Pleiotropic effects of gold(I) mixed-ligand complexes of 9-deazahypoxanthine on transcriptional activity of receptors for steroid hormones, nuclear receptors and xenoreceptors in human hepatocytes and cell lines

Kubešová, Kateřina; Trávnı́ček, Zdeněk; Dvořák, Zdeněk

doi:10.1016/j.ejmech.2016.05.064

Cited by 5 publications

(3 citation statements)

References 38 publications

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“…The quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) was performed on the Lightcycler 480 II using the LightCycler ® 480 Probes Master (Roche Diagnostic Corporation, Prague, Czech Republic). The levels of CYP1A1, CYP1A2 and GAPDH mRNAs were determined using the Universal Probe Library probes (UPL; Roche Diagnostic Corporation, Prague, Czech Republic) in combination with specific primers as described previously (Kubesova et al, 2016). The following protocol was used: an activation step at 95 °C for 10 min was followed by 45 cycles of PCR (denaturation at 95 °C for 10 s; annealing with elongation at 60 °C for 30 s).…”

Section: Methodsmentioning

confidence: 99%

Mono-methylindoles induce CYP1A genes and inhibit CYP1A1 enzyme activity in human hepatocytes and HepaRG cells

et al. 2019

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Mono-methylindoles (MMI) were described as agonists and/or antagonists of the human aryl hydrocarbon receptor (AhR). Here, we investigated the effects of MMI on AhR-CYP1A pathway in human hepatocytes and HepaRG cells derived from human progenitor hepatic cells. All MMI, except of 2-methylindole, strongly induced CYP1A1 and CYP1A2 mRNAs in HepaRG cells. Induction of CYP1A genes was absent in AhR-knock-out HepaRG cells. Consistently, CYP1A1 and CYP1A2 mRNAs and proteins were induced by all MMIs (except 2-methylindole), in human hepatocytes. The enzyme activity of CYP1A1 was inhibited by MMIs in human hepatocytes and LS180 colon cancer cells in a concentration-dependent manner (IC50 values from 1.2 μM to 23.8 μM and from 3.4 μM to 11.4 μM, respectively). Inhibition of CYP1A1 activity by MMI in human liver microsomes was much weaker as compared to that in intact cells. Incubation of parental MMI with human hepatocytes either diminished (4-methylindole, 6-methylindole) or enhanced (7-methylindole) their agonist effects on AhR in AZ-AHR reporter cells. In conclusion, overall effects of MMI on AhR-CYP1A pathway in human cells comprise the induction of CYP1A genes through AhR, the inhibition of CYP1A catalytic activity and possibly the metabolic transformation causing loss or gain of AhR agonist activity of parental compounds.

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Section: Methodsmentioning

confidence: 99%

Mono-methylindoles induce CYP1A genes and inhibit CYP1A1 enzyme activity in human hepatocytes and HepaRG cells

et al. 2019

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“…The following cell lines, endogenously expressing the respective receptors and stably transfected with corresponding luciferase reporter genes were used to estimate specific receptor activation: AZ-AHR cell line was used to quantify the AhR- and anti-AhR-mediated activity (Novotná et al, 2011); AZ-GR cell line was used to determine the GR-mediated activity (Novotná et al, 2012); IZ-VDRE and IZ-CYP24 cell lines were used for detection of VDR activation (Bartoňková et al, 2016); PZ-TR cell line was used for determination of TR-mediated activity (Illés et al, 2015); T47D.luc cell line, kindly provided by BioDetection Systems BV (BDS, Amsterdam, The Netherlands), was used to estimate the ER-mediated activity (Legler et al, 1999); AIZ-AR cell line was used for determination of androgen receptor (AR) activation (Bartoňková et al, 2015); HT-29 cell stably transfected with PPARγ reporter were used for determination of PPARγ-mediated activity (Tylichová et al, 2017). For detection of PXR-mediated activity, we employed human colon adenocarcinoma LS180 (purchased from the European Collection of Cell Cultures, Salisbury, UK) transiently transfected with PXR-regulated reporter gene, as described previously (Kubešová et al, 2016). Description of all individual assays is provided in Supplemental Experimental Procedures.…”

Section: Methodsmentioning

confidence: 99%

In vitro profiling of toxic effects of prominent environmental lower-chlorinated PCB congeners linked with endocrine disruption and tumor promotion

Pěnčíková

Svržková

Strapáčová

et al. 2018

Environmental Pollution

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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.

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“…The quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) was performed on the Lightcycler 480 II using the LightCycler ® 480 Probes Master (Roche Diagnostic Corporation, Prague, Czech Republic). The levels of CYP1A1 and GAPDH mRNAs were determined using the Universal Probe Library probes (UPL; Roche Diagnostic Corporation, Prague, Czech Republic) in combination with specific primers, using a protocol described elsewhere [36]. All measurements were performed in triplicates, and the gene expression was normalized to glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as a house-keeping gene.…”

Section: Mrna Isolation and Quantitative Real-time Reverse Transcriptmentioning

confidence: 99%

Gut Microbial Catabolites of Tryptophan Are Ligands and Agonists of the Aryl Hydrocarbon Receptor: A Detailed Characterization

Vyhlídalová

Krasulová

Pečinková

et al. 2020

IJMS

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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.

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Pleiotropic effects of gold(I) mixed-ligand complexes of 9-deazahypoxanthine on transcriptional activity of receptors for steroid hormones, nuclear receptors and xenoreceptors in human hepatocytes and cell lines

Cited by 5 publications

References 38 publications

Mono-methylindoles induce CYP1A genes and inhibit CYP1A1 enzyme activity in human hepatocytes and HepaRG cells

Mono-methylindoles induce CYP1A genes and inhibit CYP1A1 enzyme activity in human hepatocytes and HepaRG cells

In vitro profiling of toxic effects of prominent environmental lower-chlorinated PCB congeners linked with endocrine disruption and tumor promotion

Gut Microbial Catabolites of Tryptophan Are Ligands and Agonists of the Aryl Hydrocarbon Receptor: A Detailed Characterization

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