Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An FMN-dependent NADH-quinone reductase is induced in Escherichia coli by growing the cells in the presence of menadione (2-methyl-1,4-naphthoquinone). Since the properties of induced enzyme are very similar to those of NAD(P)H: (quinone-acceptor) oxidoreductase (EC 1.6.99.2), known as DT-diaphorase, from animal cells, structural requirements of quinone derivatives as an inducer of NADH-quinone reductase in E. coli were examined. Among quinone derivatives examined, it was found that 2-alkyl-1,4-quinone structure with C-3 unsubstituted or substituted with Br is critical as a common inductive signal. Michael reaction acceptors which have been reported to be strong inducers of DT-diaphorase in mouse hepatoma cells were not always effective inducers in E. coli. However, several compounds, such as 2-methylene-4-butyrolactone, methylacrylate and methyl vinyl ketone, showed a slight inductive activity. The efficient inducers of NADH-quinone reductase in E. coli contain 1,4-quinone structure as a part of the inductive signal. These compounds belong to Michael acceptors and are likely to conjugate with thiol compounds such as glutathione.
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PMID:Chemical structures critical for the induction of FMN-dependent NADH-quinone reductase in Escherichia coli. 154 1

DT diaphorase (NAD(P)H dehydrogenase (quinone), EC 1.6.99.2) isolated from Walker 256 rat carcinoma cells can convert CB 1954 (5-(aziridin-1-yl)-2,4-dinitrobenzamide) to a cytotoxic DNA interstrand cross-linking agent. This is achieved by reduction of the 4-nitro group of CB 1954 to produce the hydroxylamino species, a bioactivation which accounts for the much greater sensitivity of Walker cells to CB 1954 when compared with other cells which are unable to carry out this reduction (Knox et al., Biochem Pharmacol 37: 4661-4669 and 4671-4677, 1988). As predicted from their measured DT diaphorase activities a number of rat hepatoma and hepatocyte cell lines were also shown to be sensitive to CB 1954. However, no CB 1954-sensitive cell lines of human origin were found, although levels of DT diaphorase similar to those in the sensitive rat cells were present in these cells. The human cells were as sensitive as rat cells to the active form of CB 1954 (5-(aziridin-1-yl)-4-hydroxyla mino-2-nitrobenzamide). DT diaphorase, purified to homogeneity from human Hep G2 cells, did metabolize CB 1954 to this 4-hydroxylamino product, but the rate of CB 1954 reduction and thus production of the cytotoxic product, was much lower than that of purified Walker enzyme (ratio of Kcat = 6.4). In addition, CB 1954 could be considered an inhibitor of, rather than a substrate for, the human form of DT diaphorase. The purified rat and human DT diaphorases possessed otherwise similar biochemical and molecular properties. These findings explain the decreased sensitivity towards CB 1954 of human cell lines when compared to rat cell lines.
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PMID:The differences in kinetics of rat and human DT diaphorase result in a differential sensitivity of derived cell lines to CB 1954 (5-(aziridin-1-yl)-2,4-dinitrobenzamide) 190 Dec 7

Transcripts of the murine CYP1A1 (cytochrome P1450) mRNA are markedly elevated in mutant hepatoma cell lines that contain missense mutations in the Cyp1a-1 structural gene. This putative derepression extends to other genes in the [Ah] battery. To test whether the Cyp1a-1 gene product is involved in a mechanism of feedback regulation of transcription, we introduced expression plasmids carrying the murine wild-type Cyp1a-1 cDNA into the mutant hepatoma cells. Measurements of steady-state mRNA levels and of transcriptional rates in the transfectants reveal that expression of a functional, exogenous CYP1A1 protein is sufficient to restore the repression of the endogenous gene, as well as restore the inducibility by dioxin, and that this effect takes place primarily at the level of transcription. Similar experiments with expression plasmids that carry the human CYP1A2 cDNA indicate that the CYP1A2 protein (cytochrome P3450) can also function as a transcriptional repressor. In addition, we find that expression of the Nmo-1 [NAD(P)H:menadione oxidoreductase] gene, a third member of the [Ah] gene battery, is also repressed by the exogenous expression of either Cyp1a-1 or CYP1A2 cDNA. These results indicate that the gene product of either member of the mammalian CYP1 family has a previously unrecognized transcriptional regulatory function, which is likely to be exerted by modification of preexisting trans-acting factors. This function may help bring about a fast reprogramming of gene expression, as might be needed during detoxification of toxic foreign chemicals.
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PMID:The murine Cyp1a-1 gene negatively regulates its own transcription and that of other members of the aromatic hydrocarbon-responsive [Ah] gene battery. 208 80

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

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

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

Induction of detoxification enzymes is a major mechanism whereby a wide variety of chemical agents protect rodents against neoplastic, mutagenic, and other toxicities of carcinogens. The enzyme NAD(P)H:(quinone acceptor) oxidoreductase (EC 1.6.99.2) can protect against the toxicities of quinones and is a useful marker for protective enzyme induction. Quinone reductase can be induced in murine Hepa 1c1c7 hepatoma cells and 3T3 embryo fibroblasts by compounds that are chemoprotectors in vivo, including some phenolic antioxidants, azo dyes, aromatic diamines, and aminophenols. Structurally dissimilar catechols (1,2-diphenols) and hydroquinones (1,4-diphenols) induce quinone reductase in these systems, but resorcinol (1,3-diphenol) and its substituted analogues are inactive. Furthermore, only aromatic 1,2- and 1,4-diamines and aminophenols are inducers, whereas the 1,3-diamines are completely inactive. These findings suggest that the functional capacity to form quinones or quinone-diimines, rather than the precise structure, is essential for inductive activity and that the generation of the signal for enzyme induction depends upon oxidation-reduction lability. The observations that some chemoprotective compounds (e.g., azo dyes, beta-naphthoflavone) induce both cytochromes P-450 and quinone reductase, whereas others (e.g., tert-butylhydroquinone) induce only quinone reductase, can be reconciled by the fact that inducers of the first type are metabolized by P-450 enzymes to form products that are functionally similar to compounds of the second type.
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PMID:On the mechanisms of induction of cancer-protective enzymes: a unifying proposal. 393 71


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