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).
Vyhlídalová, Barbora; Krasulová, Kristýna; Pečinková, Petra; Marcalíková, Adéla; Vrzal, Radim; Zemánková, Lenka; Vančo, Jan; Trávníček, Zdeněk; Vondráček, Jan; Karasová, Martina; Mani, Sridhar; Dvořák, Zdeněk
Gut Microbial Catabolites of Tryptophan Are Ligands and Agonists of the Aryl Hydrocarbon Receptor: A Detailed Characterization. Journal Article
In: International journal of molecular sciences, vol. 21, no. 7, 2020, ISSN: 1422-0067, (Place: Switzerland).
Abstract | Links | BibTeX | Tags: *Gastrointestinal Microbiome/drug effects, Animals, Aryl hydrocarbon receptor, Aryl Hydrocarbon/*agonists/*metabolism, Basic Helix-Loop-Helix Transcription Factors/*agonists/*metabolism, Cell Line, Cytochrome P-450 CYP1A1/genetics, Gene Expression, Genes, Genetic, Humans, Indoles, Ligands, Metabolic Networks and Pathways, Mice, Microbiome, Promoter Regions, Protein Binding, Protein Multimerization, Receptors, Reporter, tryptophan, Tryptophan/*metabolism, Tumor
@article{vyhlidalova_gut_2020,
title = {Gut Microbial Catabolites of Tryptophan Are Ligands and Agonists of the Aryl Hydrocarbon Receptor: A Detailed Characterization.},
author = {Barbora Vyhlídalová and Kristýna Krasulová and Petra Pečinková and Adéla Marcalíková and Radim Vrzal and Lenka Zemánková and Jan Vančo and Zdeněk Trávníček and Jan Vondráček and Martina Karasová and Sridhar Mani and Zdeněk Dvořák},
doi = {10.3390/ijms21072614},
issn = {1422-0067},
year = {2020},
date = {2020-04-01},
journal = {International journal of molecular sciences},
volume = {21},
number = {7},
abstract = {We examined the effects of gut microbial catabolites of tryptophan on the aryl hydrocarbon receptor (AhR). Using a reporter gene assay, we show that all studied catabolites are low-potency agonists of human AhR. The efficacy of catabolites differed substantially, comprising agonists with no or low (i3-propionate, i3-acetate, i3-lactate, i3-aldehyde), medium (i3-ethanol, i3-acrylate, skatole, tryptamine), and high (indole, i3-acetamide, i3-pyruvate) efficacies. We displayed ligand-selective antagonist activities by i3-pyruvate, i3-aldehyde, indole, skatole, and tryptamine. Ligand binding assay identified low affinity (skatole, i3-pyruvate, and i3-acetamide) and very low affinity (i3-acrylate, i3-ethanol, indole) ligands of the murine AhR. Indole, skatole, tryptamine, i3-pyruvate, i3-acrylate, and i3-acetamide induced CYP1A1 mRNA in intestinal LS180 and HT-29 cells, but not in the AhR-knockout HT-29 variant. We observed a similar CYP1A1 induction pattern in primary human hepatocytes. The most AhR-active catabolites (indole, skatole, tryptamine, i3-pyruvate, i3-acrylate, i3-acetamide) elicited nuclear translocation of the AhR, followed by a formation of AhR-ARNT heterodimer and enhanced binding of the AhR to the CYP1A1 gene promoter. Collectively, we comprehensively characterized the interactions of gut microbial tryptophan catabolites with the AhR, which may expand the current understanding of their potential roles in intestinal health and disease.},
note = {Place: Switzerland},
keywords = {*Gastrointestinal Microbiome/drug effects, Animals, Aryl hydrocarbon receptor, Aryl Hydrocarbon/*agonists/*metabolism, Basic Helix-Loop-Helix Transcription Factors/*agonists/*metabolism, Cell Line, Cytochrome P-450 CYP1A1/genetics, Gene Expression, Genes, Genetic, Humans, Indoles, Ligands, Metabolic Networks and Pathways, Mice, Microbiome, Promoter Regions, Protein Binding, Protein Multimerization, Receptors, Reporter, tryptophan, Tryptophan/*metabolism, Tumor},
pubstate = {published},
tppubtype = {article}
}
We examined the effects of gut microbial catabolites of tryptophan on the aryl hydrocarbon receptor (AhR). Using a reporter gene assay, we show that all studied catabolites are low-potency agonists of human AhR. The efficacy of catabolites differed substantially, comprising agonists with no or low (i3-propionate, i3-acetate, i3-lactate, i3-aldehyde), medium (i3-ethanol, i3-acrylate, skatole, tryptamine), and high (indole, i3-acetamide, i3-pyruvate) efficacies. We displayed ligand-selective antagonist activities by i3-pyruvate, i3-aldehyde, indole, skatole, and tryptamine. Ligand binding assay identified low affinity (skatole, i3-pyruvate, and i3-acetamide) and very low affinity (i3-acrylate, i3-ethanol, indole) ligands of the murine AhR. Indole, skatole, tryptamine, i3-pyruvate, i3-acrylate, and i3-acetamide induced CYP1A1 mRNA in intestinal LS180 and HT-29 cells, but not in the AhR-knockout HT-29 variant. We observed a similar CYP1A1 induction pattern in primary human hepatocytes. The most AhR-active catabolites (indole, skatole, tryptamine, i3-pyruvate, i3-acrylate, i3-acetamide) elicited nuclear translocation of the AhR, followed by a formation of AhR-ARNT heterodimer and enhanced binding of the AhR to the CYP1A1 gene promoter. Collectively, we comprehensively characterized the interactions of gut microbial tryptophan catabolites with the AhR, which may expand the current understanding of their potential roles in intestinal health and disease.