GSH) status, and NAD(P)H:quinone oxidoreductase and heme oxygenase-1 mRNA levels. Liver histopathology showed significantly larger area of liver necrosis and more degenerative lobules in BALB/cA in the order of BALB/cA > C57BL/6J > DBA/2J. BALB/cA showed higher CYP2E1 protein level and lower total GSH content and GST activity in the liver than DBA/2J. These results indicate that BALB/cA mice are the most susceptible to hepatotoxicity of 1BP among the three strains tested, and that CYP2E1, GSH level/GST activity may contribute to the susceptibility to 1BP hepatotoxicity. Exposure to > or = 50 ppm of 1BP also decreased sperm count and sperm motility and increased sperms with abnormal heads in all three strains mice in a dose-dependent manner. Comparison with previous studies in rats indicates that mice are far more susceptible than rats to 1BP regarding hepatotoxicity and reproductive toxicity.
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PMID:Comparative study on susceptibility to 1-bromopropane in three mice strains. 1963 32