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 induction of CYP2B gene expression by phenobarbital (PB) is mediated by the translocation of the constitutive androstane receptor (CAR) from the cytoplasm to the nucleus. The CAR/RXR heterodimer binds to two DR-4 sites in a complex phenobarbital responsive unit (PBRU) in the CYP2B gene. The short heterodimer partner (SHP), an orphan nuclear receptor that lacks a conventional DNA binding domain, was initially identified by its interaction with CAR. We have examined the role of SHP in CAR-mediated transactivation of the CYP2B gene. Coexpression of SHP inhibited the transactivation of the CYP2B gene by CAR in cultured hepatoma cells and the p160 coactivator GRIP1 reversed the inhibition. The interaction of CAR with SHP was confirmed by GST pulldown experiments. SHP did not block the binding of either CAR/RXR to the PBRU or binding of GRIP1 to the CAR/RXR complex in gel mobility shift assays, but slightly increased CAR/RXR binding and slightly altered the mobility of the CAR/RXR/GRIP1 complex, suggesting an interaction of SHP with these complexes. The presence of SHP in the complexes, however, could not be detected in an antibody supershift assay. Recombinant corepressors mSin3A, SMRT, and HDAC1, but not NCoR1, interacted with GST-SHP but each of these corepressors in liver nuclear extracts bound to GST-SHP. SMRT and NCoR1 inhibited CAR-mediated activation independent of SHP, but mSin3A and HDAC1 had little effect alone, and were additive with SHP. These studies demonstrate that SHP does not inhibit CAR-mediated trans-activation by interfering with DNA binding or by competition with GRIP1. Instead, SHP may either inhibit recruitment of other coactivators by GRIP1 or actively recruit corepressors directly to the CAR/RXR/PBRU complex.
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PMID:Repression of CAR-mediated transactivation of CYP2B genes by the orphan nuclear receptor, short heterodimer partner (SHP). 1500 Jul 48

Both simultaneous and sequential exposure to heavy metals and aryl hydrocarbon receptor (AHR)-ligands potentially occur in human populations, yet there have been relatively few studies of combined effects of heavy metals and AHR-ligands on AHR-regulated genes. To investigate the effects of heavy metals on AHR-regulated genes; cytochrome P450 1a1 (cyp1a1), NAD(P)H:quinone oxidoreductase (QOR) and glutathione S-transferase Ya (GST Ya), murine hepatoma Hepa 1c1c7 cells were incubated with increasing concentrations of Hg2+ (2.5-10 microM), Pb2+ (10-100 microM), and Cu2+ (1-100 microM) alone or with the AHR-ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (0.1 nM), 3-methylcholanthrene (0.25 microM), beta-naphthoflavone (10 microM), or benzo[a]pyrene (1 microM). The results clearly showed that metals alone did not significantly alter the cyp1a1 activity and protein levels but increased its mRNA expression, whereas a significant reduction in AHR ligand-mediated induction of cyp1a1 activity was observed by all metals. The decrease in cyp1a1 activity was associated with an increase, no change, or decrease in cyp1a1 mRNA and protein levels by Hg2+, Pb2+ and Cu2+ respectively, suggesting pre- and post-transcription mechanisms are involved. With respect to QOR, the activity and mRNA levels were increased by all metals in the absence or presence of an AHR-ligand, with the exception of Cu2+ which significantly decreased the induction of QOR. Differently, GST Ya activity was significantly increased by Cu2+ and Pb2+ and inhibited by Hg2+, while its mRNA was increased by Hg2+ and Pb2+ and decreased by Cu2+. All metals significantly increased the expression of heme oxygenase-1, which coincided with the changes in the phase I and phase II enzyme activities. These results demonstrate that heavy metals differentially modulate the constitutive and the inducible expression of AHR-regulated genes.
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PMID:Differential effects of mercury, lead and copper on the constitutive and inducible expression of aryl hydrocarbon receptor (AHR)-regulated genes in cultured hepatoma Hepa 1c1c7 cells. 1529 30

Aryl hydrocarbon receptor (AhR) ligands and heavy metals are environmental co-contaminants and their molecular interaction may disrupt the coordinated regulation of AhR-dependent phase I and II drug metabolizing enzymes. To determine the effect of heavy metals on the AhR-regulated genes: cytochrome P4501A1 (Cyp1a1), NAD(P)H: quinone oxidoreductase (QOR) and glutathione S-transferase Ya (GST Ya), murine hepatoma Hepa 1c1c7 cells were treated with increasing concentrations of As3+ (1-10 microM), Cd2+ (1-25 microM) and Cr6+ (1-25 microM) with or without the AhR ligands: 2,3,7,8-tetrachlorodibenzo-p-dioxin (0.1 nM), 3-methylcholanthrene (0.25 microM), beta-naphthoflavone (10 uM), or benzo[a]pyrene (1 microM). Our results show that AhR ligands alone and As3+ or Cd2+ alone increased the catalytic activities and mRNA levels of all AhR-regulated genes. When metals were co-administered with an AhR ligand, all three metals inhibited the induction of Cyp1a1 activity by the AhR ligands but potentiated its mRNA and protein expression. In addition, all metals enhanced QOR and GST Ya at the activity and mRNA levels but modulated their induction by AhR ligands in a concentration, metal, and AhR ligand-dependent manner. Generally, Cr6+ inhibited while As3+ and Cd2+ potentiated the induction of QOR and GST Ya activities and mRNA levels. The three metals enhanced the expression of heme oxygenase-1, which coincided with the changes in the phase I and phase II enzyme activities. These results show that the ability of metals to alter the capacity of AhR ligands to induce the bioactivating phase I and the detoxifying phase II enzymes will influence the carcinogenicity and mutagenicity of the AhR ligands.
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PMID:Modulation of aryl hydrocarbon receptor-regulated gene expression by arsenite, cadmium, and chromium. 1533 87

The carcinogen-resistant inbred rat strain DRH established from closed-colony Donryu rats by use of selective brother-sister mating over 20 generations under continuous feeding of 3'-methyl-4-dimethylaminoazobenzene (3'-Me-DAB) maintains a highly resistant phenotype without carcinogen exposure for many years. We reported that the clonal expansion of preneoplastic glutathione S-transferase-P(GST-P)-positive foci induced by 3'-Me-DAB was less extensive in the liver of DRH rats than in the liver of susceptible strains, such as Donryu and F344, although levels of DNA adducts were comparable among these rats. Comparative studies of the events after initiation indicate that DRH rats are constitutionally less prone to cellular damage caused by continuous administration of 3'-Me-DAB than are parental Donryu rats. Consequently, the reduced growth response of the liver during the promotion stage may contribute to the low susceptibility to development of liver tumors. Genetic analysis of (F344 x DRH)F2 rats identified two quantitative trait loci, Drh1 on chromosome 1 and Drh2 on chromosome 4, which provide resistance to the development of GST-P-positive preneoplastic foci induced by 3'-Me-DAB during the early stage of its administration. The resistance to progression to hepatocellular carcinoma is affected solely by Drh2. These observations indicate that at least two genetic loci are critically involved in the steps leading to chemical hepatocarcinogenesis. The DRH rat is a useful experimental model with which to study genetic susceptibility and resistance to chemically induced liver cancers.
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PMID:Genetic resistance to chemical hepatocarcinogenesis in the DRH rat strain. 1535 16

We tried to identify a novel marker characteristic for rat hepatocellular preneoplastic and neoplastic lesions, undetectable by well established cytochemical markers. Glutathione S-transferase placental (GST-P)-negative hepatocellular altered foci (HAF), hepatocellular adenoma (HCA), and hepatocellular carcinoma (HCC) were generated by two initiation-promotion models with N-nitrosodiethylamine (NDEN) and peroxisome proliferators, Wy-14,643 and clofibrate. Total RNAs isolated from laser-microdissected GST-P-negative HAF (amphophilic cell foci) and adjacent normal tissues were applied to microarray analysis. As a result, five up-regulated genes were identified, and further detailed examinations of the gene demonstrating most fluctuation, ie, that for alpha(2)-macroglobulin (alpha(2)M) were performed. In reverse transcriptase-polymerase chain reaction, alpha(2)M mRNA was overexpressed not only in amphophilic GST-P-negative HAF but also in amphophilic GST-P-negative HCA and HCC. In situ hybridization showed accumulation of alpha(2)M mRNA to be evenly distributed within GST-P-negative HAF (predominantly amphophilic cell foci). Distinctive immunohistochemical staining for alpha(2)M could be consistently demonstrated in GST-P-negative HAF, HCA, and HCC induced not only by peroxisome proliferators but also N-nitrosodiethylamine alone. Thus our findings suggest that alpha(2)M is an important novel cytochemical marker to identify hepatocellular preneoplastic and neoplastic lesions, particularly amphophilic cell foci, undetectable by established cytochemical markers and is tightly linked to rat hepatocarcinogenesis.
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PMID:alpha(2)-Macroglobulin: a novel cytochemical marker characterizing preneoplastic and neoplastic rat liver lesions negative for hitherto established cytochemical markers. 1550 19

Epirubicin HCl is a new anthracycline analog and derivative of doxorubicin. Doxorubicin is a potent anticancer agent, the use of which is limited by its cumulative dose-dependent cardiotoxicity. Epirubicin HCl has more favorable therapeutic index than doxorubicin and possesses less hematologic and cardiac toxicity at comparable doses. Hepatoma G2 cells are a valuable model to study hepatocellular carcinoma and the liver, where drugs are metabolized. The goal of our study was to evaluate the cytotoxic effect of epirubicin HCl on viability of Hep G2 cells measured using the MTT cytotoxicity test. Epirubicin HCl produced a concentration- and time-dependent cytotoxicity to Hep G2 cells. The mechanism of cytotoxicity of epirubicin HCl (IC(50) value of 1.6 mug/ml within 24 h) appeared to involve a production of free radical species since activities of free radical scavenging enzymes (SOD, catalase, Se-dependent GPx) were increased. Addition of SOD prevented cytotoxicity of epirubicin HCl, and also counteracted the apoptosis. DNA fragmentation was determined to evaluate apoptosis. Western blot analysis indicated a decrease in GST-pi expression and increased activity of NADPH-dependent cytochrome P450 reductase which is a major enzyme in the conversion of epirubicin HCl to a free radical. It is proposed that production of reactive oxygen species increased by the treatment with epirubicin HCl can cause lipid peroxidation, which subsequently promotes apoptosis and reduces cell viability. Superoxide dismutase, catalase and glutathione peroxidase must be considered as a part of the intracellular antioxidant defense mechanism of Hep G2 cells against single electron reducing quinone-containing anticancer antibiotics.
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PMID:Epirubicin HCl toxicity in human-liver derived hepatoma G2 cells. 1552 Apr 98

Although much is known concerning the effects of inflammation and oxidative stress on the cytochrome P450 1A1 (CYP1A1), little is known about the modulation of other aryl hydrocarbon receptor (AHR)-regulated genes such as glutathione-S-transferase Ya (GST Ya) and NAD(P)H:quinone oxidoreductase (QOR) by inflammation. In the present study, the effect of tumor necrosis factor (TNF)-alpha and lipopolysaccharides (LPS) on the constitutive and inducible expression of the AHR-regulated genes cyp1a1, GST Ya, and QOR was determined in murine hepatoma Hepa 1c1c7 (WT), AHR-deficient (C12), and AHR nuclear translocator protein (ARNT)-deficient (C4) cells. We found that both TNF-alpha and LPS strongly repressed the constitutive expression and the beta-naphthoflavone-mediated induction of cyp1a1, GST Ya, and QOR in WT but not in C12 and C4 cells. The induction of GST Ya and QOR activities and mRNA levels by phenolic antioxidant, tert-butylhydroquinone, through the antioxidant response element was not significantly affected by TNF-alpha or LPS. In addition, a significant increase in reactive oxygen species was observed in WT, C12, and C4 cells treated with TNF-alpha or LPS which was completely prevented by tert-butylhydroquinone. These results show that the down-regulation of AHR-regulated genes by TNF-alpha and LPS is dependent on the presence of both heterodimeric transcription factors, AHR and ARNT. Furthermore, reactive oxygen species may be involved in the down-regulation of AHR-regulated genes.
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PMID:Down-regulation of aryl hydrocarbon receptor-regulated genes by tumor necrosis factor-alpha and lipopolysaccharide in murine hepatoma Hepa 1c1c7 cells. 1562 57

The transcription factor nuclear factor-kappa B (NF-kappaB) subunit p65 is phosphorylated by IkappaB kinase (IKK) at S536 in transactivation domain (TAD) 1. In this study, we investigate the presence of IKK sites in TAD2 of p65. Recombinant IKKbeta, but not IKKalpha, phosphorylated a GST-p65 substrate in which TAD1 was deleted. Mutational analysis revealed S468 as the only IKK site in TAD2. S468 phosphorylation occurred rapidly after TNF-alpha and IL-1beta in T cell, B cell, cervix carcinoma, hepatoma, breast cancer, and astrocytoma lines and in primary hepatic stellate cells as well as peripheral blood mononuclear cells. S468-phosphorylated p65 coimmunoprecipitated with IkappaBalpha, indicating that p65 is phosphorylated while bound to IkappaBalpha. Dominant negative IKKbeta or pharmacological IKK inhibition blocked S468 phosphorylation after TNF-alpha or IL-1beta, whereas dominant negative IKKalpha or inhibitors of MEK, p38, JNK, PI-3 kinase, or GSK-3 had no effect. p65S468A-reconstituted p65-/- mouse embryonic fibroblasts (MEFs) showed a small, but significant, elevation of NF-kappaB-driven luciferase activity and RANTES mRNA levels after TNF-alpha and IL-1beta in comparison to wtp65-reconstituted MEFs. p65 nuclear translocation was not altered in p65S468A-expressing MEFs. In conclusion, our results indicate that 1) IKKbeta phosphorylates multiple p65 sites, 2) IKKbeta phosphorylates p65 in an IkappaB-p65 complex, and 3) S468 phosphorylation slightly reduces TNF-alpha- and IL-1beta-induced NF-kappaB activation.
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PMID:IKKbeta phosphorylates p65 at S468 in transactivaton domain 2. 1604 71

Hepatitis B virus X protein (HBx) has many cellular functions and is a major factor in hepatitis and hepatocellular carcinoma caused by HBV infection. A proteomic approach was used to search for HBx-interacting proteins in order to elucidate the molecular mechanism of hepatocarcinogenesis. HBx was attached to myc and flag tags (MEF tags) and expressed in 293T cells; the protein complex formed within the cells was purified and characterized by mass spectrometry. COP9 signalosome (CSN) subunits 3 and 4 were subsequently identified as HBx-interacting proteins. In addition, CSN subunit 5, Jun activation domain-binding protein 1 (Jab1), was shown to be a novel cellular target of HBx. In vivo and in vitro interactions between HBx and Jab1 were confirmed by standard immunoprecipitation and GST pull-down assays. An analysis of HBx deletion constructs showed that amino acids 30-125 of HBx were responsible for binding to Jab1. Confocal laser microscopy demonstrated that HBx was mainly localized in the cytoplasm, while Jab1 was found mainly in the nucleus and partially in the cytoplasm, and that the two proteins colocalized in the cytoplasm. The cotransfection of HBx and Jab1 resulted in substantial activator protein 1 (AP-1) activation and knockdown of endogenous Jab1 attenuated AP-1 activation caused by HBx. In addition, the coexpression of HBx and Jab1 potentiated phosphorylation of JNK, leading to the subsequent phosphorylation of c-Jun, whereas the level of c-Jun and JNK phosphorylation induced by HBx was decreased in Jab1 knockdown cells. These results suggest that the interaction between HBx and Jab1 enhances HBx-mediated AP-1 activation.
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PMID:The hepatitis B virus X protein enhances AP-1 activation through interaction with Jab1. 1624 77

Aflatoxin B1 (AFB1) has been classified as a category I human carcinogen, which is responsible for a high incidence of hepatocellular carcinoma. Since exposure to AFB1 can occur through skin contact in addition to ingestion and inhalation, the carcinogenic potential of topically applied AFB1 on mouse skin was investigated. Our results show that single topical application of AFB1 (80 nmol) as a tumor initiator, followed by twice weekly application of 12-tetradecanoyl phorbol myristate acetate (TPA, 4 nmol), resulted in tumor formation after 13 weeks. However, no tumorigenic potential was observed when AFB1 (16 nmol) was used either as a complete carcinogen or as a tumor promoter (4 nmol). Histological analysis of skin showed squamous cell carcinoma in the AFB1/TPA treated group. The application of AFB1 as a complete carcinogen, an initiator or a promoter after 24 weeks demonstrated widespread degenerative and necrotic changes in hepatic tissue as well, suggesting liver to be the target organ following percutaneous absorption. Additionally, twice weekly topical application of AFB1 caused significant induction of cutaneous CYP IA monoxygenases without any effect on hepatic levels while glutathione-S-transferase activity was induced more in the liver than skin. The topical application of AFB1 also resulted in increased hepatic and cutaneous lipid peroxidation with concomitant depletion of glutathione content. It is likely that due to higher induction of hepatic GST activity, products of lipid peroxidation may be detoxified and therefore unable to cause DNA damage making mice resistant to hepatic tumor formation. The overall results indicate a tumor initiating potential of AFB1 in mice and suggest that continued dermal exposure of AFB1, even at low doses, might lead to degenerative changes in hepatocytes.
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PMID:Skin tumorigenic potential of aflatoxin B1 in mice. 1629 33


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