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 volume of aqueous solvent present during subcellular fractionation of mouse hepatoma (Hepa 1c1c7) cells influences the distribution of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) receptors between the nuclear and cytosolic fractions. When the effects of dilution are minimized, at least 80% of the receptors associate with nuclei. The receptors bind relatively strongly to nuclei, as measured by their release by KCl. TCDD-receptor complexes bind more strongly to nuclei than do unoccupied receptors. A temperature-dependent event further enhances the binding of TCDD-receptor complexes to nuclei. A class of variant cells contains receptors which bind relatively weakly to nuclei; this defect accounts for the variant phenotype. We conclude that, in the intact cell, TCDD receptors are located within the nucleus and that the temperature-dependent event in the induction of cytochrome P1-450 gene expression is one which strengthens the binding of the TCDD-receptor complex to chromatin.
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PMID:2,3,7,8-Tetrachlorodibenzo-p-dioxin receptors in wild type and variant mouse hepatoma cells. Nuclear location and strength of nuclear binding. 631 94

Using the fluorescence-activated cell sorter, we have isolated a population of variant mouse hepatoma cells which have a markedly increased ability to metabolize benzo(a)pyrene. Compared with wild-type (Hepa 1c1c7) cells, the variant cells exhibit increased aryl hydrocarbon hydroxylase activity and increased responsiveness of the aryl hydrocarbon hydroxylase induction mechanism to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Cell fusion experiments indicate that the variant phenotype is co-dominant with respect to wild-type. Filter hybridization analyses indicate that increased accumulation of cytochrome P1-450-specific mRNA accounts for the overproduction of aryl hydrocarbon hydroxylase activity. Measurements of RNA synthesis in isolated nuclei reveal that the variants exhibit an increased rate of transcription of the cytochrome P1-450 gene in response to TCDD. The variant cells contain no detectable alteration in their TCDD receptors, nor is the cytochrome P1-450 gene amplified in the variants. Filter hybridization analyses of restriction endonuclease-digested DNA indicate that the variant cytochrome P1-450 gene is relatively undermethylated, compared with the wild-type gene. We conclude that the variant cells contain an altered cis-acting genomic element(s) which regulates the expression of the cytochrome P1-450 gene.
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PMID:Biochemical and genetic analysis of variant mouse hepatoma cells which overtranscribe the cytochrome P1-450 gene in response to 2,3,7,8-tetrachlorodibenzo-p-dioxin. 649 Jun 16

Using RNA synthesized in isolated nuclei, we have measured the effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on the rate of synthesis of cytochrome P1-450 mRNA in wild type mouse hepatoma (Hepa 1c1c7) cells and in variant (BPrc1) cells, which fail to accumulate the TCDD-receptor complex within the nucleus. In wild type cells, TCDD induces a 20-fold increase in the rate of synthesis of cytochrome P1-450 mRNA within 30 min. This effect persists for at least 18 h. In contrast, TCDD has no effect on cytochrome P1-450 mRNA synthesis in the variant cells. The results demonstrate that TCDD increases the rate of transcription of the cytochrome P1-450 gene and suggest that transcription requires nuclear localization of the TCDD-receptor complex.
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PMID:Regulation of cytochrome P1-450 gene transcription by 2,3,7, 8-tetrachlorodibenzo-p-dioxin in wild type and variant mouse hepatoma cells. 671 50

Fractions containing polycyclic aromatic hydrocarbons (PAHs), polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) and polychlorinated biphenyls (PCBs) were extracted from river sediments by various extraction methods. The amount of individual pollutants was determined analytically and data compared with biological assays. These were based on the induction of cytochrome P450 1A1 (CYPIA1) after treatment with sediment fractions in two different biological model systems, a mouse hepatoma cell line Hepa-1 and a chick embryo. In the hepatoma cell culture Hepa-1 significant correlations with analytical results were found for fractions containing PCDD/Fs and planar and mono-ortho-chlorinated PCBs. However for PAH fraction an undesirable decrease of P450 1A1 induction was observed in higher concentrations of this fraction. This decrease was not observed in the chick embryo liver microsomes and biological responses towards the PAH fractions correlated with analytical data. Comparative investigations demonstrated that the chicken embryo hepatic microsomes were more sensitive for PAHs, and the hepatoma cell line Hepa-1 for PCDD/Fs and planar and mono-ortho-chlorinated PCBs.
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PMID:Biochemical screening of highly toxic aromatic contaminants in river sediment and comparison of sensitivity of biological model systems. 774 25

The induction of cytochrome P450IA1 (CYP1A1) activity in human hepatoma cell lines has been used as a model response for exposure to the environmental contaminant, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). CYP1A1 induction is mediated by the intracellular Ah receptor. We have designed a cell culture analogue system to evaluate the effect of low dose continuous exposures to TCDD such that the responses can be compared with traditional static in vitro exposures. The two-compartment model is designed to mimic aspects of time-dependent dose exposure in humans and consists of a 'liver' compartment with HepG2 cells and an 'other tissues' compartment. Exposure of microcarrier-attached HepG2 cells in spinner flask to a single dose of TCDD resulted in an EC(50) for ethoxyresorufin-o-deethylase (EROD) activity induction of 1.49nm. Using a one-compartment reactor with continuous TCDD dosing resulted in an EC(50) for EROD induction of 0.69nm TCDD. Finally, using a two-compartment reactor with continuous TCDD dosing resulted in an EC(50) for EROD induction of about 0.05nm. Parallel studies using (3)H-TCDD were performed to determine the amount of cell associated (3)H-TCDD and subsequently to estimate the amount of bound Ah receptor. CYPIA1 mediated EROD activities in both cell lines correlated with the estimated amount of bound Ah receptor. To illustrate how these systems might alter estimates of risk, the data were evaluated to estimate the TCDD level which would increase CYPIA1 mediated EROD activity to 0.01% of the maximal response. The two-compartment reactor data yielded an estimate of allowable TCDD exposure of 1x10(-5)nm for an acceptable 'risk' level of 0.01%. In contrast, values were estimated as 4x10(-4)nm from the one compartment reactor and 4x10(-3)nm from spinner flasks. This work demonstrates the importance of design of the in vitro system on risk assessment.
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PMID:Different In Vitro Systems Affect CYPIA1 Activity in Response to 2,3,7,8-Tetrachlorodibenzo-p-dioxin. 2065 8


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