Latest Publications

@article{krkoska_role_2022,

title = {Role of miR-653 and miR-29c in downregulation of CYP1A2 expression in hepatocellular carcinoma.},

author = {Martin Krkoška and Jana Nekvindová and Kateřina Nevědělová and Veronika Zubáňová and Lenka Radová and Jan Vondráček and Jarmila Herůdková and Ondřej Slabý and Igor Kiss and Lucia Bohovicová and Pavel Fabian and Zuzana Tylichová and Zdeněk Kala and Petr Kysela and Lenka Ostřížková and Vladimír Palička and Alena Hyršlová Vaculová},

doi = {10.1007/s43440-021-00338-9},

issn = {2299-5684 1734-1140},

year  = {2022},

date = {2022-02-01},

journal = {Pharmacological reports : PR},

volume = {74},

number = {1},

pages = {148–158},

abstract = {BACKGROUND: Hepatocellular carcinoma (HCC) is a major contributor to the worldwide cancer burden. Recent studies on HCC have demonstrated dramatic alterations in expression of several cytochrome P450 (CYP) family members that play a crucial role in biotransformation of many drugs and other xenobiotics; however, the mechanisms responsible for their deregulation remain unclear. METHODS: We investigated a potential involvement of miRNAs in downregulation of expression of CYPs observed in HCC tumors. We compared miRNA expression profiles (TaqMan Array Human MicroRNA v3.0 TLDA qPCR) between HCC human patient tumors with strong (CYP-) and weak/no (CYP+) downregulation of drug-metabolizing CYPs. The role of significantly deregulated miRNAs in modulation of expression of the CYPs and associated xenobiotic receptors was then investigated in human liver HepaRG cells transfected with relevant miRNA mimics or inhibitors. RESULTS: We identified five differentially expressed miRNAs in CYP- versus CYP+ tumors, namely miR-29c, miR-125b1, miR-505, miR-653 and miR-675. The two most-upregulated miRNAs found in CYP- tumor samples, miR-29c and miR-653, were found to act as efficient suppressors of CYP1A2 or AHR expression. CONCLUSIONS: Our results revealed a novel role of miR-653 and miR-29c in regulation of expresion of CYPs involved in crucial biotransformation processes in liver, which are often deregulated during liver cancer progression.},

note = {Place: Switzerland},

keywords = {*Carcinoma, *Liver Neoplasms/genetics/metabolism, AhR, Biotransformation, Cell Line, CYP1A2, Cytochrome P-450 CYP1A2/*metabolism, Down-Regulation, Gene Expression Regulation, Hepatocellular carcinoma, Hepatocellular/genetics/metabolism, Hepatocytes/metabolism, Humans, MicroRNA, MicroRNAs/*metabolism, Neoplastic, Tumor, Xenobiotics/metabolism},

pubstate = {published},

tppubtype = {article}

}

@article{zapletal_butyrate_2019,

title = {Butyrate interacts with benzo[a]pyrene to alter expression and activities of xenobiotic metabolizing enzymes involved in metabolism of carcinogens within colon epithelial cell models.},

author = {Ondřej Zapletal and Jiřina Procházková and Vít Dubec and Jiřina Hofmanová and Alois Kozubík and Jan Vondráček},

doi = {10.1016/j.tox.2018.11.001},

issn = {1879-3185 0300-483X},

year  = {2019},

date = {2019-01-01},

journal = {Toxicology},

volume = {412},

pages = {1–11},

abstract = {Butyrate helps to maintain colon homeostasis and exhibits chemopreventive effects in colon epithelium. We examined the interactive effects of butyrate and benzo[a]pyrene (BaP), dietary carcinogen, in regulation of expression of a panel of phase I and II xenobiotic metabolizing enzymes (XMEs) in human colon cells. In human colon carcinoma HCT-116 and HT-29 cell lines, butyrate alone increased mRNA levels of some enzymes, such as N-acetyltransferases (in particular NAT2). In combination with BaP, butyrate potentiated induction of cytochrome P450 family 1 enzymes (CYP1A1), aldo-keto reductases (AKR1C1) or UDP-glucuronosyltransferases (UGT1A1). There were some notable differences between cell lines, as butyrate potentiated induction of NAD(P)H:quinone oxidoreductase 1 (NQO1) and UGT1A4 only in HCT-116 cells, and it even repressed AKR1C3 induction in HT-29 cells. Butyrate also promoted induction of CYP1, NQO1, NAT2, UGT1A1 or UGT1A4 in human colon Caco-2 cells, in a differentiation-dependent manner. Differentiated Caco-2 cells exhibited a higher inducibility of selected XME genes than undifferentiated cells. Butyrate increased induction of enzymatic activities of NATs, NQO1 and UGTs by BaP in HCT-116 and HT29 cells, whereas in differentiated Caco-2 cells it helped to increase only enzymatic activity of NQO1 and UGTs. Together, the present data suggest that butyrate may modulate expression/activities of several enzymes involved in metabolism of carcinogens in colon. In some cases (NAT2, UGT1 A1), this was linked to inhibition of histone deacetylases (HDAC), as confirmed by using HDAC inhibitor trichostatin A. These results may have implications for our understanding of the role of butyrate in regulation of XMEs and carcinogen metabolism in colon.},

note = {Place: Ireland},

keywords = {Benzo(a)pyrene/*toxicity, Butyrate, Butyrates/*pharmacology, Carcinogens/*toxicity, Cell Line, Colon epithelium, Colon/cytology, Epithelial Cells/drug effects/metabolism, Humans, N-acetyltransferases, NAD(P)H:quinone oxidoreductase 1, Oxidoreductases/genetics/*metabolism, Polycyclic aromatic hydrocarbons, Transferases/genetics/*metabolism, UDP-glucuronosyltransferases, Xenobiotics/metabolism},

pubstate = {published},

tppubtype = {article}

}

@article{vondracek_interactions_2011,

title = {Interactions of the aryl hydrocarbon receptor with inflammatory mediators: beyond CYP1A regulation.},

author = {Jan Vondrácek and Lenka Umannová and Miroslav Machala},

doi = {10.2174/138920011795016827},

issn = {1875-5453 1389-2002},

year  = {2011},

date = {2011-02-01},

journal = {Current drug metabolism},

volume = {12},

number = {2},

pages = {89–103},

abstract = {The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor, which plays a major role in toxic effects of environmental pollutants. It is a pivotal regulator of several xenobiotic-metabolizing enzymes (XMEs), and is now considered to play an important role also in control of cell cycle, apoptosis and cell differentiation. The accumulating evidence suggests that there exists a multiple crosstalk between AhR activation and the signaling pathways activated by inflammatory mediators, such as nuclear factor-κB, a pleiotropic transcription factor controlling the immune/inflammatory responses. In this review, we summarize the current knowledge about the interactions of AhR with inflammatory mediators leading to deregulation of the AhR-dependent XMEs, as well as the evidence pointing to the role of AhR in modulation of inflammatory signals. These include altered expression of proinflammatory cytokines, such as tumor necrosis factor-alpha or interleukin-6, and deregulation of expression/activity of principle enzymes producing inflammatory mediators, such as cyclooxygenase-2. Recent studies also indicate that various classes of AhR ligands may differentially modulate AhR-dependent toxic responses and inflammation, which opens an interesting opportunity for a targeted synthesis of AhR ligands with anti-inflammatory properties. Although the role of activated AhR in the regulation of inflammation is still far from being completely understood, the close interactions between AhR and inflammatory signaling evidently can play a significant role in immune dysfunctions, metabolism of xenobiotics or carcinogenesis. The current review will focus mostly on the interaction of AhR and inflammation relative to mechanisms associated with the pathology of carcinogenesis.},

note = {Place: Netherlands},

keywords = {Animals, Anti-Inflammatory Agents/pharmacology, Aryl Hydrocarbon Hydroxylases/*genetics/metabolism/*physiology, Aryl Hydrocarbon/drug effects/*physiology, Enzymologic/*physiology, Gene Expression Regulation, Humans, Inflammation Mediators/metabolism/*physiology, Inflammation/drug therapy/metabolism/physiopathology, Receptors, Signal Transduction/*physiology, Xenobiotics/metabolism},

pubstate = {published},

tppubtype = {article}

}