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

The genotoxicity of polycyclic aromatic hydrocarbons (PAHs) and nitrated PAHs may be influenced by the interaction of the compounds. In this study, our data showed that benzo[a]pyrene (BaP)-DNA adduct levels were decreased in a dose-dependent manner when the human hepatoma cell line HepG2 simultaneously treated with BaP and 1-nitropyrene (1-NP). To further investigate the molecular mechanism by which 1-NP interferes with the covalent binding of BaP to DNA, we conducted experiments to analyze the mRNA level and protein stability of cytochrome P450 1A1 (CYP1A1), which is engaged in the activation of BaP, leading to the generation of BaP-DNA adducts. Northern blot analysis presented that 1-NP attenuated BaP-induced CYP1A1 mRNA expression by 30.4-39.6% (p < 0.05). Western blot analysis revealed that the co-treatment with BaP and 1-NP resulted in a significant inhibition of BaP-induced CYP1A1 protein expression (70.7-88.2%, p < 0.05). However, the decrease in CYP1A1 protein levels was significantly larger than that in CYP1A1 mRNA levels. To confirm the effect of 1-NP on the CYP1A1 protein expression, in vitro proteolysis of CYP1A1 protein was evaluated. The results demonstrated that the addition of 1-NP enhanced CYP1A1 protein degradation and the proteolysis of CYP1A1 protein was inhibited by the addition of an antioxidant, dithiothreitol. In addition, the relative levels of reactive oxygen species (ROS) were elevated in HepG2 cells co-treated with BaP and 1-NP, indicating that the decrease of CYP1A1 protein level was probably attributed to the production of ROS generated by binary mixture. Taken together, these findings suggested that the transcriptional suppression and posttranslational mechanism may be involved in loss of CYP1A1 protein, causing the decrease of BaP-DNA adduct levels in the presence of binary mixtures of 1-NP and BaP.
 ...
PMID:Suppressive effect of 1-nitropyrene on benzo[a]pyrene-induced CYP1A1 protein expression in HepG2 cells. 1628 Feb 10

The aim of this study was to examine the arsenic effect on activation of aryl hydrocarbon receptor (AhR)-mediated gene expression by 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD) in human hepatoma cells. The human hepatoma Huh7 cells were treated with sodium arsenite (NaAsO2) from 0.5 to 20 microM for 24 h. Our data revealed that NaAsO2 < or = 10 microM caused no significant cytotoxic effect on Huh7 cells (p>0.05). We also established a dioxin-responsive element (DRE)-mediated Chemical Activated LUciferase eXpression (CALUX) cell line, Huh7-DRE-Luc, by stable transfection of Huh7 with a DRE-driven firefly luciferase reporter plasmid (4xDRE-TATA-Luc). Treatments of Huh7-DRE-Luc and Huh7 with NaAsO2 attenuated the 2,3,7,8-TCDD-induced DRE-CALUX and cytochrome P450 1A1 (CYP1A1) activations, respectively, in a dose-dependent manner. We found that the calculated CALUX-toxic equivalent (TEQ) levels induced by cotreatment of NaAsO2 > or = 3.0 microM and 10 nM 2,3,7,8-TCDD were significantly lower than that induced by 2,3,7,8-TCDD alone (p<0.05). In the present study, we demonstrated that arsenic not only inhibited the TCDD-induced CYP1A1 activation but also interfered with DRE-CALUX bioassay in human hepatoma cells. Our finding also suggests that extensive cleanup of sample for removal of any possible interfering factor is critical to guarantee the accuracy of dioxin-TEQ levels using DRE-CALUX bioassay.
 ...
PMID:Arsenic inhibits induction of cytochrome P450 1A1 by 2,3,7,8-tetrachlorodibenzo-p-dioxin in human hepatoma cells. 1671 74

Exposure to hepatitis C virus (HCV) can lead to the development of cirrhosis and hepatocellular carcinoma. To examine the effects of long-term HCV infection on hepatic cytochrome P450 1A1 (CYP1A1) expression and function, we used a human hepatoma cell line expressing the HCV subgenomic replicon (Huh.8) to evaluate CYP1A1 induction by the aryl hydrocarbon receptor (AhR) ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). In this study, we demonstrate that the induction of CYP1A1 expression in Huh.8 cells by TCDD but not by beta-naphthoflavone or 3-methylcholanthrene was significantly diminished. TCDD exposure of Huh.8 cells resulted in greater than 55% suppression of CYP1A1 transcription compared with the parent cell line Huh7, whereas protein levels and enzyme activities were further diminished. Suppression of CYP1A1 mRNA expression in TCDD-treated Huh.8 cells was partially reversed after pretreatment with the antioxidants N-acetylcysteine and nordihydroguaiaretic acid, suggesting a role for oxidative stress. Induced CYP1A1 message, protein, and enzyme activity were partially restored in an Huh7 cell line expressing the HCV replicon containing a deletion in the nonstructural protein NS5A. Furthermore, adenoviral expression of NS5A in Huh7 partially suppressed TCDD-induced CYP1A1 protein and enzyme activity, implicating this protein in the mechanism of suppression. These findings demonstrate that TCDD-mediated AhR signaling is impaired in hepatocytes in which HCV is present and that NS5A alone or in the presence of other nonstructural proteins of the subgenomic replicon is in part responsible.
 ...
PMID:Regulation of the CYP1A1 gene by 2,3,7,8-tetrachlorodibenzo-p-dioxin but not by beta-naphthoflavone or 3-methylcholanthrene is altered in hepatitis C virus replicon-expressing cells. 1678 90

Genome-wide oligonucleotide DNA microarrays and real time RT-PCR were used to assess differential gene expression in rat glioma and hepatoma cell lines after exposure to the aryl hydrocarbon receptor (AhR) agonist 3,3',4,4',5-pentachlorobiphenyl (penta-CB). Under maximal inducing concentrations for cytochrome P450 1A1 (CYP1A1) in H4IIE rat hepatoma cells, both H4IIE and C6 rat glioma cells were exposed to sub-micromolar concentrations of penta-CB for 24h. Differential gene expression for approximately 28,000 gene probes were computationally analyzed and compared. As expected, penta-CB potently activated CYP1A1/2 transcription in liver-derived H4IIE hepatoma cells yet did not do so in brain-derived C6 glioma cells. Additionally, we show that penta-CB causes: (1) distinct patterns of gene expression between tumor cells derived from liver or brain; (2) robust transcriptional activation of select C6 glioma gene ontologies; (3) over-expression of H4IIE hepatoma genes associated with tumor progression in liver; (4) greater than 100-fold over-expression of C6 glioma genes associated with protein processing and programmed cell death and/or metastasis; (5) tissue-selective histone deacetylase inhibition in C6 glioma, but not H4IIE hepatoma cells as signaled by galectin-1 over-expression.
 ...
PMID:The aryl hydrocarbon receptor agonist 3,3',4,4',5-pentachlorobiphenyl induces distinct patterns of gene expression between hepatoma and glioma cells: chromatin remodeling as a mechanism for selective effects. 1731 8

The arylhydrocarbon receptor (AhR) mediates toxicities of dioxins, including the most potent congener 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), by being translocated to the nucleus upon ligand-binding and inducing expression of target genes. Although the species-specific activity of the AhR is primarily attributable to species-specific AhR-ligand affinity, the precise mechanism has not been clarified. We investigated the modulation mechanisms of AhR in Hepa1c1c7 and HepG2 hepatoma cells, which were derived from high-affinity-AhR-expressing C57BL/6 mice and low-affinity-AhR-expressing humans, respectively. Although, consistent with their AhR affinities, TCDD induced a greater amount of cytochrome P450 1A1 (CYP1A1) mRNA, one of the most sensitive AhR-targets, in Hepa1c1c7 cells than in HepG2 cells immediately after exposure, both cells expressed a similar level of CYP1A1 mRNA from 4 h onward. A rapid decrease in the AhR protein after nuclear translocation in Hepa1c1c7 cells was suggested to contribute to suppression of CYP1A1 induction to the same level as in HepG2 cells. Different profiles of histone deacetylase 1 (HDAC1)-binding to the CYP1A1 promoter and histone acetylation between both cell lines and lower degradation rate of CYP1A1 mRNA in HepG2 cells were also implicated in regulating their target gene expression. These factors have been highly suggested to be involved in the species-specific modulation mechanism of AhR function.
 ...
PMID:Regulatory factors involved in species-specific modulation of arylhydrocarbon receptor (AhR)-dependent gene expression in humans and mice. 1765 29

Dioxin-responsive element-mediated chemical activated luciferase expression (DRE-CALUX) is one of alternative bioassays for the determination of dioxin levels. We have previously established a DRE-CALUX cell line, Huh7-DRE-Luc, by using stable transfection of Huh-7 cells with a reporter plasmid (4xDRE-TATA-Luc) carrying a DRE-driven firefly luciferase gene. It was also shown that arecoline, a major areca nut alkaloid, inhibited the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced cytochrome P450 1A1 (CYP1A1) activation in Huh-7 cells. The TCDD-activated aryl hydrocarbon receptor (AhR) induces the DRE-CALUX activation and CYP1A1 gene expression via binding to DRE in promoter regions of these dioxin-responsive genes. In the present study, the effect of arecoline on the TCDD-induced activation of DRE-CALUX and CYP1A1 enzyme in Huh7-DRE-Luc and Huh-7 cells, respectively, was examined. It was found that arecoline inhibited TCDD-induced CYP1A1 activation and however enhanced TCDD-induced DRE-CALUX activation. This finding indicates the differential effect of arecoline on the endogenous dioxin-responsive CYP1A1 and on a stably transfected DRE-driven reporter in human hepatoma cells. The present study suggests that induction of DRE-CALUX alone does not necessarily parallel with endogenous CYP1A1 gene expression, and that the reporter assay may detect interactions that are not functional in endogenous gene.
 ...
PMID:Differential effect of arecoline on the endogenous dioxin-responsive cytochrome P450 1A1 and on a stably transfected dioxin-responsive element-driven reporter in human hepatoma cells. 1770 85

Co-contamination with complex mixtures of heavy metals and polycyclic aromatic hydrocarbons (PAHs) is a common environmental problem with multiple biological consequences. In this study, we tested in human hepatoma HepG2 cells the potential effects of three prominent environmental heavy metals, mercury (Hg(2+)), lead (Pb(2+)), and copper (Cu(2+)), on the induction of cytochrome P450 1A1 (CYP1A1) by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the most potent PAH. Our results show that TCDD in the absence and presence of heavy metals did not significantly affect HepG2 cell viability using MTT and LDH leakage assays. Exposure of HepG2 cells with either Hg(2+) or Pb(2+) significantly decreased, whereas Cu(2+) potentiated the CYP1A1 induction mediated by TCDD at the activity levels. In a manner similar to CYP1A1 activity, both Hg(2+) and Pb(2+) significantly down-regulated, while Cu(2+) up-regulated, the induction of CYP1A1 protein mediated by TCDD, suggesting that the modulations of CYP1A1 by heavy metals are mediated at least in part at the translational level. Based on these results, exposure to metal/PAH mixtures would differentially modulate PAHs-mediated carcinogenicity.
 ...
PMID:Modulation of TCDD-mediated induction of cytochrome P450 1A1 by mercury, lead, and copper in human HepG2 cell line. 1788

In most laboratory-scale mammalian cell cultures, the primary mode of oxygen delivery to cultured cells is by passive diffusion through a thin layer of culture medium, and the height of culture medium chosen may therefore have a significant effect on the phenotype of oxygen-sensitive cell types. Many of the liver functions performed by hepatocytes are thought to be regulated into zones by the local oxygen concentration; of particular interest to in vitro toxicologists, the cytochrome P450 family of detoxification enzymes is known to be preferentially expressed by hepatocytes at low (perivenous) oxygen concentrations. Using an array of different medium heights in a 12-well plate format, we show that the height of culture medium has a significant effect on cytochrome P450 1A1 detoxification activity, glucose metabolism, and cell morphology of HepG2 hepatocellular carcinoma cultures. In particular, cytochrome P450 activity exhibits a maximum at medium heights corresponding to perivenous oxygen concentrations. This work demonstrates that optimizing cell culture performance is not always the same as maximizing oxygen delivery.
 ...
PMID:Induction of zone-like liver function gradients in HepG2 cells by varying culture medium height. 1795 43

Polybrominated diphenyl ethers (PBDE) are found as ubiquitous contaminants in the environment, e.g., in sediments and biota as well as in human blood samples and mother's milk. PBDEs are neuro- and developmental toxins, disturb the endocrine system and some are even carcinogenic. Structural similarities of PBDEs with dioxin-like compounds, e.g., 2,3,7,8-tetrachloro-dibenzodioxin (TCDD), have raised concern about a possible "dioxin-like" action of PBDEs. TCDD exerts its toxicity via binding to and activation of the aryl hydrocarbon receptor (AhR). AhR ligands are in contrast to PBDEs usually coplanar compounds. Thus, PBDEs are not likely to be strong AhR agonists. The aim of this study was to analyze the effects of the most abundant PBDE congener, 2,2',4,4'-tetrabromo diphenyl ether (BDE47), on AhR activity and signaling. Initially, we measured cytochrome P450 1A1 (Cyp1A1) induction as a readout for AhR activation by BDE47. Low grade purified BDE47 increased CYP1A1 levels in transformed and primary rat hepatocytes and human hepatoma cells. Chemical analysis of the BDE47 sample identified trace contaminations with brominated furans such as 2,3,7,8-tetrabromo dibenzodioxin (TBDF), which most likely were responsible for the observed activation of AhR. Subsequently, the BDE47 mixture was studied for its effect on AhR mediated toxicity and global gene expression. Indeed, in rat hepatoma cells and in zebrafish embryos the BDE47 mixture provoked changes in gene expression and toxicity similar to known AhR agonists. In addition to the dioxin-like actions, the BDE47 sample enhanced Cyp2B and Cyp3A expression suggesting that commercial PBDE mixtures, which also often contain brominated furans, may disturb cellular homeostasis at multiple levels.
 ...
PMID:A technical mixture of 2,2',4,4'-tetrabromo diphenyl ether (BDE47) and brominated furans triggers aryl hydrocarbon receptor (AhR) mediated gene expression and toxicity. 1861 40

Omeprazole is a drug used for treating gastro-oesophageal reflux disease and duodenal ulcers. Omeprazole induces a xenobiotic-metabolizing enzyme, cytochrome P450 1A1 (CYP1A1), as its ligand by aryl hydrocarbon receptor (AhR) activation without binding. CYP1A1-inducible chemicals, such as benzo[a]pyrene and 2,3,7,8-tetrachlorodibenzo-p-dioxin, are known to have adverse effects (i.e. carcinogenesis, mutagenesis and malformation). Unlike these typical AhR activators, omeprazole has shown no experimental evidence of carcinogenic activity. The possibility, however, remains that omeprazole may aggravate the effect of environmental carcinogens through CYP1A1 induction. We exposed benzo[a]pyrene and omeprazole simultaneously to human and mouse hepatoma cells to investigate the synergistic effect of these chemicals. Contrary to our prediction, cytotoxicity of benzo[a]pyrene was inhibited by the omeprazole exposure in a dose-dependent manner. Omeprazole did not alter CYP1A1 mRNA and protein levels induced by benzo[a]pyrene. The 7-ethoxy-resorufin-O-deethylase assay revealed that omeprazole inhibited CYP1A1 enzyme activity. Kinetic analysis also demonstrated that it is a competitive inhibitor for CYP1A1. The K(m) value of omeprazole against CYP1A1 activity was 50.1 microM. We conclude that the effects of omeprazole on CYP1A1 involve not only induction through AhR activation but also inhibition of its enzyme activity, and that the protective effect of omeprazole against benzo[a]pyrene cytotoxicity depends on the latter.
 ...
PMID:Omeprazole alleviates benzo[a]pyrene cytotoxicity by inhibition of CYP1A1 activity in human and mouse hepatoma cells. 1879 72


<< Previous 1 2 3 4 5 6 Next >>