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)

Cultured murine hepatoma 1c1c7 cells were treated with either the actin filament-disrupting drug cytochalasin D or the microtubule inhibitors colchicine and nocadazole (NOC) to assess the role of the cytoskeleton in the process of cytochrome P450 Cyp1a-1 induction. Indirect fluorescence analyses demonstrated that microtubule or actin networks were disrupted within 1 hr of treatment and remained altered as long as cultures were maintained in the presence of the drugs. Treatment of cultures with cytochalasin D, colchicine, or NOC for 1 hr before the addition of dibenz[a,c]anthracene had no effect of Cyp1a-1 induction, as monitored by measurements of CYP1A1 mRNA. Pretreatment with NOC for > or = 18 hr produced populations of cells that had either a flat or rounded morphology. Both populations, when isolated 20-24 hr after NOC treatment, were arrested in the G2/M phase of the cell cycle (83-98% in G2/M versus approximately 7-10% in nontreated or solvent-treated cultures). Cyp1a-1 induction was suppressed in both of these populations, as monitored by measurement of CYP1A1 mRNA content (reductions of > 68%), 7-ethoxyresorufin O-deethylase activity (reductions of > 80%), or microsomal CYP1A1 protein content (reductions of > 80%). In contrast, overall [3H]leucine incorporation into protein was not affected. Cytosol prepared from these NOC-treated cultures bound approximately 39% of the radiolabeled 2,3,7,8-tetrachlorodibenzo-p-dioxin bound by cytosol isolated from solvent-treated cultures. Nuclear extracts prepared from cultures treated with NOC for 20-24 hr before in vivo exposure to inducer and cytoplasmic extracts isolated from similarly NOC-treated cultures that were exposed to inducer in vitro demonstrated reductions of > or = 54% and > or = 55%, respectively, in their abilities to bind to DNA, when analyzed by gel retardation analyses using an oligonucleotide corresponding to dioxin-responsive element D of the Cyp1a-1 gene. These studies suggest that ligand-dependent induction of Cyp1a-1 transcription is unaffected by short term disruption of the microfilament or microtubule network. However, long term exposure to microtubule inhibitors causes cells to pause in the G2/M stage of the cell cycle and modulates processes involved in the induction of Cyp1a-1 in these cells.
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PMID:Short and long term effects of cytoskeleton-disrupting drugs on cytochrome P450 Cyp1a-1 induction in murine hepatoma 1c1c7 cells: suppression by the microtubule inhibitor nocodazole. 819 Jan 10

1. Rat hepatoma 27 after intrahepatic transplantation shows a low but detectable level of cytochrome P450 and P450-dependent activities. The same hepatoma transplanted intramuscularly does not show a detectable amount of cytochrome P450 and P450-dependent activities. 2. Different types of cytochrome P4501A inducers were able to induce 1A isoforms in the intrahepatic hepatoma 27 transplants but not in the intramuscular transplants. 3. Immunohistochemical analysis demonstrates that not all cells in hepatoma 27 transplanted into the liver could be induced with 1A-inducer. The cells of the adenomatous structures of hepatoma 27 are not reactive with 1A antibodies.
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PMID:Regulation of CYP1A induction in hepatoma 27 depending on the site of transplantation. 821 43

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

Metabolism of the synthetic steroid 17 beta-hydroxy-11 beta-(4-dimethylaminophenyl)17 alpha-1-propynyl-estra-4,9-dien-3-one (RU486) occurs in the dedifferentiated S-H56-125 variant of Reuber hepatoma. Considering that rat liver cytochrome P450 (P450) monooxygenases are engaged in different oxidative steps of the metabolism of RU486, the influence of several prototype P450 inducers was investigated. The data obtained by treating H56 and S-H56-125 hepatoma cells with different P450 inducers (dexamethasone (DEX), benzanthracene, phenobarbital) or with a specific P450 inhibitor, troleandomycin, led us to conclude that CYP3A is involved in the hydroxylation of RU486. This form is induced by DEX independently of the availability of the canonical glucocorticoid receptor.
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PMID:Biotransformation of 17 beta-hydroxy-11 beta-(4-dimethylaminophenyl)17 alpha-1-propynyl-estra-4,9-dien-3-one (RU486) in rat hepatoma variants. 826 60

Selective induction in vitro of cytochrome P450-dependent mixed-function oxidase (MFO) and UDP-glucuronyltransferase (GT) activities was observed in the human HepG2 hepatoma cell line. 1,2-Benzanthracene (BA) induced MFO O-dealkylation activities for ethoxyresorufin, methoxyresorufin and benzyloxyresorufin, whereas phenobarbitone (PB) selectively induced pentoxyresorufin O-dealkylation and rifampicin (RIF) selectively induced benzyloxyresorufin O-dealkylation. Antibody inhibition experiments indicated that ethoxyresorufin and methoxyresorufin O-dealkylations were catalysed mainly by the P450 1A subfamily in untreated and BA-induced HepG2 cells, that additional unidentified P450 forms were considerably involved in methoxyresorufin and benzyloxyresorufin O-dealkylations and that the P450 2B subfamily was partially responsible for pentoxyresorufin O-dealkylation in PB-induced cells. Bilirubin GT activity was induced by PB, BA, RIF and dexamethasone, but 1-naphthol, morphine and testosterone GT activities were not induced by any of these treatments.
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PMID:The effects of inducing agents on cytochrome P450 and UDP-glucuronyltransferase activities in human HEPG2 hepatoma cells. 839 42

Polychlorinated biphenyls (PCBs) are industrial chemicals which have been detected in fish, birds and humans. They are known to exert marked effects on the liver. They induce hepatocellular carcinoma in rats and birds, and are suspected of being carcinogenic to humans. To better understand the genotoxic effects of PCBs, we used 32P-postlabelling to investigate DNA adduct formation, after exposure to PCBs (Aroclor 1254 and 3,3',4,4'-tetrachlorobiphenyl), in primary cultures of fetal hepatocytes from two animal species and in a human cell line (Hep G2). We also studied the induction of 7-ethoxyresorufin-O-deethylase (EROD) in these PCB-treated cells. The three cell types used are known to express different cytochrome P450 families. The aim was to see whether a correlation could be established between EROD activity (a CYP1A1-related activity) and DNA adduct formation. DNA adducts were found in all three models after exposure to 50 microM 3,3',4,4'-tetrachlorobiphenyl. The number of adducts was higher in quail hepatocytes (37 adducts per 10(9) nucleotides) than in rat hepatocytes or Hep G2 cells (20 adducts per 10(9) nucleotides in both cases). The major adduct was the same in all three cell types, but some adducts were found in only one or two species. These inter-species differences probably reflect metabolic differences leading to different ultimate carcinogens. Exposure to Aroclor 1254 failed to produce significant levels of DNA adducts, suggesting that pre-treated cells are required to magnify Aroclor 1254 metabolism. No correlation was found between adduct formation and the level of EROD induction.
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PMID:DNA adducts and P450 induction in human, rat and avian liver cells after exposure to polychlorobiphenyls. 855 39

Exposure of iron-loaded C57BL/10ScSn mice to the polychlorinated biphenyls (PCBs) mixture Aroclor 1254 in the diet (0.01%) for 5 weeks caused massive hepatic porphyria far greater than occurred with PCBs alone. This regime eventually causes hepatocellular carcinoma. Hepatic microsomal ethoxy-, pentoxy-, and benzyloxyresorufin dealkylase activities (respectively EROD, PROD, and BROD) catalyzed primarily by cytochrome P4501A1 and 2B isoenzymes were markedly induced after 2 weeks of diet (when no porphyria had developed) but showed little effect of iron. EROD activity in the nuclear membrane was also induced by the PCBs as was CYP1A1 protein when shown by immunoblotting. Nuclear dealkylase activities of PCBs-treated mice were considerably less than microsomal activities but were stimulated by iron pretreatment. The mechanism of the iron-enhanced toxicity may be due to oxidative damage associated with chronic induction of CYP1A1 isoforms. Lucigenin-enhanced chemiluminescence (CL) by microsomes and nuclear membranes was used as a method to estimate their potential to form reactive oxygen species. Despite CL being induced by PCBs it was less with microsomes from iron-treated mice. In a comparison of a variety of inducers of microsomal cytochrome P450 there was no correlation between inducer, uroporphyrogenic agent, and intensity of CL. On the other hand, cytosolic glutathione S-transferase (GST) activities with 1-chloro-2,4-dinitrobenzene and 1,2-dichloro-4-nitrobenzene (DCNB) as substrates, were also induced by the PCBs mixture, the induction with DCNB being synergistically potentiated by iron pretreatment. Complementary results were observed by immunocytochemistry using anti alpha-GST antibody. In contrast, total glutathione peroxidase activity and selenium-dependent glutathione peroxidase activity were depressed by PCBs but particularly in mice also administered iron. The results illustrate that PCBs not only induce CYP1A1 in microsomes but also in the nuclear membrane, which may be of significance in the mechanism of the iron-enhanced carcinogenicity of these chemicals. The iron-enhanced induction of GST with accompanying depletion of glutathione peroxidase provides evidence for oxidative processes induced in vivo by the PCBs.
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PMID:Modulation by iron of hepatic microsomal and nuclear cytochrome P450, and cytosolic glutathione S-transferase and peroxidase in C57BL/10ScSn mice induced with polychlorinated biphenyls (Aroclor 1254). 856 Apr 83

1. Mechanisms of drug toxicity operating in human HepG2 hepatoma cells have been assessed using cyclosporin A (CsA) and tamoxifen as examples. 2. Either 150 microM CsA or 50 microM tamoxifen caused approximately 50% loss of HepG2 cell viability. alpha-Tocopherol (32 microM) almost completely prevented cell death due to either CsA or tamoxifen. Tamoxifen stimulated malondialdehyde formation. The toxicity of CsA but not tamoxifen was increased by the glutathione synthesis inhibitor, buthionine-S,R-sulphoximine, and decreased by the glutathione precursor, L-cysteine. Thus, while both CsA and tamoxifen toxicities involved lipid peroxidation, reduced glutathione (or sulphydryl groups) protected against CsA but not tamoxifen. 3. CsA was metabolized to M1 and/or M17 in HepG2 cells. The effects of the cytochrome P450 inhibitors, ketoconazole and metyrapone, indicated that P450 played a role in the toxicity of CsA but not tamoxifen. The effects of superoxide dismutase and cytochrome c indicated that tamoxifen toxicity involved superoxide formation. 4. These results show that several oxidative mechanisms of drug toxicity operate in HepG2 cells.
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PMID:Drug toxicity mechanisms in human hepatoma HepG2 cells: cyclosporin A and tamoxifen. 857 71

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

Sterol biosynthesis requires the removal of the 14 alpha-methyl group from lanosterol in animals and fungi and from obtusifoliol in plants. This reaction is catalyzed by a microsomal cytochrome P450, the sterol 14 alpha-demethylase (P450(14DM), which is the only P450 described so far to be expressed in different phyla. A cDNA encoding human P450(14DM) was isolated from a liver cDNA library using a partial rat lanosterol 14 alpha-demethylase cDNA probe. The deduced amino acid sequence is 93% and 38--42% identical to rat and fungal P450(14DM), respectively. Expression of the human CYP51 cDNA in Escherichia coli showed that the cDNA encodes an enzyme having lanosterol 14 alpha-demethylase activity. Northern blot analysis showed that CYP51 mRNA is ubiquitously expressed with highest levels in testis, ovary, adrenal, prostate, liver, kidney, and lung. Many genes involved in cholesterol homeostasis are regulated by cholesterol or its metabolites. In the case of CYP51, cholesterol deprivation led to a 2.6- to 3.8-fold induction of mRNA levels in human adrenocortical H295R cells and this effect was suppressed by the addition of 25-hydroxycholesterol. In human hepatoma HepG2 cells, no effect of cholesterol deprivation was observed; however, the levels of CYP51 mRNA were reduced 4- to 6-fold by the addition of 25-hydroxycholesterol. Thus, like several other genes in the cholesterol biosynthetic pathway, including the 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) synthase, HMG CoA reductase, squalene synthase, and farnesyl diphosphate synthase, the expression of the human CYP51 is suppressed by oxysterols.
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PMID:The ubiquitously expressed human CYP51 encodes lanosterol 14 alpha-demethylase, a cytochrome P450 whose expression is regulated by oxysterols. 861 37


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