Zearalenone activates pregnane X receptor, constitutive androstane receptor and aryl hydrocarbon receptor and corresponding phase I target genes mRNA in primary cultures of human hepatocytes

2011 ◽  
Vol 31 (1) ◽  
pp. 79-87 ◽  
Author(s):  
Imen Ayed-Boussema ◽  
Jean Marc Pascussi ◽  
Patrick Maurel ◽  
Hassen Bacha ◽  
Wafa Hassen
Keyword(s):  
Phase I ◽  
Aryl Hydrocarbon Receptor ◽  
Target Genes ◽  
Primary Cultures ◽  
Constitutive Androstane Receptor ◽  
Pregnane X Receptor ◽  
Human Hepatocytes ◽  
Aryl Hydrocarbon

scholarly journals Transporter Gene Regulation in Sandwich Cultured Human Hepatocytes Through the Activation of Constitutive Androstane Receptor (CAR) or Aryl Hydrocarbon Receptor (AhR)

2021 ◽  
Vol 11 ◽  
Author(s):  
Congrong Niu ◽  
Bill Smith ◽  
Yurong Lai
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Constitutive Androstane Receptor ◽  
Gene Induction ◽  
Human Hepatocytes ◽  
Drug Transporter ◽  
Transporter Gene ◽  
Aryl Hydrocarbon ◽  
Multiple Donors ◽  
Metabolizing Enzyme ◽  
Nuclear Receptor Ligands

The induction potentials of ligand-activated nuclear receptors on metabolizing enzyme genes are routinely tested for new chemical entities. However, regulations of drug transporter genes by the nuclear receptor ligands are underappreciated, especially in differentiated human hepatocyte cultures. In this study, gene induction by the ligands of constitutive androstane receptor (CAR) and aryl hydrocarbon receptor (AhR) was characterized in sandwich-cultured human hepatocytes (SCHH) from multiple donors. The cells were treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), omeprazole (OP), 6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime (CITCO) and phenobarbital (PB) for three days. RNA samples were analyzed by qRT-PCR method. As expected, CITCO, the direct activator, and PB, the indirect activator of CAR, induced CYP3A4 (31 and 40-fold), CYP2B6 (24 and 28-fold) and UGT1A1 (2.9 and 4.2-fold), respectively. Conversely, TCDD and OP, the activators of AhR, induced CYP1A1 (38 and 37-fold), and UGT1A1 (4.3 and 5.0-fold), respectively. In addition, OP but not TCDD induced CY3A4 by about 61-fold. Twenty-four hepatic drug transporter genes were characterized, and of those, SLC51B was induced the most by PB and OP by about 3.3 and 6.5 fold, respectively. Marginal inductions (about 2-fold) of SLC47A1 and SLCO4C1 genes by PB, and ABCG2 gene by TCDD were observed. In contrast, SLC10A1 gene was suppressed about 2-fold by TCDD and CITCO. While clinical relevance of SLC51B gene induction or SLC10A1 gene suppression warrants further investigation, the results verified that the assessment of transporter gene inductions are not required for new drug entities, when a drug does not remarkably induce metabolizing enzyme genes by CAR and AhR activation.

Effect of Aflatoxin B1 on Nuclear Receptors PXR, CAR, and AhR and Their Target Cytochromes P450 mRNA Expression in Primary Cultures of Human Hepatocytes

2011 ◽  
Vol 31 (1) ◽  
pp. 86-93 ◽  
Author(s):  
Imen Ayed-Boussema ◽  
Jean-Marc Pascussi ◽  
Patrick Maurel ◽  
Hassen Bacha ◽  
Wafa Hassen
Keyword(s):  
Mrna Expression ◽  
Aflatoxin B1 ◽  
Messenger Rna ◽  
Animal Feed ◽  
Cytochromes P450 ◽  
Primary Cultures ◽  
Constitutive Androstane Receptor ◽  
Pregnane X Receptor ◽  
Receptor Activation ◽  
Human Hepatocytes

Aflatoxin B1 (AFB1), one of the most common mycotoxins found in human foods and animal feed, is principally hepatotoxic and hepatocarcinogenic. The aim of the present study was to explore the effect of AFB1 on messenger RNA (mRNA) expression of pregnane X receptor (PXR), constitutive androstane receptor (CAR), and aryl hydrocarbon receptor (AhR) and some of their target cytochromes using primary cultures of human hepatocytes. Our results showed that AFB1, at noncytotoxic increasing concentrations, caused a significant upregulation of cytochrome P 2B6 (CYP2B6), CYP3A5, and to a lesser extent CYP3A4 and CYP2C9. Pregnane X receptor and CAR mRNA expression increased in the 3 treated livers. Aflatoxin B1 was found also to induce an overexpression of CYP1A1 and CYP1A2 genes accompanied by an increase in AhR mRNA expression. These findings suggest that AFB1 could activate PXR, CAR, and AhR; however, further investigations are needed to confirm nuclear receptor activation by AFB1.

scholarly journals Antimigraine Drug Avitriptan Is a Ligand and Agonist of Human Aryl Hydrocarbon Receptor that Induces CYP1A1 in Hepatic and Intestinal Cells

2020 ◽  
Vol 21 (8) ◽  
pp. 2799
Author(s):  
Barbora Vyhlídalová ◽  
Kristýna Krasulová ◽  
Petra Pečinková ◽  
Karolína Poulíková ◽  
Radim Vrzal ◽  
...  
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Nuclear Translocation ◽  
Primary Cultures ◽  
Human Colon ◽  
Human Hepatocytes ◽  
Intestinal Cells ◽  
Competitive Binding Assay ◽  
Aryl Hydrocarbon ◽  
Affinity Ligand ◽  
Cyp1a1 Mrna

The efforts for therapeutic targeting of the aryl hydrocarbon receptor (AhR) have emerged in recent years. We investigated the effects of available antimigraine triptan drugs, having an indole core in their structure, on AhR signaling in human hepatic and intestinal cells. Activation of AhR in reporter gene assays was observed for Avitriptan and to a lesser extent for Donitriptan, while other triptans were very weak or no activators of AhR. Using competitive binding assay and by homology docking, we identified Avitriptan as a low-affinity ligand of AhR. Avitriptan triggered nuclear translocation of AhR and increased binding of AhR in CYP1A1 promotor DNA, as revealed by immune-fluorescence microscopy and chromatin immune-precipitation assay, respectively. Strong induction of CYP1A1 mRNA was achieved by Avitriptan in wild type but not in AhR-knockout, immortalized human hepatocytes, implying that induction of CYP1A1 is AhR-dependent. Increased levels of CYP1A1 mRNA by Avitriptan were observed in human colon carcinoma cells LS180 but not in primary cultures of human hepatocytes. Collectively, we show that Avitriptan is a weak ligand and activator of human AhR, which induces the expression of CYP1A1 in a cell-type specific manner. Our data warrant the potential off-label therapeutic application of Avitriptan as an AhR-agonist drug.

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