2012
Valovičová, Zuzana; Mesárošová, Monika; Trilecová, Lenka; Hrubá, Eva; Marvanová, Soňa; Krčmář, Pavel; Milcová, Alena; Schmuczerová, Jana; Vondráček, Jan; Machala, Miroslav; Topinka, Jan; Gábelová, Alena
Genotoxicity of 7H-dibenzo[c,g]carbazole and its methyl derivatives in human keratinocytes. Journal Article
In: Mutation research, vol. 743, no. 1-2, pp. 91–98, 2012, ISSN: 0027-5107, (Place: Netherlands).
Abstract | Links | BibTeX | Tags: Carbazoles/chemistry/*toxicity, Carcinogens/*toxicity, Cell Line, Cytochrome P-450 CYP1A1/metabolism, DNA Breaks, Humans, Keratinocytes/*drug effects/metabolism, Mutagenicity Tests, Mutagens/*toxicity, Organ Specificity, Single-Stranded
@article{valovicova_genotoxicity_2012,
title = {Genotoxicity of 7H-dibenzo[c,g]carbazole and its methyl derivatives in human keratinocytes.},
author = {Zuzana Valovičová and Monika Mesárošová and Lenka Trilecová and Eva Hrubá and Soňa Marvanová and Pavel Krčmář and Alena Milcová and Jana Schmuczerová and Jan Vondráček and Miroslav Machala and Jan Topinka and Alena Gábelová},
doi = {10.1016/j.mrgentox.2011.12.030},
issn = {0027-5107},
year = {2012},
date = {2012-03-01},
journal = {Mutation research},
volume = {743},
number = {1-2},
pages = {91–98},
abstract = {Differences between tissues in the expression of drug-metabolizing enzymes may substantially contribute to tissue-specificity of chemical carcinogens. To verify this hypothesis, the spontaneously immortalized human keratinocytes HaCaT were used, in order to evaluate the genotoxic potential of 7H-dibenzo[c,g]carbazole (DBC), a known hepatocarcinogen and sarcomagen, and its synthetic tissue-specific derivatives, 5,9-dimethyl-DBC (DiMeDBC) and N-methyl-DBC (N-MeDBC), which manifest specific tropism to the liver and skin, respectively. HaCaT cells mainly express cytochrome P4501A1 (CYP1A1), which is involved in metabolism of DBC and N-MeDBC, but not DiMeDBC [10]. Both DBC and the sarcomagen N-MeDBC induced significant levels of DNA strand-breaks, micronuclei, and DNA adducts followed by the phosphorylation of the p53 protein and histone H2AX in HaCaT cells. In contrast, the specific hepatocarcinogen DiMeDBC was devoid of any significant genotoxic activity in this cell line. Our study demonstrates that the absence of drug-metabolizing enzyme(s) involved in DiMeDBC metabolism may contribute substantially to the tissue-specific genotoxicity of this hepatocarcinogen.},
note = {Place: Netherlands},
keywords = {Carbazoles/chemistry/*toxicity, Carcinogens/*toxicity, Cell Line, Cytochrome P-450 CYP1A1/metabolism, DNA Breaks, Humans, Keratinocytes/*drug effects/metabolism, Mutagenicity Tests, Mutagens/*toxicity, Organ Specificity, Single-Stranded},
pubstate = {published},
tppubtype = {article}
}
Differences between tissues in the expression of drug-metabolizing enzymes may substantially contribute to tissue-specificity of chemical carcinogens. To verify this hypothesis, the spontaneously immortalized human keratinocytes HaCaT were used, in order to evaluate the genotoxic potential of 7H-dibenzo[c,g]carbazole (DBC), a known hepatocarcinogen and sarcomagen, and its synthetic tissue-specific derivatives, 5,9-dimethyl-DBC (DiMeDBC) and N-methyl-DBC (N-MeDBC), which manifest specific tropism to the liver and skin, respectively. HaCaT cells mainly express cytochrome P4501A1 (CYP1A1), which is involved in metabolism of DBC and N-MeDBC, but not DiMeDBC [10]. Both DBC and the sarcomagen N-MeDBC induced significant levels of DNA strand-breaks, micronuclei, and DNA adducts followed by the phosphorylation of the p53 protein and histone H2AX in HaCaT cells. In contrast, the specific hepatocarcinogen DiMeDBC was devoid of any significant genotoxic activity in this cell line. Our study demonstrates that the absence of drug-metabolizing enzyme(s) involved in DiMeDBC metabolism may contribute substantially to the tissue-specific genotoxicity of this hepatocarcinogen.
2011
Gábelová, Alena; Valovičová, Zuzana; Mesárošová, Monika; Trilecová, Lenka; Hrubá, Eva; Marvanová, Soňa; Krčmár, Pavel; Milcová, Alena; Schmuczerová, Jana; Vondráček, Jan; Machala, Miroslav; Topinka, Jan
Genotoxicity of 7H-dibenzo[c,g]carbazole and its tissue-specific derivatives in human hepatoma HepG2 cells is related to CYP1A1/1A2 expression. Journal Article
In: Environmental and molecular mutagenesis, vol. 52, no. 8, pp. 636–645, 2011, ISSN: 1098-2280 0893-6692, (Place: United States).
Abstract | Links | BibTeX | Tags: Base Sequence, Blotting, Carbazoles/*toxicity, Cell Survival/drug effects, Chromosome-Defective/chemically induced/statistics & numerical data, Comet assay, Cytochrome P-450 CYP1A1/*genetics, Cytochrome P-450 CYP1A2/*genetics, DNA adducts, DNA Breaks, Dose-Response Relationship, Drug, Hep G2 Cells, Histones/metabolism, Humans, Micronuclei, Micronucleus Tests, Mitotic Index, Molecular Sequence Data, Mutagens/*toxicity, Phosphorylation, Real-Time Polymerase Chain Reaction, Tumor Suppressor Protein p53/metabolism, Western
@article{gabelova_genotoxicity_2011,
title = {Genotoxicity of 7H-dibenzo[c,g]carbazole and its tissue-specific derivatives in human hepatoma HepG2 cells is related to CYP1A1/1A2 expression.},
author = {Alena Gábelová and Zuzana Valovičová and Monika Mesárošová and Lenka Trilecová and Eva Hrubá and Soňa Marvanová and Pavel Krčmár and Alena Milcová and Jana Schmuczerová and Jan Vondráček and Miroslav Machala and Jan Topinka},
doi = {10.1002/em.20664},
issn = {1098-2280 0893-6692},
year = {2011},
date = {2011-10-01},
journal = {Environmental and molecular mutagenesis},
volume = {52},
number = {8},
pages = {636–645},
abstract = {The goal of this study was to investigate the genotoxicity of 7H-dibenzo[c,g]carbazole (DBC), a ubiquitous environmental pollutant, and its methyl derivatives, 5,9-dimethylDBC (DiMeDBC), a strict hepatocarcinogen, and N-methylDBC (N-MeDBC), a specific sarcomagen in human hepatoma HepG2 cells, and to infer potential mechanisms underlying the biological activity of particular carcinogen. All dibenzocarbazoles, regardless the tissue specificity, induced significant DNA strand break levels and micronuclei in HepG2 cells; though a mitotic spindle dysfunction rather than a chromosome breakage was implicated in N-MeDBC-mediated micronucleus formation. While DBC and N-MeDBC produced stable DNA adducts followed with p53 protein phosphorylation at Ser-15, DiMeDBC failed. A significant increase in DNA strand breaks following incubation of exposed cells with a repair-specific endonuclease (Fpg protein) suggested that either oxidative DNA damage or unstable DNA-adducts might underlie DiMeDBC genotoxicity in human hepatoma cells. DiMeDBC and N-MeDBC increased substantially also the amount of CYP1A1/2 expression in HepG2 cells. Pretreatment of cells with substances affecting AhR-mediated CYP1A family of enzymes expression; however, diminished DiMeDBC and N-MeDBC genotoxicity. Our data clearly demonstrated differences in the mechanisms involved in the biological activity of DiMeDBC and N-MeDBC in human hepatoma cells; the genotoxicity of these DBC derivatives is closely related to CYP1A1/2 expression.},
note = {Place: United States},
keywords = {Base Sequence, Blotting, Carbazoles/*toxicity, Cell Survival/drug effects, Chromosome-Defective/chemically induced/statistics & numerical data, Comet assay, Cytochrome P-450 CYP1A1/*genetics, Cytochrome P-450 CYP1A2/*genetics, DNA adducts, DNA Breaks, Dose-Response Relationship, Drug, Hep G2 Cells, Histones/metabolism, Humans, Micronuclei, Micronucleus Tests, Mitotic Index, Molecular Sequence Data, Mutagens/*toxicity, Phosphorylation, Real-Time Polymerase Chain Reaction, Tumor Suppressor Protein p53/metabolism, Western},
pubstate = {published},
tppubtype = {article}
}
The goal of this study was to investigate the genotoxicity of 7H-dibenzo[c,g]carbazole (DBC), a ubiquitous environmental pollutant, and its methyl derivatives, 5,9-dimethylDBC (DiMeDBC), a strict hepatocarcinogen, and N-methylDBC (N-MeDBC), a specific sarcomagen in human hepatoma HepG2 cells, and to infer potential mechanisms underlying the biological activity of particular carcinogen. All dibenzocarbazoles, regardless the tissue specificity, induced significant DNA strand break levels and micronuclei in HepG2 cells; though a mitotic spindle dysfunction rather than a chromosome breakage was implicated in N-MeDBC-mediated micronucleus formation. While DBC and N-MeDBC produced stable DNA adducts followed with p53 protein phosphorylation at Ser-15, DiMeDBC failed. A significant increase in DNA strand breaks following incubation of exposed cells with a repair-specific endonuclease (Fpg protein) suggested that either oxidative DNA damage or unstable DNA-adducts might underlie DiMeDBC genotoxicity in human hepatoma cells. DiMeDBC and N-MeDBC increased substantially also the amount of CYP1A1/2 expression in HepG2 cells. Pretreatment of cells with substances affecting AhR-mediated CYP1A family of enzymes expression; however, diminished DiMeDBC and N-MeDBC genotoxicity. Our data clearly demonstrated differences in the mechanisms involved in the biological activity of DiMeDBC and N-MeDBC in human hepatoma cells; the genotoxicity of these DBC derivatives is closely related to CYP1A1/2 expression.