Latest Publications

@article{valovicova_differences_2009,

title = {Differences in DNA damage and repair produced by systemic, hepatocarcinogenic and sarcomagenic dibenzocarbazole derivatives in a model of rat liver progenitor cells.},

author = {Zuzana Valovicová and Sona Marvanová and Monika Mészárosová and Annamária Srancíková and Lenka Trilecová and Alena Milcová and Helena Líbalová and Jan Vondrácek and Miroslav Machala and Jan Topinka and Alena Gábelová},

doi = {10.1016/j.mrfmmm.2009.02.014},

issn = {0027-5107},

year  = {2009},

date = {2009-06-01},

journal = {Mutation research},

volume = {665},

number = {1-2},

pages = {51–60},

abstract = {Liver progenitor (oval) cells are a potential target cell population for hepatocarcinogens. Our recent study showed that the liver carcinogens 7H-dibenzo[c,g]carbazole (DBC) and 5,9-dimethyldibenzo[c,g]carbazole (DiMeDBC), but not the sarcomagen N-methyldibenzo[c,g]carbazole (N-MeDBC), induced several cellular events associated with tumor promotion in WB-F344 cells, an in vitro model of liver oval cells [J. Vondracek, L. Svihalkova-Sindlerova, K. Pencikova, P. Krcmar, Z. Andrysik, K. Chramostova, S. Marvanova, Z. Valovicova, A. Kozubik, A. Gabelova, M. Machala, 7H-Dibenzo[c,g]carbazole and 5,9-dimethyldibenzo[c,g]carbazole exert multiple toxic events contributing to tumor promotion in rat liver epithelial 'stem-like' cells, Mutat. Res. Fundam. Mol. Mech. Mutagen. 596 (2006) 43-56]. In this study, we focused on the genotoxic effects generated by these dibenzocarbazoles in WB-F344 cells to better understand the cellular and molecular mechanisms involved in hepatocarcinogenesis. Lower IC(50) values determined for DBC and DiMeDBC, as compared with N-MeDBC, indicated a higher sensitivity of WB-F344 cells towards hepatocarcinogens. Accordingly, DBC produced a dose-dependent DNA-adduct formation resulting in substantial inhibition of DNA replication and transcription. In contrast, DNA-adduct number detected in DiMeDBC-exposed cells was almost negligible, whereas N-MeDBC produced a low level of DNA adducts. Although all dibenzocarbazoles significantly increased the level of strand breaks (p<0.05) and micronuclei (p<0.001) after 2-h treatment, differences in the kinetics of strand break rejoining were found. The strand break level in DiMeDBC- and N-MeDBC-exposed cells returned to near the background level within 24h after treatment, whereas a relatively high DNA damage level was detected in DBC-treated cells up to 48h after exposure. Additional breaks detected after incubation of DiMeDBC-exposed WB-F344 cells with a repair-specific endonuclease, along with a nearly 3-fold higher level of reactive oxygen species found in these cells as compared with control, suggest a possible role of oxidative stress in DiMeDBC genotoxicity. We demonstrated qualitative differences in the DNA damage profiles produced by hepatocarcinogens DBC and DiMeDBC in WB-F344 cells. Different lesions may trigger distinct cellular pathways involved in hepatocarcinogenesis. The low amount of DNA damage, together with an efficient repair, may explain the lack of hepatocarcinogenicity of N-MeDBC.},

note = {Place: Netherlands},

keywords = {*DNA Damage, *DNA Repair, Animals, Biological, Carbazoles/*toxicity, Carcinogens/*toxicity, Cell Line, DNA Adducts/metabolism, Experimental/chemically induced, Histones/metabolism, Kinetics, Liver Neoplasms, Liver/cytology/*drug effects/*metabolism, Models, Mutagens/toxicity, Oxidative Stress/drug effects, Rats, Sarcoma, Stem Cells/cytology/*drug effects/*metabolism},

pubstate = {published},

tppubtype = {article}

}

@article{marvanova_toxic_2008,

title = {Toxic effects of methylated benz[a]anthracenes in liver cells.},

author = {Sona Marvanová and Jan Vondrácek and Katerrina Penccíková and Lenka Trilecová and Pavel Krcmárr and Jan Topinka and Zuzana Nováková and Alena Milcová and Miroslav Machala},

doi = {10.1021/tx700305x},

issn = {0893-228X},

year  = {2008},

date = {2008-02-01},

journal = {Chemical research in toxicology},

volume = {21},

number = {2},

pages = {503–512},

abstract = {Monomethylated benz[ a]anthracenes (MeBaAs) are an important group of methylated derivatives of polycyclic aromatic hydrocarbons (PAHs). Although the methyl substitution reportedly affects their mutagenicity and tumor-initiating activity, little is known about the impact of methylation on the effects associated with activation of the aryl hydrocarbon receptor (AhR)-dependent gene expression and/or toxic events associated with tumor promotion. In the present study, we studied the effects of a series of MeBaAs on the above-mentioned end points in rat liver cell lines and compared them with the effects of benz[ a]anthracene (BaA) and the potent carcinogen 7,12-dimethylbenz[ a]anthracene (DMBA). Methyl substitution enhanced the AhR-mediated activity of BaA derivatives determined in a reporter gene assay, as the induction equivalency factors (IEFs) of all MeBaAs were higher than that of BaA. IEFs of 6-MeBaA and 9-MeBaA, two of the most potent MeBaAs, were more than two orders of magnitude higher than the IEF of BaA. Correspondingly, all MeBaAs induced higher levels of cytochrome P450 1A1 mRNA. Both BaA and MeBaAs had similar effects on the expression of cytochrome P450 1B1 or aldo-keto reductase 1C9 in rat liver epithelial WB-F344 cells. In contrast to genotoxic DMBA, MeBaAs induced low DNA adduct formation. Only 10-MeBaA induced apoptosis and accumulation of phosphorylated p53, which could be associated with the induction of oxidative stress, similar to DMBA. With the exception of 10-MeBaA, all MeBaAs induced cell proliferation in contact-inhibited WB-F344 cells, which corresponded with their ability to activate AhR. 1-, 2-, 8-, 10-, 11-, and 12-MeBaA inhibited gap junctional intercellular communication (GJIC) in WB-F344 cells. This mode of action, like disruption of cell proliferation control, might contribute to tumor promotion. Taken together, these data showed that the methyl substitution significantly influences those effects of MeBaAs associated with AhR activation or GJIC inhibition.},

note = {Place: United States},

keywords = {10-Dimethyl-1, 2-benzanthracene/chemistry/metabolism/toxicity, 9, Animals, Apoptosis/drug effects, Benz(a)Anthracenes/chemistry/metabolism/*toxicity, Carcinoma, Cell Line, Cell Proliferation/drug effects, Cytochrome P-450 Enzyme System/genetics/metabolism, DNA Adducts/analysis/metabolism, DNA/drug effects/metabolism, Dose-Response Relationship, Drug, Enzyme Induction, Enzymologic/drug effects, Gap Junctions/drug effects, Gene Expression Regulation, Genes, Hepatocellular, Hepatocytes/*drug effects/metabolism/pathology, Inbred F344, Liver Neoplasms, Messenger/metabolism, Methylation, Rats, Reporter/drug effects, RNA, Stem Cells/*drug effects/metabolism/pathology, Tumor},

pubstate = {published},

tppubtype = {article}

}