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)

The environmental contaminant, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces the expression of a number of genes. The biochemical process of the induction of aldehyde dehydrogenase (ALDH-3) was investigated in rat H4IIE hepatoma cells in culture. The kinetics of ALDH-3-induction exhibited parallel increases in the rate of transcription, mRNA, protein, and enzyme activity, all reaching a plateau at 36-48 h after addition of TCDD. Half maximal and maximal inductions occurred at 0.1 and 1 nM of TCDD, respectively. No significant changes in the half-life of ALDH-3 mRNA (14 h) were observed in the cells exposed to three different concentrations of TCDD. Other inducers of xenobiotic metabolism, such as 3-methylcholanthrene and beta-naphthoflavone, also induced ALDH-3 mRNA to a similar level as TCDD, whereas antioxidants or electrophiles, such as tert-butylhydroquinone and dimethyl fumarate, did not show any induction of ALDH-3 mRNA. To examine the involvement of the aryl hydrocarbon receptor (Ah receptor) in the induction of ALDH-3, mouse variant cell lines defective in cytochrome P450IA1-induction and a parental wild type cell line (Hepa1c1c7) were studied. ALDH-3 mRNA and the transcription of its gene were detected in TCDD-treated wild type cells, but not in the treated and untreated variant cells. These results demonstrate that TCDD induces transcription of the ALDH-3 gene via its binding to the Ah receptor.
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PMID:Regulation of 2,3,7,8-tetrachlorodibenzo-p-dioxin-inducible expression of aldehyde dehydrogenase in hepatoma cells. 141 78

Consumption of vegetables, especially crucifers, reduces the risk of developing cancer. Although the mechanisms of this protection are unclear, feeding of vegetables induces enzymes of xenobiotic metabolism and thereby accelerates the metabolic disposal of xenobiotics. Induction of phase II detoxication enzymes, such as quinone reductase [NAD(P)H:(quinone-acceptor) oxidoreductase, EC 1.6.99.2] and glutathione S-transferases (EC 2.5.1.18) in rodent tissues affords protection against carcinogens and other toxic electrophiles. To determine whether enzyme induction is responsible for the protective properties of vegetables in humans requires isolation of enzyme inducers from these sources. By monitoring quinone reductase induction in cultured murine hepatoma cells as the biological assay, we have isolated and identified (-)-1-isothiocyanato-(4R)-(methylsulfinyl)butane [CH3-SO-(CH2)4-NCS, sulforaphane] as a major and very potent phase II enzyme inducer in SAGA broccoli (Brassica oleracea italica). Sulforaphane is a monofunctional inducer, like other anticarcinogenic isothiocyanates, and induces phase II enzymes selectively without the induction of aryl hydrocarbon receptor-dependent cytochromes P-450 (phase I enzymes). To elucidate the structural features responsible for the high inducer potency of sulforaphane, we synthesized racemic sulforaphane and analogues differing in the oxidation state of sulfur and the number of methylene groups: CH3-SOm-(CH2)n-NCS, where m = 0, 1, or 2 and n = 3, 4, or 5, and measured their inducer potencies in murine hepatoma cells. Sulforaphane is the most potent inducer, and the presence of oxygen on sulfur enhances potency. Sulforaphane and its sulfide and sulfone analogues induced both quinone reductase and glutathione transferase activities in several mouse tissues. The induction of detoxication enzymes by sulforaphane may be a significant component of the anticarcinogenic action of broccoli.
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PMID:A major inducer of anticarcinogenic protective enzymes from broccoli: isolation and elucidation of structure. 154 3

Glutathione S-transferase (GST) Ya subunit gene expression is induced in mammalian tissues by two types of chemical agents: (i) planar aromatic compounds (e.g., 3-methylcholanthrene, beta-naphthoflavone, and 2,3,7,8-tetrachlorodibenzo-p- dioxin) and (ii) electrophiles (e.g., trans-4-phenyl-3-buten-2-one and dimethyl fumarate) or compounds easily oxidized to electrophiles (e.g., tert-butylhydroquinone). To study the mechanism of this induction, we have introduced deletions in the 5' flanking region of a mouse GST Ya subunit gene, fused it to the coding sequence for chloramphenicol acetyltransferase (CAT) activity, and transfected the Ya-CAT genes for expression into hepatoma cells. We show that a single cis-regulatory element, between nucleotides -754 and -713 from the start of transcription, is responsible for the induction by both planar aromatic and electrophilic compounds. Using murine hepatoma cell mutants defective in either the Ah-encoded aryl hydrocarbon receptor (BPrc1 mutant) or in cytochrome P1-450 gene (c1 mutant), we show that induction by planar aromatic but not by electrophilic inducers requires a functional Ah receptor and cytochrome P1-450 activity. From this it is concluded that Ya gene activation by planar aromatic compounds involves metabolism of these inducers by the phase I xenobiotic-metabolizing cytochrome P1-450 system into electrophilic compounds, which is consistent with a recently proposed model [Prochaska, H. J. & Talalay, P. (1988) Cancer Res. 48, 4776-4782]. Therefore, the regulatory sequence of the Ya gene should be considered an electrophile-responsive element (EpRE) activated exclusively by inducers containing an electrophilic center. An EpRE-containing 41-bp oligonucleotide ligated at the -187 site of the Ya gene promoter confers upon it an increase in basal activity and xenobiotic inducibility. The basal activity augments with the number of EpRE copies. DNase I protection patterns show the protection of the EpRE domain by a nuclear factor(s) that becomes more abundant upon exposure of Hepa 1c1c7 cells to tert-butylhydroquinone.
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PMID:Xenobiotic-inducible expression of murine glutathione S-transferase Ya subunit gene is controlled by an electrophile-responsive element. 216 52

The 1,2-dithiol-3-thiones are a class of five-membered cyclic sulfur compounds which have chemotherapeutic and chemoprotective properties. The parent 1,2-dithiol-3-thione nucleus and a series of six substituted analogs all induced NAD(P)H: quinone reductase (EC 1.6.99.2) activity and elevated glutathione levels in Hepa 1c1c7 murine hepatoma cells in culture thereby enhancing detoxification potential. These analogs included monosubstituted derivatives with phenyl, p-methoxyphenyl or 2-pyrazinyl groups at C-4 or C-5, and disubstituted compounds bearing phenyl or 2-pyrazinyl moieties at C-5 and an additional methyl group at C-4. This system can be used as an in vitro model for the study of the specificity and mechanism of action of the 1,2-dithiol-3-thiones as already demonstrated for several other classes of chemoprotective agents. The 1,2-dithiol-3-thiones also elevated quinone reductase and glutathione levels in the Hepa 1c1c7 cell mutants (BPrc1 and TAOBPrc1) that are defective in aryl hydrocarbon receptor functions. We conclude that the 1,2-dithiol-3-thiones are largely concerned with the stimulation of metabolic inactivation of electrophiles.
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PMID:1,2-Dithiol-3-thione analogs: effects on NAD(P)H:quinone reductase and glutathione levels in murine hepatoma cells. 370 58

Rat hepatoma H4IIE and mouse hepatoma Hepa 1c1c7 cells were transiently transfected with a plasmid construct that contained the bacterial chloramphenicol acetyltransferase (CAT) gene under the control of the mouse mammary tumor virus promoter and one copy of the dioxin responsive element. Treatment of transfected H4IIE and Hepa 1c1c7 cells with 10(-13) to 10(-6) M 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) resulted in a concentration-dependent increase in transient CAT activity. Maximum CAT activity was induced in both cell lines by exposure to 10(-9) M TCDD. The induction of CAT activity correlated well with the TCDD-induced, P4501A1-dependent ethoxyresorufin O-deethylase activity. Cotreatment of transfected cells with 10(-9) M TCDD and 10(-8) to 10(-6) M alpha-naphthoflavone (alpha NF) or 6-methyl-1,3,8-trichlorodibenzofuran (MCDF) resulted in a concentration-dependent reduction of TCDD-induced CAT activity. Treatment of cells with 10(-6) M alpha NF or MCDF alone resulted in only minimal induction of CAT activity. Both antagonists inhibited the induction of genes under the control of the CYP1A1 and mouse mammary tumor virus promoters, which indicates that the alpha NF- and MCDF-mediated antagonism of TCDD-induced, aryl hydrocarbon receptor-dependent gene transcription does not depend on promoter context.
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PMID:In vitro inhibition of 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced activity by alpha-naphthoflavone and 6-methyl-1,3,8-trichlorodibenzofuran using an aryl hydrocarbon (Ah)-responsive construct. 766 69

The aryl hydrocarbon receptor (AhR) and the AhR nuclear translocator protein (ARNT) are basic-helix-loop-helix-PAS (HLH) proteins involved in transcriptional regulation. Polycyclic aromatic halogenated chemicals, of which 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is the most potent, bind to the AhR. In the cellular cytoplasm, the AhR exists as a complex with the heat shock protein HSP90 and other small peptides. This complex dissociates following ligand binding and then the ligand-bound AhR binds ARNT. The ligand-AhR-ARNT complex interacts with a specific, nuclear DNA sequence, the dioxin response element (DRE), altering transcription of a regulated gene. Studies in hepatoma cell lines indicate that both proteins are required for regulation of transcription. In this study, AhR and ARNT were localized immunohistochemically in human embryonic palatal cells and specific patterns of expression were seen for each protein. A double-staining protocol revealed that epithelial cells expressed both AhR and ARNT, but in mesenchyme and nasal spine cartilage individual cells were identified which expressed either AhR or ARNT. This heterogeneous pattern may be a means of suppressing transcriptional regulation and also suggests the existence of other, unidentified basic-helix-loop-helix partner(s). The heterogeneous expression pattern may also reflect a complex role for these HLH proteins as transcriptional regulators of embryonic development.
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PMID:Immunohistochemical double-staining for Ah receptor and ARNT in human embryonic palatal shelves. 771 43

The effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD) and the coplanar 3,3',4,4'-tetrachlorobiphenyl (3,3',4,4'-TCB) and 3,3',4,4',5,5'-hexachlorobiphenyl (3,3',4,4',5,5'-HCB) on intercellular communication (IC) were determined in order to investigate the in vitro tumor promoting potency of these compounds. 2,3,7,8-TCDD and the two coplanar PCBs tested caused a rapid (2 hr) and a sustained inhibition (48 hr) of IC in the mouse hepatoma cell line (Hepa1c1c7) to 20 and 50% of the unexposed control, respectively. Inhibition of IC was dose dependent with an EC50 range of about 50-100 pM for 2,3,7,8-TCDD, 2-5 nM for 3,3',4,4'-TCB, and 10-15 nM for 3,3',4,4',5,5'-HCB, respectively. A comparison of the IC inhibitory effects of 2,3,7,8-TCDD and PCBs with a well-known aryl hydrocarbon receptor (AhR)-mediated response, the induction of ethoxyresorufin O-deethylase (EROD) activity, in the same cells revealed EROD induction by 2,3,7,8-TCDD, 3,3',4,4'-TCB, and 3,3',4,4',5,5'-HCB with EC50 ranges of 100-200 pM, 20-70 nM, and 5-10 nM, respectively. The time course of IC inhibition was paralleled by EROD induction, although the time of onset of the response was earlier for IC (1 hr) than for EROD (2.5 hr). A role of the AhR in the inhibition of IC by 2,3,7,8-TCDD and PCBs was demonstrated by the lack of inhibition in AhR-defective Hepa1c1c7 cells. Transient inhibition of IC was observed in the mutant cells only at early time points (within 2 hr of exposure). These results and the observation that alpha-naphtoflavone (an AhR antagonist) greatly reduced the 2,3,7,8-TCDD-dependent sustained inhibition of IC strongly support a role of the AhR in the sustained inhibition of IC by these compounds. Furthermore, these data suggest that the mouse Hepa1c1c7 cells may be a good model in which to study in vitro tumor promoting capacity of dioxins, PCBs, and related compounds.
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PMID:Inhibition of intercellular communication by 2,3,7,8-tetrachlorodibenzo-p-dioxin and dioxin-like PCBs in mouse hepatoma cells (Hepa1c1c7): involvement of the Ah receptor. 799 18

Polychlorinated biphenyls (PCBs) are nonplanar aromatic xenobiotics that are not structurally related to polychlorinated dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs), yet, some PCBs are potent ligands for the aryl hydrocarbon receptor (AhR), active inducers of aryl hydrocarbon hydroxylase (AHH) and 7-ethoxyresorufin O-deethylase (EROD), and elicit toxicological responses in animals similar to PCDDs and PCDFs. We report new methodologies for quantifying the affinities of PCBs for AhR and corresponding potencies as AHH and EROD inducers. The models show that lipophilicities, electron affinities, entropies and electronic energy gaps of PCBs are key physicochemical properties controlling their AhR, AHH and EROD activities. Using 3,3',4,4'-tetrachlorobiphenyl (TCB) as the reference compound, it is shown that PCBs having higher electron affinities, lower lipophilicities and entropies than TCB are potent ligands for rat hepatic AhR. In addition, the congeners having higher binding affinities to AhR and smaller energy gaps than TCB are potent AHH and EROD inducers in rat hepatoma cells in culture. The reported models qualitatively explain and quantify AhR, AHH and EROD activities of all 209-PCBs and related xenobiotics, e.g. PCDDs and PCDFs. Furthermore, we demonstrated that AhR and AHH activities of PCBs relative to 2,3,7,8-tetrachlorodibenzo-p-dioxin correlate with corresponding in vivo relative toxicities in animals as well as assigned toxic equivalency factors. The reported methodologies are likely to be useful for identifying potentially toxic aromatic xenobiotics in mammals, and minimizing the need for animal testing.
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PMID:Affinities for the aryl hydrocarbon receptor, potencies as aryl hydrocarbon hydroxylase inducers and relative toxicities of polychlorinated biphenyls. A congener specific approach. 822 55

A new mathematical model relating the affinities of aromatic xenobiotics for the aryl hydrocarbon receptor (AhR) to their potencies as aryl hydrocarbon hydroxylase (AHH) and 7-ethoxyresorufin O-deethylase inducers and toxic activities in animals is reported. Taking polychlorinated dibenzo-p-dioxins (PCDDs) as examples, the AHH activity of a PCDD relative to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is shown to be analytically related to corresponding relative affinities for AhR, and electronic energy gaps of PCDD and TCDD. (The electronic energy gap of a chemical is the difference between its ionization potential and electron affinity.) The reported model is capable of qualitatively explaining and quantitatively estimating potencies of PCDDs and related xenobiotics as AHH inducers in rat hepatoma H-4-II E cells in culture. Therefore, a PCDD is expected to be a potent AHH inducer if its affinity for AhR is high and has a smaller energy gap than TCDD. In addition, it is shown that the derived equations for AHH induction by PCDDs apply equally well to 7-ethoxyresorufin O-deethylase (EROD) activities; that is, there is a 1:1 correspondence between AHH and EROD activities for PCDDs, in agreement with experimental findings. Furthermore, in harmony with experimental observations, AHH (and EROD) activities of PCDDs relative to TCDD parallel the corresponding toxic equivalency factors and AhR mediated in vivo toxicities of these xenobiotics in animals, such as thymic atrophy, body weight loss, and acute lethalities. Moreover, the developed methodology for AHH and EROD induction by PCDDs is shown to apply to polychlorinated dibenzofurans, thus, eliminating cross-class comparison problem of traditional structure-activity studies.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Relationship between aryl hydrocarbon receptor binding, induction of aryl hydrocarbon hydroxylase and 7-ethoxyresorufin O-deethylase enzymes, and toxic activities of aromatic xenobiotics in animals. A new model. 839 39

Glucocorticoids are being found to influence expression of cytochrome P450 (CYP) genes in multiple subfamilies in mammals (J.S. Sidhu, and C.J. Omiecinski (1995) Pharmacogenetics 5, 24--36). In the present study we investigated CYP1A and CYP3A expression in the fish Poeciliopsis lucida hepatocellular carcinoma cell line (PLHC-1) after coadministration of CYP1A and CYP3A inducers, including glucocorticoids. A putative CYP3A protein is expressed in PLHC-1 cells but its content was not altered by exposure of cultures to the prototypical mammalian CYP3A inducers dexamethasone (DEX), pregnenolone-16 alpha-carbonitrile (PCN), or rifampicin (RIF). However, when coadministered with 3,3', 4,4'-tetrachlorobiphenyl or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), DEX but not PCN or RIF caused increases in the degree of CYP1A induction by these aryl hydrocarbon receptor (AHR) agonists. This increase was seen both in CYP1A protein content and rates of ethoxyresorufin-O-deethylase (EROD) activity. DEX alone caused no induction of CYP1A, indicating that the enhancement of CYP1A induction caused by DEX + AHR agonists was not an additive effect but rather a potentiation. The dose of DEX required for maximal potentiation was three orders of magnitude greater at 48 h than the dose required at 24 h. Moreover, the degree of potentiation of CYP1A induction was much greater at the lower doses than at the highest doses of TCDD. There was up to 20-fold potentiation of EROD induction in cultures exposed to 0.1 nM TCDD. Two other glucocorticoid receptor (GR) agonists, cortisol and prednisone, also produced a strong potentiation of CYP1A induction, but other mammalian CYP3A inducers that are not GR agonists, such as the anti-glucocorticoid PCN, the anti-mineralocorticoid spironolactone, or the macrolide antibiotics RIF and troleandomycin, did not potentiate the CYP1A induction in PLHC-1 cells. Addition of the mammalian GR antagonists PCN or RU 38486 reduced the DEX-mediated potentiation of CYP1A induction, whereas spironolactone had no effect on the potentiation. RU 38486 also potentiated the induction of EROD activity by the TCDD, which suggests that RU 38486 acts as a partial GR agonist in PLHC-1 cells. These results suggest that potentiation of CYP1A induction in this nonmammalian cell line proceeds by a classical GR-mediated pathway, independently of the expression of CYP3A. However, the complex interaction between doses of both GR and AHR agonists and duration of exposure, suggests that additional processes influence this potentiation. The unusually strong potentiation at lower doses of TCDD may make PLHC-1 cells particularly suitable in exploring further the consequences of this potentiation.
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PMID:Cytochromes P450 (CYP) in the Poeciliopsis lucida hepatocellular carcinoma cell line (PLHC-1): dose- and time-dependent glucocorticoid potentiation of CYP1A induction without induction of CYP3A. 861 27


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