2005
Vondrácek, Jan; Machala, Miroslav; Bryja, Vítezslav; Chramostová, Katerina; Krcmár, Pavel; Dietrich, Cornelia; Hampl, Ales; Kozubík, Alois
In: Toxicological sciences : an official journal of the Society of Toxicology, vol. 83, no. 1, pp. 53–63, 2005, ISSN: 1096-6080 1096-0929, (Place: United States).
Abstract | Links | BibTeX | Tags: Animals, Aryl Hydrocarbon/*metabolism, Cell Line, Cell Proliferation/*drug effects, Cyclin A/biosynthesis, Cyclin D2, Cyclin-Dependent Kinases/biosynthesis, Cyclins/biosynthesis, Dose-Response Relationship, Drug, Epithelial Cells/*drug effects/enzymology/metabolism, Hydroxylation, Liver/*cytology, Polychlorinated Biphenyls/metabolism/*toxicity, Rats, Receptors, Stem Cells/*drug effects/enzymology/metabolism, Up-Regulation
@article{vondracek_aryl_2005,
title = {Aryl hydrocarbon receptor-activating polychlorinated biphenyls and their hydroxylated metabolites induce cell proliferation in contact-inhibited rat liver epithelial cells.},
author = {Jan Vondrácek and Miroslav Machala and Vítezslav Bryja and Katerina Chramostová and Pavel Krcmár and Cornelia Dietrich and Ales Hampl and Alois Kozubík},
doi = {10.1093/toxsci/kfi009},
issn = {1096-6080 1096-0929},
year = {2005},
date = {2005-01-01},
journal = {Toxicological sciences : an official journal of the Society of Toxicology},
volume = {83},
number = {1},
pages = {53–63},
abstract = {Polychlorinated biphenyls (PCBs) exhibit tumor-promoting effects in experimental animals. We investigated effects of six model PCB congeners and hydroxylated PCB metabolites on proliferation of contact-inhibited rat liver epithelial WB-F344 cells. The 'dioxin-like' PCB congeners, PCB 126, PCB 105, and 4'-OH-PCB 79, a metabolite of the planar PCB 77 congener, induced cell proliferation in a concentration-dependent manner. In contrast, the 'non-dioxin-like' compounds that are not aryl hydrocarbon receptor (AhR) agonists, PCB 47, PCB 153, and 4-OH-PCB 187, an abundant noncoplanar PCB metabolite, had no effect on cell proliferation at concentrations up to 10 muM. The concentrations of dioxin-like PCBs leading to cell proliferation corresponded with the levels inducing the expression of cytochrome P450 1A1 mRNA, suggesting that the release from contact inhibition was associated with AhR activation. The effects of PCB 126 and PCB 153 on expression of proteins controlling G0/G1-S-phase transition and S-phase progression were compared. Only PCB 126 was found to upregulate cyclin A and D2 protein levels, and to increase both total cyclin-dependent kinase 2 (cdk2) and cyclin A/cdk2 complex activities. Despite the observed upregulation of cyclin D2, no increase in cdk4 activity was observed. The expression of cdk inhibitor p27Kip1 was not affected by either PCB 126 or PCB 153. These results suggest that dioxin-like PCBs can induce cell proliferation of contact-inhibited rat liver epithelial cells by increasing cyclin A protein levels, a process that then leads to upregulation of cyclin A/cdk2 activity and initiation of DNA replication. This mechanism could be involved in tumor-promoting effects of dioxin-like PCBs.},
note = {Place: United States},
keywords = {Animals, Aryl Hydrocarbon/*metabolism, Cell Line, Cell Proliferation/*drug effects, Cyclin A/biosynthesis, Cyclin D2, Cyclin-Dependent Kinases/biosynthesis, Cyclins/biosynthesis, Dose-Response Relationship, Drug, Epithelial Cells/*drug effects/enzymology/metabolism, Hydroxylation, Liver/*cytology, Polychlorinated Biphenyls/metabolism/*toxicity, Rats, Receptors, Stem Cells/*drug effects/enzymology/metabolism, Up-Regulation},
pubstate = {published},
tppubtype = {article}
}
Polychlorinated biphenyls (PCBs) exhibit tumor-promoting effects in experimental animals. We investigated effects of six model PCB congeners and hydroxylated PCB metabolites on proliferation of contact-inhibited rat liver epithelial WB-F344 cells. The 'dioxin-like' PCB congeners, PCB 126, PCB 105, and 4'-OH-PCB 79, a metabolite of the planar PCB 77 congener, induced cell proliferation in a concentration-dependent manner. In contrast, the 'non-dioxin-like' compounds that are not aryl hydrocarbon receptor (AhR) agonists, PCB 47, PCB 153, and 4-OH-PCB 187, an abundant noncoplanar PCB metabolite, had no effect on cell proliferation at concentrations up to 10 muM. The concentrations of dioxin-like PCBs leading to cell proliferation corresponded with the levels inducing the expression of cytochrome P450 1A1 mRNA, suggesting that the release from contact inhibition was associated with AhR activation. The effects of PCB 126 and PCB 153 on expression of proteins controlling G0/G1-S-phase transition and S-phase progression were compared. Only PCB 126 was found to upregulate cyclin A and D2 protein levels, and to increase both total cyclin-dependent kinase 2 (cdk2) and cyclin A/cdk2 complex activities. Despite the observed upregulation of cyclin D2, no increase in cdk4 activity was observed. The expression of cdk inhibitor p27Kip1 was not affected by either PCB 126 or PCB 153. These results suggest that dioxin-like PCBs can induce cell proliferation of contact-inhibited rat liver epithelial cells by increasing cyclin A protein levels, a process that then leads to upregulation of cyclin A/cdk2 activity and initiation of DNA replication. This mechanism could be involved in tumor-promoting effects of dioxin-like PCBs.
2004
Chramostová, Katerina; Vondrácek, Jan; Sindlerová, Lenka; Vojtesek, Borivoj; Kozubík, Alois; Machala, Miroslav
Polycyclic aromatic hydrocarbons modulate cell proliferation in rat hepatic epithelial stem-like WB-F344 cells. Journal Article
In: Toxicology and applied pharmacology, vol. 196, no. 1, pp. 136–148, 2004, ISSN: 0041-008X, (Place: United States).
Abstract | Links | BibTeX | Tags: Animals, Apoptosis/drug effects, Aryl Hydrocarbon/metabolism, Cell Division/drug effects, Cells, Cultured, Cytochrome P-450 CYP1A1/metabolism, Dose-Response Relationship, Drug, Epithelial Cells/*drug effects/enzymology/metabolism, Liver/*cytology, Mutagens/*toxicity, Polycyclic Aromatic Hydrocarbons/*toxicity, Rats, Receptors, Stem Cells/*drug effects/enzymology/metabolism, Tumor Suppressor Protein p53/biosynthesis
@article{chramostova_polycyclic_2004,
title = {Polycyclic aromatic hydrocarbons modulate cell proliferation in rat hepatic epithelial stem-like WB-F344 cells.},
author = {Katerina Chramostová and Jan Vondrácek and Lenka Sindlerová and Borivoj Vojtesek and Alois Kozubík and Miroslav Machala},
doi = {10.1016/j.taap.2003.12.008},
issn = {0041-008X},
year = {2004},
date = {2004-04-01},
journal = {Toxicology and applied pharmacology},
volume = {196},
number = {1},
pages = {136–148},
abstract = {Although many polycyclic aromatic hydrocarbons (PAHs) are recognized as potent mutagens and carcinogens, relatively little is known about their role in the tumor promotion. It is known that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) can induce release of rat hepatic oval epithelial cells from contact inhibition by a mechanism possibly involving the aryl hydrocarbon receptor (AhR) activation. Many PAHs are AhR ligands and are known to act as transient inducers of AhR-mediated activity. In this study, effects of 19 selected PAHs on proliferation of confluent rat liver epithelial WB-F344 cells were investigated. Non-mutagens that are weak activators or nonactivators of AhR-mediated activity had no effect on cell proliferation. Relatively strong or moderate AhR ligands with low mutagenic potencies, such as benzofluoranthenes, benz[a]anthracene, and chrysene, were found to increase cell numbers, which corresponded to an increased percentage of cells entering S-phase. Strong mutagens, including benzo[a]pyrene and dibenzo[a,l]pyrene, increased a percentage of cells in S-phase without inducing a concomitant increase in cell numbers. The treatment with mutagenic PAHs was associated with an increased DNA synthesis and induction of cell death, which corresponded with the activation of p53 tumor suppressor. Apoptosis was blocked by pifithrin-alpha, the chemical inhibitor of p53. Both weakly and strongly mutagenic PAHs known as AhR ligands were found to induce significant increase of cytochrome P4501A activity, suggesting a presence of functional AhR. The results of the present study seem to suggest that a release from contact inhibition could be a part of tumor promoting effects of AhR-activating PAHs; however, the genotoxic effects of some PAHs associated with p53 activation might interfere with this process.},
note = {Place: United States},
keywords = {Animals, Apoptosis/drug effects, Aryl Hydrocarbon/metabolism, Cell Division/drug effects, Cells, Cultured, Cytochrome P-450 CYP1A1/metabolism, Dose-Response Relationship, Drug, Epithelial Cells/*drug effects/enzymology/metabolism, Liver/*cytology, Mutagens/*toxicity, Polycyclic Aromatic Hydrocarbons/*toxicity, Rats, Receptors, Stem Cells/*drug effects/enzymology/metabolism, Tumor Suppressor Protein p53/biosynthesis},
pubstate = {published},
tppubtype = {article}
}
Although many polycyclic aromatic hydrocarbons (PAHs) are recognized as potent mutagens and carcinogens, relatively little is known about their role in the tumor promotion. It is known that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) can induce release of rat hepatic oval epithelial cells from contact inhibition by a mechanism possibly involving the aryl hydrocarbon receptor (AhR) activation. Many PAHs are AhR ligands and are known to act as transient inducers of AhR-mediated activity. In this study, effects of 19 selected PAHs on proliferation of confluent rat liver epithelial WB-F344 cells were investigated. Non-mutagens that are weak activators or nonactivators of AhR-mediated activity had no effect on cell proliferation. Relatively strong or moderate AhR ligands with low mutagenic potencies, such as benzofluoranthenes, benz[a]anthracene, and chrysene, were found to increase cell numbers, which corresponded to an increased percentage of cells entering S-phase. Strong mutagens, including benzo[a]pyrene and dibenzo[a,l]pyrene, increased a percentage of cells in S-phase without inducing a concomitant increase in cell numbers. The treatment with mutagenic PAHs was associated with an increased DNA synthesis and induction of cell death, which corresponded with the activation of p53 tumor suppressor. Apoptosis was blocked by pifithrin-alpha, the chemical inhibitor of p53. Both weakly and strongly mutagenic PAHs known as AhR ligands were found to induce significant increase of cytochrome P4501A activity, suggesting a presence of functional AhR. The results of the present study seem to suggest that a release from contact inhibition could be a part of tumor promoting effects of AhR-activating PAHs; however, the genotoxic effects of some PAHs associated with p53 activation might interfere with this process.