2014
Ghorbanzadeh, Mehdi; Ede, Karin I.; Larsson, Malin; Duursen, Majorie B. M.; Poellinger, Lorenz; Lücke-Johansson, Sandra; Machala, Miroslav; Pěnčíková, Kateřina; Vondráček, Jan; Berg, Martin; Denison, Michael S.; Ringsted, Tine; Andersson, Patrik L.
In: Chemical research in toxicology, vol. 27, no. 7, pp. 1120–1132, 2014, ISSN: 1520-5010 0893-228X, (Place: United States).
Abstract | Links | BibTeX | Tags: 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
@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}
}
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.
2009
Simecková, Pavlína; Vondrácek, Jan; Andrysík, Zdenek; Zatloukalová, Jirina; Krcmár, Pavel; Kozubík, Alois; Machala, Miroslav
The 2,2',4,4',5,5'-hexachlorobiphenyl-enhanced degradation of connexin 43 involves both proteasomal and lysosomal activities. Journal Article
In: Toxicological sciences : an official journal of the Society of Toxicology, vol. 107, no. 1, pp. 9–18, 2009, ISSN: 1096-0929, (Place: United States).
Abstract | Links | BibTeX | Tags: Analysis of Variance, Animals, Cell Communication/drug effects, Cell Line, Cell Membrane/drug effects, Connexin 43/genetics/*metabolism, Extracellular Signal-Regulated MAP Kinases/antagonists & inhibitors/metabolism, Gap Junctions/*drug effects/metabolism, Leupeptins/pharmacology, Liver/metabolism, Lysosomes/*drug effects/metabolism, Metabolic Networks and Pathways/drug effects, Polychlorinated Biphenyls/*pharmacology, Proteasome Endopeptidase Complex/*drug effects/metabolism, Proteasome Inhibitors, Rats
@article{simeckova_224455-hexachlorobiphenyl-enhanced_2009,
title = {The 2,2',4,4',5,5'-hexachlorobiphenyl-enhanced degradation of connexin 43 involves both proteasomal and lysosomal activities.},
author = {Pavlína Simecková and Jan Vondrácek and Zdenek Andrysík and Jirina Zatloukalová and Pavel Krcmár and Alois Kozubík and Miroslav Machala},
doi = {10.1093/toxsci/kfn202},
issn = {1096-0929},
year = {2009},
date = {2009-01-01},
journal = {Toxicological sciences : an official journal of the Society of Toxicology},
volume = {107},
number = {1},
pages = {9–18},
abstract = {One of the toxic effects of non-dioxin-like polychlorinated biphenyls (NDL-PCBs) is the acute inhibition of gap junctional intercellular communication (GJIC), an event possibly associated with tumor promotion. The model NDL-PCB-2,2',4,4',5,5'-hexachlorobiphenyl (PCB 153)-induces a sustained GJIC inhibition in rat liver epithelial WB-F344 cells. As this effect might be related to deregulation of connexin 43 (Cx43) synthesis, trafficking, or degradation, we investigated the impact of PCB 153 on these events. Although PCB 153 had no effect on Cx43 mRNA levels, it induced a gradual loss of Cx43 protein and significantly decreased the amount of gap junction plaques in plasma membrane. PCB 153 contributed to extracellular signal-regulated kinases 1 and 2 (ERK1/2)-dependent accumulation of hyperphosphorylated Cx43-P3 form, thus indicating that ERK1/2 activation by PCB 153 might contribute to its effects on Cx43 internalization or degradation. Inhibition of either proteasomes or lysosomes with their specific inhibitors largely restored total Cx43 protein levels, thus suggesting that both proteasomes and lysosomes may participate in the PCB 153-enhanced Cx43 internalization and degradation. However, neither the proteasomal nor the lysosomal inhibitors restored normal GJIC or number/size of gap junction plaques. Finally, PCB 153 also interfered with restoration of gap junction plaques following the inhibition of Cx43 transport to plasma membrane. Taken together, multiple modes of action seem to contribute to downregulation of Cx43 in PCB 153-treated rat liver epithelial cells. The enhanced degradation of Cx43, together with persistent inhibition of GJIC, might contribute to tumor-promoting effects of NDL-PCBs.},
note = {Place: United States},
keywords = {Analysis of Variance, Animals, Cell Communication/drug effects, Cell Line, Cell Membrane/drug effects, Connexin 43/genetics/*metabolism, Extracellular Signal-Regulated MAP Kinases/antagonists & inhibitors/metabolism, Gap Junctions/*drug effects/metabolism, Leupeptins/pharmacology, Liver/metabolism, Lysosomes/*drug effects/metabolism, Metabolic Networks and Pathways/drug effects, Polychlorinated Biphenyls/*pharmacology, Proteasome Endopeptidase Complex/*drug effects/metabolism, Proteasome Inhibitors, Rats},
pubstate = {published},
tppubtype = {article}
}
One of the toxic effects of non-dioxin-like polychlorinated biphenyls (NDL-PCBs) is the acute inhibition of gap junctional intercellular communication (GJIC), an event possibly associated with tumor promotion. The model NDL-PCB-2,2',4,4',5,5'-hexachlorobiphenyl (PCB 153)-induces a sustained GJIC inhibition in rat liver epithelial WB-F344 cells. As this effect might be related to deregulation of connexin 43 (Cx43) synthesis, trafficking, or degradation, we investigated the impact of PCB 153 on these events. Although PCB 153 had no effect on Cx43 mRNA levels, it induced a gradual loss of Cx43 protein and significantly decreased the amount of gap junction plaques in plasma membrane. PCB 153 contributed to extracellular signal-regulated kinases 1 and 2 (ERK1/2)-dependent accumulation of hyperphosphorylated Cx43-P3 form, thus indicating that ERK1/2 activation by PCB 153 might contribute to its effects on Cx43 internalization or degradation. Inhibition of either proteasomes or lysosomes with their specific inhibitors largely restored total Cx43 protein levels, thus suggesting that both proteasomes and lysosomes may participate in the PCB 153-enhanced Cx43 internalization and degradation. However, neither the proteasomal nor the lysosomal inhibitors restored normal GJIC or number/size of gap junction plaques. Finally, PCB 153 also interfered with restoration of gap junction plaques following the inhibition of Cx43 transport to plasma membrane. Taken together, multiple modes of action seem to contribute to downregulation of Cx43 in PCB 153-treated rat liver epithelial cells. The enhanced degradation of Cx43, together with persistent inhibition of GJIC, might contribute to tumor-promoting effects of NDL-PCBs.