Latest Publications

@article{vazquez-gomez_aryl_2023,

title = {Aryl hydrocarbon receptor (AhR) and pregnane X receptor (PXR) play both distinct and common roles in the regulation of colon homeostasis and intestinal carcinogenesis.},

author = {Gerardo Vázquez-Gómez and Jiří Petráš and Zdeněk Dvořák and Jan Vondráček},

doi = {10.1016/j.bcp.2023.115797},

issn = {1873-2968 0006-2952},

year  = {2023},

date = {2023-10-01},

journal = {Biochemical pharmacology},

volume = {216},

pages = {115797},

abstract = {Both aryl hydrocarbon receptor (AhR) and pregnane X receptor (PXR) belong among key regulators of xenobiotic metabolism in the intestinal tissue. AhR in particular is activated by a wide range of environmental and dietary carcinogens. The data accumulated over the last two decades suggest that both of these transcriptional regulators play a much wider role in the maintenance of gut homeostasis, and that both transcription factors may affect processes linked with intestinal tumorigenesis. Intestinal epithelium is continuously exposed to a wide range of AhR, PXR and dual AhR/PXR ligands formed by intestinal microbiota or originating from diet. Current evidence suggests that specific ligands of both AhR and PXR can protect intestinal epithelium against inflammation and assist in the maintenance of epithelial barrier integrity. AhR, and to a lesser extent also PXR, have been shown to play a protective role against inflammation-induced colon cancer, or, in mouse models employing overactivation of Wnt/β-catenin signaling. In contrast, other evidence suggests that both receptors may contribute to modulation of transformed colon cell behavior, with a potential to promote cancer progression and/or chemoresistance. The review focuses on both overlapping and separate roles of the two receptors in these processes, and on possible implications of their activity within the context of intestinal tissue.},

note = {Place: England},

keywords = {*Receptors, Animals, Aryl hydrocarbon receptor, Aryl Hydrocarbon/genetics/metabolism, Carcinogenesis/genetics/metabolism, Colon cancer, Colon/metabolism, Dietary contaminants, Epithelial barrier, Inflammation, Inflammation/metabolism, Intestine, Mice, Microbial agonists, Pregnane X receptor, Pregnane X Receptor/metabolism, Steroid/metabolism},

pubstate = {published},

tppubtype = {article}

}

@article{sladekova_switching_2023,

title = {Switching on/off aryl hydrocarbon receptor and pregnane X receptor activities by chemically modified tryptamines.},

author = {Lucia Sládeková and Eliška Zgarbová and Radim Vrzal and David Vanda and Miroslav Soural and Klára Jakubcová and Gerardo Vázquez-Gómez and Jan Vondráček and Zdeněk Dvořák},

doi = {10.1016/j.toxlet.2023.09.012},

issn = {1879-3169 0378-4274},

year  = {2023},

date = {2023-09-01},

journal = {Toxicology letters},

volume = {387},

pages = {63–75},

abstract = {Microbial indoles have been demonstrated as selective or dual agonists and ligands of the pregnane X receptor (PXR) and aryl hydrocarbon receptor (AhR). However, structural determinants of microbial indoles selectivity towards both receptors remain elusive. Here, we studied the effects of existing and newly synthesized derivatives of indole microbial metabolite tryptamine on the activity of AhR and PXR receptors. We show that the elongation of indolyl-3-alkaneamine chain, indole N-methylation and conversion of indolyl-3-alkaneamines to oleamides resulted in a major increase of PXR activity and in parallel loss of AhR activity. Using reporter gene assays, RT-PCR and TR-FRET techniques, we have characterized in detail the activation of PXR by novel indolyl-3-alkanyl-oleamides, 1-methyltryptamine and 1-methyltryptamine-acetamide. As a proof of concept, we demonstrated anti-inflammatory and epithelial barrier-protective activity of lead derivatives in intestinal Caco-2 cells, employing the measurement of expression of pro-inflammatory chemokines, tight junction genes, trans-epithelial electric resistance TEER, and dextran-FITC permeability assay. In conclusion, we show that a subtle chemical modifications of simple microbial indole metabolite tryptamine, leads to substantial changes in AhR and PXR agonist activities.},

note = {Place: Netherlands},

keywords = {*Receptors, Aryl hydrocarbon receptor, Aryl Hydrocarbon/metabolism, Caco-2 Cells, Humans, Indoles/pharmacology, Microbial indoles, Pregnane X receptor, Pregnane X Receptor/genetics, Steroid/metabolism, Tryptamine, Tryptamines/pharmacology},

pubstate = {published},

tppubtype = {article}

}

@article{pencikova_vitro_2018,

title = {In vitro profiling of toxic effects of prominent environmental lower-chlorinated PCB congeners linked with endocrine disruption and tumor promotion.},

author = {Kateřina Pěnčíková and Lucie Svržková and Simona Strapáčová and Jiří Neča and Iveta Bartoňková and Zdeněk Dvořák and Martina Hýžďalová and Jakub Pivnička and Lenka Pálková and Hans-Joachim Lehmler and Xueshu Li and Jan Vondráček and Miroslav Machala},

doi = {10.1016/j.envpol.2018.02.067},

issn = {1873-6424 0269-7491},

year  = {2018},

date = {2018-06-01},

journal = {Environmental pollution (Barking, Essex : 1987)},

volume = {237},

pages = {473–486},

abstract = {The mechanisms contributing to toxic effects of airborne lower-chlorinated PCB congeners (LC-PCBs) remain poorly characterized. We evaluated in vitro toxicities of environmental LC-PCBs found in both indoor and outdoor air (PCB 4, 8, 11, 18, 28 and 31), and selected hydroxylated metabolites of PCB 8, 11 and 18, using reporter gene assays, as well as other functional cellular bioassays. We focused on processes linked with endocrine disruption, tumor promotion and/or regulation of transcription factors controlling metabolism of both endogenous compounds and xenobiotics. The tested LC-PCBs were found to be mostly efficient anti-androgenic (within nanomolar - micromolar range) and estrogenic (at micromolar concentrations) compounds, as well as inhibitors of gap junctional intercellular communication (GJIC) at micromolar concentrations. PCB 8, 28 and 31 were found to partially inhibit the aryl hydrocarbon receptor (AhR)-mediated activity. The tested LC-PCBs were also partial constitutive androstane receptor (CAR) and pregnane X receptor (PXR) agonists, with PCB 4, 8 and 18 being the most active compounds. They were inactive towards other nuclear receptors, such as vitamin D receptor, thyroid receptor α, glucocorticoid receptor or peroxisome proliferator-activated receptor γ. We found that only PCB 8 contributed to generation of oxidative stress, while all tested LC-PCBs induced arachidonic acid release (albeit without further modulations of arachidonic acid metabolism) in human lung epithelial cells. Importantly, estrogenic effects of hydroxylated (OH-PCB) metabolites of LC-PCBs (4-OH-PCB 8, 4-OH-PCB 11 and 4'-OH-PCB 18) were higher than those of the parent PCBs, while their other toxic effects were only slightly altered or suppressed. This suggested that metabolism may alter toxicity profiles of LC-PCBs in a receptor-specific manner. In summary, anti-androgenic and estrogenic activities, acute inhibition of GJIC and suppression of the AhR-mediated activity were found to be the most relevant modes of action of airborne LC-PCBs, although they partially affected also additional cellular targets.},

note = {Place: England},

keywords = {Air Pollutants/*toxicity, Airborne polychlorinated biphenyls, Cell Line, Constitutive Androstane Receptor, Cytoplasmic and Nuclear/metabolism, Endocrine disruption, Endocrine Disruptors/metabolism/*toxicity, Epithelial Cells/drug effects, Humans, HydroxyLated PCBs, Hydroxylation, Metabolism of xenobiotics, Neoplasms/metabolism, Polychlorinated Biphenyls/metabolism/*toxicity, Pregnane X receptor, Receptors, Signal Transduction/drug effects, Steroid/metabolism, Tumor promotion},

pubstate = {published},

tppubtype = {article}

}

@article{pencikova_atropisomers_2018,

title = {Atropisomers of 2,2',3,3',6,6'-hexachlorobiphenyl (PCB 136) exhibit stereoselective effects on activation of nuclear receptors in vitro.},

author = {Kateřina Pěnčíková and Petra Brenerová and Lucie Svržková and Eva Hrubá and Lenka Pálková and Jan Vondráček and Hans-Joachim Lehmler and Miroslav Machala},

doi = {10.1007/s11356-017-0683-x},

issn = {1614-7499 0944-1344},

year  = {2018},

date = {2018-06-01},

journal = {Environmental science and pollution research international},

volume = {25},

number = {17},

pages = {16411–16419},

abstract = {PCB 136 is an environmentally relevant chiral PCB congener, which has been found in vivo to be present in form of rotational isomers (atropisomers). Its atropselective biotransformation or neurotoxic effects linked with sensitization of ryanodine receptor suggest that it might interact also with other intracellular receptors in a stereospecific manner. However, possible atropselective effects of PCB 136 on nuclear receptor transactivation remain unknown. Therefore, in this study, atropselective effects of PCB 136 on nuclear receptors controlling endocrine signaling and/or expression of xenobiotic and steroid hormone catabolism were investigated. PCB136 atropisomers were found to exert differential effects on estrogen receptor (ER) activation; (+)-PCB 136 was estrogenic, while (-)-PCB 136 was antiestrogenic. In contrast, inhibition of androgen receptor (AR) activity was not stereospecific. Both PCB136 stereoisomers induced the constitutive androgen receptor (CAR)-dependent gene expression; however, no significant stereospecificity of PCB 136 atropisomers was observed. PCB136 was a partial inducer of the pregnane X receptor (PXR)-dependent gene expression. Here, (-)-PCB 136 was a significantly more potent inducer of PXR activity than (+)-PCB 136. Taken together, the present results indicate that at least two nuclear receptors participating in endocrine regulation or metabolism, ER and PXR, could be regulated in an atropselective manner by chiral PCB 136. The enantioselective enrichment of PCB atropisomers in animal and human tissues may thus have significant consequences for endocrine-disrupting effects of chiral ortho-substituted PCB congeners.},

note = {Place: Germany},

keywords = {Androgen receptor, Animals, Atropisomer, Biotransformation, Chiral, Constitutive Androstane Receptor, Cytoplasmic and Nuclear/*chemistry/metabolism, Estrogen receptors, Humans, Polychlorinated biphenyl, Polychlorinated Biphenyls/*chemistry, Pregnane X receptor, Receptors, Stereoisomerism, Steroid/chemistry/metabolism},

pubstate = {published},

tppubtype = {article}

}