Latest Publications

@article{ghorbanzadeh_vitro_2014,

title = {In vitro and in silico derived relative effect potencies of ah-receptor-mediated effects by PCDD/Fs and PCBs in rat, mouse, and guinea pig CALUX cell lines.},

author = {Mehdi Ghorbanzadeh and Karin I. Ede and Malin Larsson and Majorie B. M. Duursen and Lorenz Poellinger and Sandra Lücke-Johansson and Miroslav Machala and Kateřina Pěnčíková and Jan Vondráček and Martin Berg and Michael S. Denison and Tine Ringsted and Patrik L. Andersson},

doi = {10.1021/tx5001255},

issn = {1520-5010 0893-228X},

year  = {2014},

date = {2014-07-01},

journal = {Chemical research in toxicology},

volume = {27},

number = {7},

pages = {1120–1132},

abstract = {For a better understanding of species-specific relative effect potencies (REPs), responses of dioxin-like compounds (DLCs) were assessed. REPs were calculated using chemical-activated luciferase gene expression assays (CALUX) derived from guinea pig, rat, and mouse cell lines. Almost all 20 congeners tested in the rodent cell lines were partial agonists and less efficacious than 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). For this reason, REPs were calculated for each congener using concentrations at which 20% of the maximal TCDD response was reached (REP20TCDD). REP20TCDD values obtained for PCDD/Fs were comparable with their toxic equivalency factors assigned by the World Health Organization (WHO-TEF), while those for PCBs were in general lower than the WHO-TEF values. Moreover, the guinea pig cell line was the most sensitive as indicated by the 20% effect concentrations of TCDD of 1.5, 5.6, and 11.0 pM for guinea pig, rat, and mouse cells, respectively. A similar response pattern was observed using multivariate statistical analysis between the three CALUX assays and the WHO-TEFs. The mouse assay showed minor deviation due to higher relative induction potential for 2,3,7,8-tetrachlorodibenzofuran and 2,3,4,6,7,8-hexachlorodibenzofuran and lower for 1,2,3,4,6,7,8-heptachlorodibenzofuran and 3,3',4,4',5-pentachlorobiphenyl (PCB126). 2,3,7,8-Tetrachlorodibenzofuran was more than two times more potent in the mouse assay as compared with that of rat and guinea pig cells, while measured REP20TCDD for PCB126 was lower in mouse cells (0.05) as compared with that of the guinea pig (0.2) and rat (0.07). In order to provide REP20TCDD values for all WHO-TEF assigned compounds, quantitative structure-activity relationship (QSAR) models were developed. The QSAR models showed that specific electronic properties and molecular surface characteristics play important roles in the AhR-mediated response. In silico derived REP20TCDD values were generally consistent with the WHO-TEFs with a few exceptions. The QSAR models indicated that, e.g., 1,2,3,7,8-pentachlorodibenzofuran and 1,2,3,7,8,9-hexachlorodibenzofuran were more potent than given by their assigned WHO-TEF values, and the non-ortho PCB 81 was predicted, based on the guinea-pig model, to be 1 order of magnitude above its WHO-TEF value. By combining in vitro and in silico approaches, REPs were established for all WHO-TEF assigned compounds (except OCDD), which will provide future guidance in testing AhR-mediated responses of DLCs and to increase our understanding of species variation in AhR-mediated effects.},

note = {Place: United States},

keywords = {Animals, Aryl Hydrocarbon/agonists/*metabolism, Benzofurans/*pharmacology, Biological, Biological Assay, Cell Line, Computer Simulation, Dibenzofurans, Dose-Response Relationship, Drug, Guinea Pigs, Luciferases/metabolism, Mice, Models, Polychlorinated, Polychlorinated Biphenyls/*pharmacology, Polychlorinated Dibenzodioxins/*analogs & derivatives/pharmacology, Quantitative Structure-Activity Relationship, Rats, Receptors, Tumor},

pubstate = {published},

tppubtype = {article}

}

@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}

}