2020
Nekvindova, Jana; Mrkvicova, Alena; Zubanova, Veronika; Vaculova, Alena Hyrslova; Anzenbacher, Pavel; Soucek, Pavel; Radova, Lenka; Slaby, Ondrej; Kiss, Igor; Vondracek, Jan; Spicakova, Alena; Bohovicova, Lucia; Fabian, Pavel; Kala, Zdenek; Palicka, Vladimir
Hepatocellular carcinoma: Gene expression profiling and regulation of xenobiotic-metabolizing cytochromes P450. Journal Article
In: Biochemical pharmacology, vol. 177, pp. 113912, 2020, ISSN: 1873-2968 0006-2952, (Place: England).
Abstract | Links | BibTeX | Tags: *Gene Expression Regulation, *Transcriptome, Adult, Aged, Carcinoma, Cohort Studies, CYP, Cytochrome P-450 Enzyme System/*genetics, Cytochrome P450, Cytoplasmic and Nuclear/genetics/metabolism, Drug metabolism, Enzymologic, Female, Gene Expression, Gene Expression Profiling, Hepatocellular carcinoma, Hepatocellular/*enzymology/pathology, Hepatocytes/metabolism, Humans, Inactivation, Liver Neoplasms/*enzymology/pathology, Liver/metabolism, Male, Metabolic/genetics, Middle Aged, Neoplasm Grading, Non-coding RNA, Receptors
@article{nekvindova_hepatocellular_2020,
title = {Hepatocellular carcinoma: Gene expression profiling and regulation of xenobiotic-metabolizing cytochromes P450.},
author = {Jana Nekvindova and Alena Mrkvicova and Veronika Zubanova and Alena Hyrslova Vaculova and Pavel Anzenbacher and Pavel Soucek and Lenka Radova and Ondrej Slaby and Igor Kiss and Jan Vondracek and Alena Spicakova and Lucia Bohovicova and Pavel Fabian and Zdenek Kala and Vladimir Palicka},
doi = {10.1016/j.bcp.2020.113912},
issn = {1873-2968 0006-2952},
year = {2020},
date = {2020-07-01},
journal = {Biochemical pharmacology},
volume = {177},
pages = {113912},
abstract = {Hepatocellular carcinoma (HCC) remains a highly prevalent and deadly disease, being among the top causes of cancer-related deaths worldwide. Despite the fact that the liver is the major site of biotransformation, studies on drug metabolizing enzymes in HCC are scarce. It is known that malignant transformation of hepatocytes leads to a significant alteration of their metabolic functions and overall deregulation of gene expression. Advanced stages of the disease are thus frequently associated with liver failure, and severe alteration of drug metabolism. However, the impact of dysregulation of metabolic enzymes on therapeutic efficacy and toxicity in HCC patients is largely unknown. Here we demonstrate a significant down-regulation in European Caucasian patients of cytochromes P450 (CYPs), the major xenobiotic-metabolizing enzymes, in HCC tumour samples as compared to their surrounding non-cancerous (reference) tissue. Moreover, we report for the first time the association of the unique CYP profiles with specific transcriptome changes, and interesting correlations with expression levels of nuclear receptors and with the histological grade of the tumours. Integrated analysis has suggested certain co-expression profiles of CYPs with lncRNAs that need to be further characterized. Patients with large tumours with down-regulated CYPs could be more vulnerable to drug toxicity; on the other hand, such tumours would eliminate drugs more slowly and should be more sensitive to pharmacotherapy (except in the case of pro-drugs where activation is necessary).},
note = {Place: England},
keywords = {*Gene Expression Regulation, *Transcriptome, Adult, Aged, Carcinoma, Cohort Studies, CYP, Cytochrome P-450 Enzyme System/*genetics, Cytochrome P450, Cytoplasmic and Nuclear/genetics/metabolism, Drug metabolism, Enzymologic, Female, Gene Expression, Gene Expression Profiling, Hepatocellular carcinoma, Hepatocellular/*enzymology/pathology, Hepatocytes/metabolism, Humans, Inactivation, Liver Neoplasms/*enzymology/pathology, Liver/metabolism, Male, Metabolic/genetics, Middle Aged, Neoplasm Grading, Non-coding RNA, Receptors},
pubstate = {published},
tppubtype = {article}
}
Hepatocellular carcinoma (HCC) remains a highly prevalent and deadly disease, being among the top causes of cancer-related deaths worldwide. Despite the fact that the liver is the major site of biotransformation, studies on drug metabolizing enzymes in HCC are scarce. It is known that malignant transformation of hepatocytes leads to a significant alteration of their metabolic functions and overall deregulation of gene expression. Advanced stages of the disease are thus frequently associated with liver failure, and severe alteration of drug metabolism. However, the impact of dysregulation of metabolic enzymes on therapeutic efficacy and toxicity in HCC patients is largely unknown. Here we demonstrate a significant down-regulation in European Caucasian patients of cytochromes P450 (CYPs), the major xenobiotic-metabolizing enzymes, in HCC tumour samples as compared to their surrounding non-cancerous (reference) tissue. Moreover, we report for the first time the association of the unique CYP profiles with specific transcriptome changes, and interesting correlations with expression levels of nuclear receptors and with the histological grade of the tumours. Integrated analysis has suggested certain co-expression profiles of CYPs with lncRNAs that need to be further characterized. Patients with large tumours with down-regulated CYPs could be more vulnerable to drug toxicity; on the other hand, such tumours would eliminate drugs more slowly and should be more sensitive to pharmacotherapy (except in the case of pro-drugs where activation is necessary).
2016
Brenerová, Petra; Hamers, Timo; Kamstra, Jorke H.; Vondráček, Jan; Strapáčová, Simona; Andersson, Patrik L.; Machala, Miroslav
Pure non-dioxin-like PCB congeners suppress induction of AhR-dependent endpoints in rat liver cells. Journal Article
In: Environmental science and pollution research international, vol. 23, no. 3, pp. 2099–2107, 2016, ISSN: 1614-7499 0944-1344, (Place: Germany).
Abstract | Links | BibTeX | Tags: Animals, Aryl hydrocarbon receptor, Aryl Hydrocarbon/genetics/*metabolism, Cell Line, Cell Proliferation/drug effects, Cytochrome P-450 CYP1A1/genetics/metabolism, Cytochrome P450, Disruption of contact inhibition, DR-CALUX® assay, Epithelial Cells/cytology/drug effects/metabolism, Gene Expression/drug effects, Hepatocytes/cytology/drug effects/metabolism, Liver/*drug effects/metabolism, NDL-PCBs, Polychlorinated Biphenyls/*chemistry/*toxicity, Rats, Receptors, Relative effect potency, Signal Transduction/drug effects
@article{brenerova_pure_2016,
title = {Pure non-dioxin-like PCB congeners suppress induction of AhR-dependent endpoints in rat liver cells.},
author = {Petra Brenerová and Timo Hamers and Jorke H. Kamstra and Jan Vondráček and Simona Strapáčová and Patrik L. Andersson and Miroslav Machala},
doi = {10.1007/s11356-015-4819-6},
issn = {1614-7499 0944-1344},
year = {2016},
date = {2016-02-01},
journal = {Environmental science and pollution research international},
volume = {23},
number = {3},
pages = {2099–2107},
abstract = {The relative potencies of non-ortho-substituted coplanar polychlorinated biphenyl (PCB) congeners to activate the aryl hydrocarbon receptor (AhR) and to cause the AhR-dependent toxic events are essential for their risk assessment. Since some studies suggested that abundant non-dioxin-like PCB congeners (NDL-PCBs) may alter the AhR activation by PCB mixtures and possibly cause non-additive effects, we evaluated potential suppressive effects of NDL-PCBs on AhR activation, using a series of 24 highly purified NDL-PCBs. We investigated their impact on the model AhR agonist-induced luciferase reporter gene expression in rat hepatoma cells and on induction of CYP1A1/1B1 mRNAs and deregulation of AhR-dependent cell proliferation in rat liver epithelial cells. PCBs 128, 138, and 170 significantly suppressed AhR activation (with IC50 values from 1.4 to 5.6 μM), followed by PCBs 28, 47, 52, and 180; additionally, PCBs 122, 153, and 168 showed low but still significant potency to reduce luciferase activity. Detection of CYP1A1 mRNA levels in liver epithelial cells largely confirmed these results for the most abundant NDL-PCBs, whereas the other AhR-dependent events (CYP1B1 mRNA expression, induction of cell proliferation in confluent cells) were less sensitive to NDL-PCBs, thus indicating a more complex regulation of these endpoints. The present data suggest that some NDL-PCBs could modulate overall dioxin-like effects in complex mixtures.},
note = {Place: Germany},
keywords = {Animals, Aryl hydrocarbon receptor, Aryl Hydrocarbon/genetics/*metabolism, Cell Line, Cell Proliferation/drug effects, Cytochrome P-450 CYP1A1/genetics/metabolism, Cytochrome P450, Disruption of contact inhibition, DR-CALUX® assay, Epithelial Cells/cytology/drug effects/metabolism, Gene Expression/drug effects, Hepatocytes/cytology/drug effects/metabolism, Liver/*drug effects/metabolism, NDL-PCBs, Polychlorinated Biphenyls/*chemistry/*toxicity, Rats, Receptors, Relative effect potency, Signal Transduction/drug effects},
pubstate = {published},
tppubtype = {article}
}
The relative potencies of non-ortho-substituted coplanar polychlorinated biphenyl (PCB) congeners to activate the aryl hydrocarbon receptor (AhR) and to cause the AhR-dependent toxic events are essential for their risk assessment. Since some studies suggested that abundant non-dioxin-like PCB congeners (NDL-PCBs) may alter the AhR activation by PCB mixtures and possibly cause non-additive effects, we evaluated potential suppressive effects of NDL-PCBs on AhR activation, using a series of 24 highly purified NDL-PCBs. We investigated their impact on the model AhR agonist-induced luciferase reporter gene expression in rat hepatoma cells and on induction of CYP1A1/1B1 mRNAs and deregulation of AhR-dependent cell proliferation in rat liver epithelial cells. PCBs 128, 138, and 170 significantly suppressed AhR activation (with IC50 values from 1.4 to 5.6 μM), followed by PCBs 28, 47, 52, and 180; additionally, PCBs 122, 153, and 168 showed low but still significant potency to reduce luciferase activity. Detection of CYP1A1 mRNA levels in liver epithelial cells largely confirmed these results for the most abundant NDL-PCBs, whereas the other AhR-dependent events (CYP1B1 mRNA expression, induction of cell proliferation in confluent cells) were less sensitive to NDL-PCBs, thus indicating a more complex regulation of these endpoints. The present data suggest that some NDL-PCBs could modulate overall dioxin-like effects in complex mixtures.