Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.6.5.2 (NQO1)
6,196 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

These studies concern the initial steps in 4-nitroquinoline 1-oxide (4NQO) metabolism in relation to mechanisms of anticarcinogenesis. Butylated hydroxyanisole (BHA) administration by a protocol known to inhibit the pulmonary tumorigenicity of 4NQO in A/HeJ mice enhanced hepatic and pulmonary activities for 4NQO metabolism by two major pathways, conjugative detoxification and nitroreductive activation. High-performance liquid chromatography analysis showed approximate doubling of two types of glutathione transferase subunits with 4NQO-conjugating activity in livers of BHA-treated mice. Similar increases were observed in hepatic 4NQO-conjugating activity and in Vmax, while Km for 4NQO was 39 to 43 microM. Pulmonary 4NQO-glutathione transferase activity increased 24 to 29%. DT diaphorase activity toward 4NQO was elevated 3.3-fold in livers and 2.7-fold in lungs of BHA-treated mice. However, the predominant 4NQO reductase of liver and lung was dicumarol resistant, had a strong preference for NADH, and showed little if any response to BHA. This Mr 200,000 enzyme, partially purified from livers of Swiss mice, exhibited the stoichiometry of 2-NADH/4NQO expected for reduction of 4NQO to 4-hydroxyaminoquinoline 1-oxide. Its high affinity for 4NQO (Km, 15 microM) signified a much greater influence on 4NQO metabolism than DT diaphorase (Km, 208 microM). The dicumarol-resistant 4NQO reductase differed from several known cytosolic nitroreductases. The results suggest that protection by BHA may result from alteration of the balance between 4NQO activation and conjugation.
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PMID:Nitroreductases and glutathione transferases that act on 4-nitroquinoline 1-oxide and their differential induction by butylated hydroxyanisole in mice. 137 76

1. The t-butylquinone metabolite of BHA was shown to redox cycle with NADPH-cytochrome P-450 reductase leading to enhanced NADPH-oxidase activity for both the purified and liver microsome-bound flavoprotein. Likewise, addition of t-butylquinone (20-100 microM) strikingly inhibited electron transfer from the flavoprotein reductase to cytochrome P-450 of liver microsomes from phenobarbital-treated rats. 2. When the effect of t-butylquinone on metabolism of biphenyl was evaluated with liver microsomal fractions or isolated hepatocytes, t-butylquinone was less effective as an inhibitor then BHA alone or vitamin K3 (menadione). Addition of dicoumarol had little or no effect on the inhibitory potency of either t-butylquinone or vitamin K3 in isolated hepatocytes. 3. t-Butylquinone was not an effective reductant for exogenous oxidants, such as cytochrome c, in the presence of purified, cytosolic NAD(P)H-quinone oxidoreductase (DT-diaphorase). This property is most probably due to the lower rate of reoxidation of t-butylquinone by molecular oxygen, relative to vitamin K3 (menadione).
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PMID:The effect of the tert-butylquinone metabolite of butylated hydroxyanisole on cytochrome P-450 monooxygenase activity. 212 6

In the presence of NADPH and oxygen, menadione (2-methyl-1,4-naphthoquinone) elicits low level red chemiluminescence from rodent liver preparations. This chemiluminescence is believed to arise from the formation of active oxygen species that are generated when the quinone undergoes oxidative cycling. The obligatory two-electron reduction of quinones to hydroquinones catalyzed by NAD(P)H:(quinone-acceptor) oxidoreductase (EC 1.6.99.2) has been implicated in the suppression of this photoemission by competing with oxidative cycling (Wefers, H., Komai, T., Talalay, P., and Sies, H. (1984) FEBS Lett. 169, 63-66 and references therein). Thus, in previous studies, we showed that treatment of mice with BHA (2(3)-tert-butyl-4-hydroxyanisole), which elevates cytosolic quinone reductase activity about 10-fold, reduced menadione-dependent chemiluminescence of hepatic post-mitochondrial supernatant fractions, whereas inhibition of quinone reductase by dicoumarol greatly intensified light emission. We demonstrate here that addition of pure quinone reductase to this preparation suppresses menadione-dependent chemiluminescence, and that the protective effect of 2(3)-tert-butyl-4-hydroxyanisole treatment can be accounted for completely by the induction of this specific enzyme. These results provide conclusive evidence that in this system the protective action of anticarcinogenic antioxidants is entirely attributable to the elevation of the level of an electrophile-processing enzyme.
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PMID:Direct protective effect of NAD(P)H:quinone reductase against menadione-induced chemiluminescence of postmitochondrial fractions of mouse liver. 243 74

Exposure of murine hepatoma (Hepa 1c1c7) cells to a variety of chemical agents known to protect animals against the neoplastic, mutagenic, and other toxic effects of chemical carcinogens results in dose- and time-dependent inductions of NAD(P)H:quinone reductase (EC 1.6.99.2). This enzyme protects against quinone toxicity by promoting obligatory two-electron reductions that divert quinones from oxidative cycling or direct interactions with critical nucleophiles. Quinone reductase levels are stable in culture, are easily measured, and are useful markers for the inductive effects of chemoprotective agents. The Hepa 1c1c7 system responds to chemoprotective compounds such as phenolic antioxidants (e.g., BHA [3(2)-tert-butyl-4-hydroxyanisole], BHT (3,5-ditert-butyl-4-hydroxytoluene), and tert-butylhydroquinone), lipophilic azo dyes belonging to the 1,1'-azonaphthalene, Sudan I (1-phenylazo-2-naphthol), and Sudan III [1-(4-phenylazophenylazo)-2-naphthol] families, polycyclic aromatic hydrocarbons, coumarin and various other lactones, flavonoids, and certain sulfur compounds (e.g., benzylisothiocyanate, dithiolthiones, and dithiocarbamates), all of which are recognized enzyme inducers and chemoprotectors in vivo. Quinone reductase induction in Hepa 1c1c7 cells therefore provides a simple, versatile, and reliable system for the evaluation of the potency, kinetics, and mechanism of action of anticarcinogens.
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PMID:Induction of NAD(P)H:quinone reductase in murine hepatoma cells by phenolic antioxidants, azo dyes, and other chemoprotectors: a model system for the study of anticarcinogens. 308 Jul 50

In toxicology, it is of interest not only to assess enzyme levels and capacities for potential fluxes, but it is also useful to develop methods for determining actual concentrations and fluxes in the intact cell and organ. To this end, several noninvasive techniques have been developed over the years. Our interest has been largely in photometric techniques. Transmission spectrophotometry through solid organs permits monitoring of the cytochromes of the mitochondrial respiratory chain and cytochrome P-450 as well as other pigments of biological interest. Furthermore, the steady state level of catalase Compound I in liver provides information on rates of H2O2 production. These are in the nM to microM concentration range. More recently, the monitoring of photoemission from intact organs has been useful in toxicological problems. The major photoemissive species, singlet molecular oxygen and excited carbonyls, can now be monitored with good signal/noise ratio. Redox cycling of quinones and the generation of photoemissive species were studied in menadione metabolism. Inhibition of phase II led to a significant increase in the steady state level of singlet oxygen, as did the inhibition of two-electron reduction by using the inhibitor dicoumarol for DT diaphorase. Conversely, the induction of DT diaphorase by pretreatment with BHA protected by decreasing the level of reactive oxygen species.
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PMID:Intact organ spectrophotometry and single-photon counting. 330 3

NAD(P)H:quinone reductase exhibits broad specificity in the reduction of endogenous and exogenous quinones and quinone imines, such as those derived from polycyclic aromatic carcinogens, phenolic steroids, vitamin K, and numerous therapeutic drugs. This enzyme is found in several cell compartments and is widely distributed among tissues. In contrast to several other flavoprotein dehydrogenases, quinone reductase catalyzes obligatorily two electron reductions. Extensive studies by Huggins and by others have shown that the quinone reductase in liver and some other tissues of rats is inducible by various polycyclic hydrocarbons and aromatic amines, as well as by certain azo dyes. Huggins perceived that the relative effectiveness of such compounds in inducing quinone reductase correlated with their abilities to protect against toxicity and carcinogenesis. Certain antioxidants are also known to protect against the tumorigenic and toxic effects of carcinogens. Studies on the mechanisms underlying the protective effects of BHA, BHT, ethoxyquin, and disulfiram have revealed that these compounds alter the activity profiles of several enzymes which metabolize carcinogenic and toxic compounds. We have observed that quinone reductase specific activity is increased markedly in mouse liver and several extrahepatic tissues in response to dietary BHA, ethoxyquin, and disulfiram, whereas BHT has been shown by others to enhance this enzymatic activity in rat liver. These findings confirm and extend the correlation between the ability to elevate quinone reductase activity and to confer protection against carcinogenesis and toxicity. The broad specificity of quinone reductase, its apparent inability to catalyze one electron reductions of quinones, its widespread distribution, and its inducibility by a variety of structurally dissimilar protective compounds, suggest that quinone reductase may play a significant local protective role in various regions of the cell.
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PMID:Elevation of quinone reductase activity by anticarcinogenic antioxidants. 618 Jun 7

Menadione elicits low-level chemiluminescence (lambda greater than 620 nm) associated with redox cycling of the quinone in mouse hepatic postmitochondrial fractions. This photoemission is suppressed when the animals are fed a diet containing the anticarcinogenic antioxidant, 2[3]-(tert-butyl)-4-hydroxyanisole (BHA), which leads to a 13-fold increase in NAD(P)H: quinone reductase (EC 1.6.99.2). Inhibition of the enzyme by dicoumarol completely abolishes the protective effect of BHA treatment and leads to higher chemiluminescence, reaching similar photoemission for BHA-treated and control animals. These findings indicate that the two-electron reduction promoted by quinone reductase prevents redox cycling and that BHA protects against reactive oxygen species by elevating the activity of this enzyme.
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PMID:Protection against reactive oxygen species by NAD(P)H: quinone reductase induced by the dietary antioxidant butylated hydroxyanisole (BHA). Decreased hepatic low-level chemiluminescence during quinone redox cycling. 620 94

Levels of mRNAs encoding class-alpha glutathione transferases, class-mu glutathione transferases, quinone reductase, and cytochrome P450 1A were measured after xenobiotic induction in murine tissues and in the Hepa1c1c7 murine hepatoma cell line. RNA levels in liver and intestinal mucosa were determined after induction with phenobarbital, butylated hydroxyanisole, beta-naphthoflavone, isosafrole, or combinations of these compounds. The tissue culture cells were presented with combinations of butylated hydroxyanisole, tert-butyl-hydroquinone, and beta-naphthoflavone. In murine liver and intestinal mucosa, the greatest induction (5-15-fold) of glutathione transferases and quinone reductase was seen with butylated hydroxyanisole. Administration of phenobarbital or beta-naphthoflavone has only a modest effect (2-3-fold). In contrast, cytochrome P450 1A mRNA levels increase only slightly after BHA induction but are induced dramatically by beta-naphthoflavone. The pattern of induction is different in Hepa1c1c7 cells; there the greatest induction of all mRNAs occurred with beta-naphthoflavone. Administration of antioxidants with other xenobiotics increases mRNA levels only slightly over the levels obtained with BHA in murine tissues, or with beta-naphthoflavone in Hepa1c1c7 cells. mGSTM1 (GT8.7, Yb1), the most abundant glutathione transferase mRNA in murine liver, is also the most abundant glutathione transferase mRNA in both normal and induced Hepa1c1c7 cells. Our results suggest that BHA induction in murine liver and intestinal mucosa of class-mu and class-alpha glutathione transferases may involve regulatory elements and mediators that function poorly in Hepa1c1c7 cells.
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PMID:Differences in induction by xenobiotics in murine tissues and the Hepa1c1c7 cell line of mRNAs encoding glutathione transferase, quinone reductase, and CYP1A P450s. 822 Apr 36

We characterized the inducing effects of two musk analogues, musk xylene and musk ambrette, on phase I and phase II drug-metabolizing enzymes in rat liver and compared their effects with 3-methylcholanthrene, isosafrole and 2(3)-tertbutylhydroxyanisole (BHA) at 0.1 mmol/kg dose level. Musk xylene and isosafrole increased more efficiently the metabolic activation of 2-amino-6-methyldipyrido[1,2-a:3',2'-d]imidazole (Glu-P-1) to mutagen than that of benzo(a)pyrene. Musk ambrette increased both the activation of Glu-P-1 and benzo(a)pyrene to the same extent. Western blot analyses revealed that musk xylene, musk ambrette, isosafrole and BHA induced more strongly cytochrome P450 1A2 (CYP1A2) in microsomes than CYP1A1. 3-Methylcholanthrene induced CYP1A1 in preference to CYP1A2. On the other hand, all drugs except for 3-methylcholanthrene did not show remarkable increases in phase II enzyme activities, such as DT-diaphorase, glutathione S-transferase and UDP-glucuronyltransferase, at 0.1 mmol/kg dose level. These results show that musk xylene, musk ambrette, isosafrole and BHA at the dose level used in this study possess the potency to induce CYP1A2 without remarkable induction of CYP1A1 and phase II enzyme activities as observed for 3-methylcholanthrene, although they have been considered to induce both phase I and phase II drug-metabolizing enzymes at higher doses.
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PMID:Induction of cytochrome P450 1A2 by musk analogues and other inducing agents in rat liver. 829 89

Recent metabolic studies have demonstrated the importance of reactive intermediates like quinones or semiquinone radicals in the covalent binding of halobenzenes to liver protein. The current studies were designed to examine if quinone intermediates are involved in the toxicity of hepatotoxic halobenzenes, bromobenzene (BB) and 1,2,4-trichlorobenzene (1,2,4-TCB). Two-electron reduction of the quinone intermediates by DT-diaphorase is considered to be a detoxication pathway since the resulting hydroquinone may be readily conjugated and excreted. Mice were pretreated with butylated hydroxyanisole (BHA; 0.5% in the diet, for 3 days), an inducer of DT-diaphorase, or dicoumarol (0.3 mmol/kg, p.o.), an inhibitor of this enzyme. The mice were then given BB (2.5 or 3.5 mmol/kg, i.p.) or 1,2,4-TCB (0.75 or 1.5 mmol/kg, i.p.). Dietary BHA markedly suppressed the hepatotoxicity caused by both BB and 1,2,4-TCB while dicoumarol significantly enhanced it, as judged by serum alanine aminotransferase activity. When mice were treated with BB at different times after the end of dietary BHA exposure, the degree of the protection against the hepatotoxicity appears to correlate to the extent of the induction of DT-diaphorase activity by BHA pretreatment. BHA pretreatment failed to protect against carbon tetrachloride-induced hepatotoxicity. These results seem to provide evidence for the involvement of the quinone metabolites in BB- and 1,2,4-TCB-induced hepatotoxicity and for the protective role of DT-diaphorase against the toxicity.
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PMID:Modulation of halobenzene-induced hepatotoxicity by DT-diaphorase modulators, butylated hydroxyanisole and dicoumarol: evidence for possible involvement of quinone metabolites in the toxicity of halobenzenes. 1009 53


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