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)

Most chemical carcinogens require activation to reactive electrophilic forms by Phase 1 enzymes (cytochromes P-450) in order to exert their toxic and neoplastic effects. The resultant electrophiles are susceptible to metabolic conjugation and other types of detoxications by Phase 2 enzymes (glutathione transferases, NAD(P)H: quinone reductase, glucuronosyltransferases). The balance between Phase 1 and Phase 2 enzymes is an important determinant of whether exposure to carcinogens will result in toxicity and neoplasia. Measurements of the activity of quinone reductase (QR) provide an efficient method for studying the potency and mechanism of Phase 2 enzyme induction. QR can be measured easily in murine hepatoma cells (Hepa lclc7) grown in microtiter plate wells, and the inductive response of these cells closely parallels the behavior of rodent tissues in vivo. Some inducers (such as large planar aromatics) are bifunctional; they induce both Phase 1 and Phase 2 enzymes and require binding to the Ah receptor and enhanced transcription of the cytochrome P1-450 system. Other inducers (e.g., phenolic antioxidants, 1, 2-dithiole-3-thiones, coumarins, thiocarbamates) are monofunctional and are independent of Ah receptor function. Monofunctional enzyme induction protects against carcinogens. The induction of Phase 2 enzymes by monofunctional inducers depends on the presence, or acquisition by metabolism, of electrophilic centers, and many of these inducers are Michael reaction acceptors. Our search for chemoprotective enzyme inducers for potential use as chemoprotectors in man is currently focused on fumarate derivatives, as well as on the identification of other monofunctional inducers in extracts of vegetables.
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PMID:Regulation of enzymes that detoxify the electrophilic forms of chemical carcinogens. 213 77

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. Our data indicate that both of these planar aromatic compounds produce a 4-5-fold elevation in quinone reductase mRNA. The induction of quinone reductase mRNA can be blocked by cycloheximide, suggesting a requirement for ongoing protein synthesis in the induction process. We have determined the exon structure of the quinone reductase structural gene. The gene is separated into six exons by five introns. A "TATA" box is located 29 base pairs upstream from the transcription initiation site. A "CCAAT" sequence is found at position -129, and an inverted "GC" box is located at position -78. Quinone reductase promoter-chlor-amphenicol acetyltransferase fusion genes containing different lengths of the 5'-flanking region were transfected into rat and human hepatoma cells. Treatment of the transfected cells with beta-naphthoflavone or sudan III resulted in a 4-5-fold elevation in chloramphenicol acetyltransferase activity. These data suggest the presence of a cis-acting regulatory element(s) in the 5'-flanking region of the quinone reductase structural gene which regulates inducible expression.
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PMID: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. 248 Sep 57

The cytotoxic properties of quinone drugs such as menadione and adriamycin are thought to be mediated through one-electron reduction to semiquinone free radicals. Redox cycling of the semiquinones results in the generation of reactive oxygen species and in oxidative damage. In this study the toxicity of mitozantrone, a novel quinone anticancer drug, was compared with that of menadione in human Hep G2 hepatoma cells. Mitozantrone toxicity in these cells was not mediated by the one-electron reduction pathway. In support of this, inhibition of the enzymes glutathione reductase and catalase, responsible for protecting the cells from oxidative damage, did not affect the response of the Hep G2 cells to mitozantrone, whereas it exacerbated menadione toxicity. In addition, the toxicity of menadione was preceded by depletion of reduced glutathione which was probably due to oxidation of the glutathione. Mitozantrone did not cause glutathione depletion prior to cell death. DT-diaphorase activity and intracellular glutathione were found to protect the cells from the toxicity of both quinones. Inhibition of epoxide hydrolase potentiated mitozantrone toxicity but did not affect that of menadione. Our experiments indicate that mitozantrone toxicity may involve activation to an epoxide intermediate. Both quinone drugs inhibited cytochrome P-450-dependent mixed-function oxidase activity, although menadione was more potent in this respect.
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PMID:The toxicity of menadione and mitozantrone in human liver-derived Hep G2 hepatoma cells. 253 22

A persuasive body of evidence indicates that substantial protection against chemical carcinogenesis can be achieved by induction of enzymes concerned with the metabolism of carcinogens. There are two classes of anticarcinogenic enzyme inducers: (a) monofunctional inducers (e.g., phenolic antioxidants, isothiocyanates, coumarins, thiocarbamates, cinnamates, 1,2-dithiol-3-thiones) that elevate Phase II enzymes (such as glutathione S-transferases, NAD(P)H:quinone reductase, UDP-glucuronosyl-transferases) in various tissues without significantly raising the Phase I enzyme, aryl hydrocarbon hydroxylase (cytochrome P1-450); and (b) bifunctional inducers (e.g., polycyclic aromatic hydrocarbons, flavonoids, and azo dyes) that induce both Phase I and Phase II enzymes of xenobiotic metabolism. Induction of Phase II enzymes appears to be a sufficient condition for achieving chemoprotection, and since certain Phase I enzymes are responsible for activating carcinogens to their ultimate reactive forms, selective Phase II enzyme inducers offer intrinsically safer prospects for achieving chemoprotection. Whereas induction of both Phase I and II enzymes by bifunctional inducers depends on the Ah receptor, induction of Phase II enzymes by monofunctional inducers is independent of a functional Ah receptor. Studies on the structural requirements for induction of quinone reductase [NAD(P)H:(quinone acceptor) oxidoreductase; EC 1.6.99.2] by monofunctional inducers in Hepa 1c1c7 murine hepatoma cells have revealed that such inducers contain a distinctive chemical feature (or acquire this feature by metabolism) that regulates the synthesis of this protective enzyme. The inducers are all Michael reaction acceptors characterized by olefinic (or acetylenic) linkages that are rendered electrophilic by conjugation with electron-withdrawing groups. Typical examples are alpha, beta-unsaturated aldehydes, ketones (including quinones), thioketones, sulfones, esters, nitriles and nitro groups. The potency of these inducers parallels their reactivity as Michael acceptors. These generalizations have provided mechanistic insight into the vexing question of how so many seemingly unrelated anticarcinogens induce chemoprotective enzymes. They have also led to the prediction of entirely new and unsuspected structures of inducers, with potential for chemoprotective activity.
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PMID:Mechanisms of induction of enzymes that protect against chemical carcinogenesis. 269 44

The metabolism of chemical carcinogens was investigated in liver preparations from 28 captive woodchucks (Marmota monax). Of these, 23 were naturally infected with the woodchuck hepatitis virus (WHV), and eight also had primary hepatocellular carcinoma (PHC). Twenty-nine parameters were investigated in liver subcellular fractions, including cross-reactivity with HBsAg, and biochemical parameters, such as gamma-glutamyl transpeptidase, cytochrome P-450 and microsomal monooxygenases (aryl hydrocarbon hydroxylase, ethoxycoumarin and ethoxyresorufin deethylases, aminopyrine and dimethylnitrosamine demethylases, and testosterone 7 alpha-, 16 alpha- and 6 beta-hydroxylases), uridine 5'-diphosphoglucuronosyl transferase, GSH and related enzymes (peroxidase, reductase and S-transferase), as well as other cytosolic enzyme activities (glucose 6-phosphate and 6-phosphogluconate dehydrogenases, NADPH- and NADH-dependent diaphorases, and DT diaphorase). In addition, liver preparations were used in order to quantify the metabolic activation into bacterial mutagens of five procarcinogens (aflatoxin B1, the pyrolysis products Trp-P-2 and MeIQ, 2-aminofluorene and dimethylnitrosamine) and the decrease of potency of three direct-acting mutagens (sodium dichromate, ICR 191 and 4-nitroquinoline 1-oxide). WHV infection produced a significant stimulation of carcinogen metabolism, as shown by the simultaneous change in detoxification parameters (GSH depletion) and activation indices (enhancement of microsomal monooxygenases and of procarcinogen activation into mutagenic metabolites). There were no significant differences between WHV-positive samples from animals without PHC and the noncancerous tissue of PHC-bearing animals, whereas a decrease of both activation and detoxification indices was recorded in the tumorous tissue. There was a considerable interindividual variability among WHV carriers, which was tentatively ascribed to genetic factors. Pregnancy was the only known factor influencing the results in WHV carriers. However, even by excluding pregnant animals, the effects on carcinogen metabolism produced by WHV infection were still statistically significant. These results, together with previous data obtained in humans, revealed that metabolic factors may play a role in the synergism between viral hepatitis and chemical hepatocarcinogens in the etiopathogenesis of PHC.
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PMID:Enhanced metabolic activation of chemical hepatocarcinogens in woodchucks infected with hepatitis B virus. 272 Sep 3

Short-term treatment of rats with hepatocarcinogens elicits a consistent pattern of phenotypic changes in hepatic drug metabolizing enzymes, the most striking of which is a marked increase in microsomal epoxide hydrolase (EH) activity. The antihistaminic drug methapyrilene induces a high incidence of hepatocellular carcinoma in F-344 rats. The studies reported here were designed to assess the effects of methapyrilene on hepatic EH activity, cytochrome P-450-dependent mixed-function oxidase activities, liver morphology, and liver-derived serum enzymes. Male F-344 rats were treated with three daily oral doses of methapyrilene-HCl, up to 300 mg/kg/day, and were sacrificed 48 hr after the last dose. Hepatic microsomal EH and cytosolic DT-diaphorase activities were increased in a dose-related fashion, to 420 and 230% of control, respectively. Cytochrome P-450 content and benzphetamine-N-demethylase and ethoxycoumarin-O-deethylase activities were concomitantly decreased to 35-50% of control. Serum gamma-glutamyl transpeptidase and alanine aminotransferase activities were elevated 22- to 27-fold, and serum bile acids to 36-fold by treatment with methapyrilene. Periportal lesions, characterized by inflammation, nuclear and nucleolar enlargement, bile duct hyperplasia, and hepatocellular necrosis, were observed following methapyrilene administration. The severity of the periportal lesion correlated with elevations in the serum chemistry parameters. The increases noted in microsomal EH activity supports the suggestion that this enzyme may be a useful biochemical marker for exposure to hepatocarcinogens.
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PMID:Effects of methapyrilene on rat hepatic xenobiotic metabolizing enzymes and liver morphology. 285 28

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

DT diaphorase catalyzes the transfer of two electrons to quinones to form relatively stable hydroquinones, thus protecting cells from damage by semiquinone production and subsequent superoxide radical formation. A rapid and substantial increase in the activity of DT diaphorase occurs in the cytosolic and microsomal fractions of livers of rats with Zajdela ascites hepatoma under conditions which generally depress the activity of other xenobiotic-metabolizing enzymes. The increase is time-dependent, parallels the increase in the specific activity of DT diaphorase of the growing hepatoma cells, and is limited to the liver. Treatment of rats with hepatoma cytosol results in a rapid increase in liver cytosolic DT diaphorase activity in a dose-dependent manner.
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PMID:The anticancer enzyme DT diaphorase is induced selectively in liver during ascites hepatoma growth. 312 84

We describe a rapid and direct assay of NAD(P)H:(quinone-acceptor) oxidoreductase (EC 1.6.99.2) activity in cultured cells suitable for identifying and purifying inducers of this detoxication enzyme. Hepa 1c1c7 murine hepatoma cells are plated in 96-well microtiter plates, grown for 24 h, and exposed to inducing agents for another 24 h. The cells are then lysed and quinone reductase activity is assayed by the addition of a reaction mixture containing an NADPH-generating system, menadione (2-methyl-1,4-naphthoquinone), and MTT [3-(4,-5-dimethylthiazo-2-yl)-2,5-diphenyltetrazolium bromide]. Quinone reductase catalyzes the reduction of menadione to menadiol by NADPH, and MTT is reduced nonenzymatically by menadiol resulting in the formation of a blue color which can be quantitated on a microtiter plate absorbance reader. The reaction is more than 90% dicoumarol inhibitable and menadione dependent. The results are comparable to those obtained by harvesting cells from larger plates, preparing cytosols, and carrying out spectrophotometric measurements.
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PMID:Direct measurement of NAD(P)H:quinone reductase from cells cultured in microtiter wells: a screening assay for anticarcinogenic enzyme inducers. 338 6

Fischer F-344 male rats, fed a choline-devoid diet that leads to a highly reproducible sequence of biochemical and biological changes with an ultimate development of hepatocellular carcinoma, show elevated levels of glutathione in the liver at 3, 6 and 8 days. Several enzymes related to the metabolism of free radicals, including superoxide dismutase, catalase, glutathione peroxidase, glutathione S-transferase and DT-diaphorase show neither increased nor decreased activity as measured between 12 h and 8 days on the diet. Thus, of several known cellular components related to the possible scavenger of free radicals in the liver, only glutathione responded to the feeding of the CD diet. It is tentatively concluded that a decrease in the levels of possible scavengers for free radicals is not a major basis for the nuclear and mitochondrial lipid peroxidation seen early in rats fed a choline-devoid diet.
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PMID:Glutathione and enzymes related to free radical metabolism in liver of rats fed a choline-devoid low-methionine diet. 339 Aug 3


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