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Research ArticleArticles

Epidermal Growth Factor Represses Constitutive Androstane Receptor Expression in Primary Human Hepatocytes and Favors Regulation by Pregnane X Receptor

Hugues de Boussac, Claire Gondeau, Philippe Briolotti, Cédric Duret, Fridolin Treindl, Michael Römer, Jean-Michel Fabre, Astrid Herrero, Jeanne Ramos, Patrick Maurel, Markus Templin, Sabine Gerbal-Chaloin and Martine Daujat-Chavanieu
Drug Metabolism and Disposition March 2018, 46 (3) 223-236; DOI: https://doi.org/10.1124/dmd.117.078683
Hugues de Boussac
IRMB, INSERM, University Montpellier, Montpellier, France (H.d.B., C.G., P.B., C.D., P.M., S.G.-C., M.D.-C.); CHU Montpellier, IRMB, Montpellier, France (C.G., C.D., M.D.-C.); Natural and Medical Sciences Institute, University of Tübingen, Reutlingen, Germany (F.T., M.T.); Centre of Bioinformatics Tübingen (ZBIT), University of Tübingen, Tübingen, Germany (M.R.); Department of Digestive Surgery, Hospital Saint Eloi, CHU Montpellier, Montpellier, France (J.-M.F.); Departments of General Surgery, Division of Transplantation, College of Medicine, University of Montpellier, Montpellier, France (A.H.); and Pathological Anatomy Department, Hospital Guy de Chauliac, CHU Montpellier, Montpellier, France (J.R.)
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Claire Gondeau
IRMB, INSERM, University Montpellier, Montpellier, France (H.d.B., C.G., P.B., C.D., P.M., S.G.-C., M.D.-C.); CHU Montpellier, IRMB, Montpellier, France (C.G., C.D., M.D.-C.); Natural and Medical Sciences Institute, University of Tübingen, Reutlingen, Germany (F.T., M.T.); Centre of Bioinformatics Tübingen (ZBIT), University of Tübingen, Tübingen, Germany (M.R.); Department of Digestive Surgery, Hospital Saint Eloi, CHU Montpellier, Montpellier, France (J.-M.F.); Departments of General Surgery, Division of Transplantation, College of Medicine, University of Montpellier, Montpellier, France (A.H.); and Pathological Anatomy Department, Hospital Guy de Chauliac, CHU Montpellier, Montpellier, France (J.R.)
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Philippe Briolotti
IRMB, INSERM, University Montpellier, Montpellier, France (H.d.B., C.G., P.B., C.D., P.M., S.G.-C., M.D.-C.); CHU Montpellier, IRMB, Montpellier, France (C.G., C.D., M.D.-C.); Natural and Medical Sciences Institute, University of Tübingen, Reutlingen, Germany (F.T., M.T.); Centre of Bioinformatics Tübingen (ZBIT), University of Tübingen, Tübingen, Germany (M.R.); Department of Digestive Surgery, Hospital Saint Eloi, CHU Montpellier, Montpellier, France (J.-M.F.); Departments of General Surgery, Division of Transplantation, College of Medicine, University of Montpellier, Montpellier, France (A.H.); and Pathological Anatomy Department, Hospital Guy de Chauliac, CHU Montpellier, Montpellier, France (J.R.)
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Cédric Duret
IRMB, INSERM, University Montpellier, Montpellier, France (H.d.B., C.G., P.B., C.D., P.M., S.G.-C., M.D.-C.); CHU Montpellier, IRMB, Montpellier, France (C.G., C.D., M.D.-C.); Natural and Medical Sciences Institute, University of Tübingen, Reutlingen, Germany (F.T., M.T.); Centre of Bioinformatics Tübingen (ZBIT), University of Tübingen, Tübingen, Germany (M.R.); Department of Digestive Surgery, Hospital Saint Eloi, CHU Montpellier, Montpellier, France (J.-M.F.); Departments of General Surgery, Division of Transplantation, College of Medicine, University of Montpellier, Montpellier, France (A.H.); and Pathological Anatomy Department, Hospital Guy de Chauliac, CHU Montpellier, Montpellier, France (J.R.)
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Fridolin Treindl
IRMB, INSERM, University Montpellier, Montpellier, France (H.d.B., C.G., P.B., C.D., P.M., S.G.-C., M.D.-C.); CHU Montpellier, IRMB, Montpellier, France (C.G., C.D., M.D.-C.); Natural and Medical Sciences Institute, University of Tübingen, Reutlingen, Germany (F.T., M.T.); Centre of Bioinformatics Tübingen (ZBIT), University of Tübingen, Tübingen, Germany (M.R.); Department of Digestive Surgery, Hospital Saint Eloi, CHU Montpellier, Montpellier, France (J.-M.F.); Departments of General Surgery, Division of Transplantation, College of Medicine, University of Montpellier, Montpellier, France (A.H.); and Pathological Anatomy Department, Hospital Guy de Chauliac, CHU Montpellier, Montpellier, France (J.R.)
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Michael Römer
IRMB, INSERM, University Montpellier, Montpellier, France (H.d.B., C.G., P.B., C.D., P.M., S.G.-C., M.D.-C.); CHU Montpellier, IRMB, Montpellier, France (C.G., C.D., M.D.-C.); Natural and Medical Sciences Institute, University of Tübingen, Reutlingen, Germany (F.T., M.T.); Centre of Bioinformatics Tübingen (ZBIT), University of Tübingen, Tübingen, Germany (M.R.); Department of Digestive Surgery, Hospital Saint Eloi, CHU Montpellier, Montpellier, France (J.-M.F.); Departments of General Surgery, Division of Transplantation, College of Medicine, University of Montpellier, Montpellier, France (A.H.); and Pathological Anatomy Department, Hospital Guy de Chauliac, CHU Montpellier, Montpellier, France (J.R.)
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Jean-Michel Fabre
IRMB, INSERM, University Montpellier, Montpellier, France (H.d.B., C.G., P.B., C.D., P.M., S.G.-C., M.D.-C.); CHU Montpellier, IRMB, Montpellier, France (C.G., C.D., M.D.-C.); Natural and Medical Sciences Institute, University of Tübingen, Reutlingen, Germany (F.T., M.T.); Centre of Bioinformatics Tübingen (ZBIT), University of Tübingen, Tübingen, Germany (M.R.); Department of Digestive Surgery, Hospital Saint Eloi, CHU Montpellier, Montpellier, France (J.-M.F.); Departments of General Surgery, Division of Transplantation, College of Medicine, University of Montpellier, Montpellier, France (A.H.); and Pathological Anatomy Department, Hospital Guy de Chauliac, CHU Montpellier, Montpellier, France (J.R.)
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Astrid Herrero
IRMB, INSERM, University Montpellier, Montpellier, France (H.d.B., C.G., P.B., C.D., P.M., S.G.-C., M.D.-C.); CHU Montpellier, IRMB, Montpellier, France (C.G., C.D., M.D.-C.); Natural and Medical Sciences Institute, University of Tübingen, Reutlingen, Germany (F.T., M.T.); Centre of Bioinformatics Tübingen (ZBIT), University of Tübingen, Tübingen, Germany (M.R.); Department of Digestive Surgery, Hospital Saint Eloi, CHU Montpellier, Montpellier, France (J.-M.F.); Departments of General Surgery, Division of Transplantation, College of Medicine, University of Montpellier, Montpellier, France (A.H.); and Pathological Anatomy Department, Hospital Guy de Chauliac, CHU Montpellier, Montpellier, France (J.R.)
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Jeanne Ramos
IRMB, INSERM, University Montpellier, Montpellier, France (H.d.B., C.G., P.B., C.D., P.M., S.G.-C., M.D.-C.); CHU Montpellier, IRMB, Montpellier, France (C.G., C.D., M.D.-C.); Natural and Medical Sciences Institute, University of Tübingen, Reutlingen, Germany (F.T., M.T.); Centre of Bioinformatics Tübingen (ZBIT), University of Tübingen, Tübingen, Germany (M.R.); Department of Digestive Surgery, Hospital Saint Eloi, CHU Montpellier, Montpellier, France (J.-M.F.); Departments of General Surgery, Division of Transplantation, College of Medicine, University of Montpellier, Montpellier, France (A.H.); and Pathological Anatomy Department, Hospital Guy de Chauliac, CHU Montpellier, Montpellier, France (J.R.)
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Patrick Maurel
IRMB, INSERM, University Montpellier, Montpellier, France (H.d.B., C.G., P.B., C.D., P.M., S.G.-C., M.D.-C.); CHU Montpellier, IRMB, Montpellier, France (C.G., C.D., M.D.-C.); Natural and Medical Sciences Institute, University of Tübingen, Reutlingen, Germany (F.T., M.T.); Centre of Bioinformatics Tübingen (ZBIT), University of Tübingen, Tübingen, Germany (M.R.); Department of Digestive Surgery, Hospital Saint Eloi, CHU Montpellier, Montpellier, France (J.-M.F.); Departments of General Surgery, Division of Transplantation, College of Medicine, University of Montpellier, Montpellier, France (A.H.); and Pathological Anatomy Department, Hospital Guy de Chauliac, CHU Montpellier, Montpellier, France (J.R.)
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Markus Templin
IRMB, INSERM, University Montpellier, Montpellier, France (H.d.B., C.G., P.B., C.D., P.M., S.G.-C., M.D.-C.); CHU Montpellier, IRMB, Montpellier, France (C.G., C.D., M.D.-C.); Natural and Medical Sciences Institute, University of Tübingen, Reutlingen, Germany (F.T., M.T.); Centre of Bioinformatics Tübingen (ZBIT), University of Tübingen, Tübingen, Germany (M.R.); Department of Digestive Surgery, Hospital Saint Eloi, CHU Montpellier, Montpellier, France (J.-M.F.); Departments of General Surgery, Division of Transplantation, College of Medicine, University of Montpellier, Montpellier, France (A.H.); and Pathological Anatomy Department, Hospital Guy de Chauliac, CHU Montpellier, Montpellier, France (J.R.)
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Sabine Gerbal-Chaloin
IRMB, INSERM, University Montpellier, Montpellier, France (H.d.B., C.G., P.B., C.D., P.M., S.G.-C., M.D.-C.); CHU Montpellier, IRMB, Montpellier, France (C.G., C.D., M.D.-C.); Natural and Medical Sciences Institute, University of Tübingen, Reutlingen, Germany (F.T., M.T.); Centre of Bioinformatics Tübingen (ZBIT), University of Tübingen, Tübingen, Germany (M.R.); Department of Digestive Surgery, Hospital Saint Eloi, CHU Montpellier, Montpellier, France (J.-M.F.); Departments of General Surgery, Division of Transplantation, College of Medicine, University of Montpellier, Montpellier, France (A.H.); and Pathological Anatomy Department, Hospital Guy de Chauliac, CHU Montpellier, Montpellier, France (J.R.)
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Martine Daujat-Chavanieu
IRMB, INSERM, University Montpellier, Montpellier, France (H.d.B., C.G., P.B., C.D., P.M., S.G.-C., M.D.-C.); CHU Montpellier, IRMB, Montpellier, France (C.G., C.D., M.D.-C.); Natural and Medical Sciences Institute, University of Tübingen, Reutlingen, Germany (F.T., M.T.); Centre of Bioinformatics Tübingen (ZBIT), University of Tübingen, Tübingen, Germany (M.R.); Department of Digestive Surgery, Hospital Saint Eloi, CHU Montpellier, Montpellier, France (J.-M.F.); Departments of General Surgery, Division of Transplantation, College of Medicine, University of Montpellier, Montpellier, France (A.H.); and Pathological Anatomy Department, Hospital Guy de Chauliac, CHU Montpellier, Montpellier, France (J.R.)
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Figures

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  • Fig. 1.
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    Fig. 1.

    Differential gene expression in PHHs following incubation with EGF. (A) DIGIWest analysis of protein expression in PHHs (Liv10, Table 1) following incubation or not with 10 ng/ml EGF for 5 days. (B) Number of upregulated genes and enriched pathways in EGF-treated PHHs [false discovery rate (FDR) = 4.7 × 10−18–1.9 × 10−5]. (C) Number of downregulated genes and enriched pathways in EGF-treated PHHs (FDR = 8.8 × 10−10–0.008). (D) Heat map showing the genes differentially expressed in PHHs (n = 5) following incubation with EGF.

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    Fig. 2.

    EGF influences specifically the expression of CAR and its target genes in PHHs. PHHs from two donors (Liv1 and Liv2, Table 1) were incubated with 1 µM CITCO, 0.5 mM PB, or dimethylsulfoxide (DMSO) (UT) for 24 hours in the absence or presence of 10 ng/ml EGF. EGF was added before [day 0 (D0)] or together [day 2 (D2)] with the inducers. The relative expression of CAR (A), CYP2B6 (B), and CYP3A4 (C) mRNA was measured by qPCR and normalized to RPLP0. Results are expressed relative to control (UT) in medium without EGF; *P < 0.05; **P < 0.01, relative to control (no EGF) in the same treatment group; #P < 0.05; ##P < 0.01, relative to control (UT).

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    Fig. 3.

    CAR depletion inhibits CYP2B6 induction by PB and CITCO only in the absence of EGF. PHHs from five donors (Liv3–7) were transfected with control (siCT) or CAR-targeting siRNAs (siCAR). Then they were incubated with 0.5 mM PB and 1 µM CITCO or DMSO (UT) for 24 hours, with or without 10 ng/ml EGF (from D0). The relative expression of CAR (A) and CYP2B26 (B) mRNA was measured by qPCR and normalized to RPLP0. Results are expressed relative to UT in siCT-transfected cells in the absence of EGF. (C) CYP2B6 protein level was assessed by Western blotting (representative experiment using PHHs from Liv12). GAPDH protein expression was used as loading control. Results are expressed relative to control (UT) in medium without EGF; ***P < 0.005, relative to control (siCT) in the same treatment group; ###P < 0.005, relative to control (UT).

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    Fig. 4.

    EGF differentially affects the response to CITCO and PB. Venn diagrams showing the overlap of genes that are differentially expressed in PHHs from five donors (Liv3–7) upon incubation with 1 µM CITCO (A) or 0.5 mM PB (B) in the absence or presence of 10 ng/ml EGF (from D0). The number of up- and downregulated genes in each experimental condition is indicated in red and green, respectively.

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    Fig. 5.

    KEGG pathway enrichment, relative to untreated cells, of siCT-transfected PHHs from five donors (Liv3–7) incubated with 0.5 mM PB (A) or 1 µM CITCO (B) for 24 hours in the presence or absence of 10 ng/ml EGF (from D0).

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    Fig. 6.

    PHHs from two donors (Liv6 and Liv7, Table 1) were transfected with control (siCT) or CAR-targeting siRNAs (siCAR). They were then incubated with 0.5 mM PB, 1 µM CITCO, or DMSO (UT) for 24 hours, in the presence or not of 10 ng/ml EGF (from D0). The relative expression of CYP2A6 (A), CYP2A7 (B), CYP3A4 (C), CYP3A43 (D), CYP3A7 (E), CYP2C8 (F), CYP2C9 (G), TSKU (H), EPHX1 (I), POR (J), ALAS1 (K), TAGLN (L), STEAP2 (M), and CEBP3 (N) mRNA was measured by qPCR and normalized to RPLP0. Results are expressed relative to not treated siCT-transfected PHHs (UT) in medium without EGF. *P < 0.05; **P < 0.01, relative to control in the same treatment group; ##P < 0.01; ###P < 0.005, relative to control (UT).

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    Fig. 7.

    PHHs from five donors (Liv3–7, Table 1) were transfected with control (siCT), CAR-targeting (siCAR), or PXR-targeting (siPXR) siRNAs. Then they were incubated with 0.5 mM PB, 1 µM CITCO, or DMSO (UT) for 24 hours in the presence or not of 10 ng/ml EGF (from D0). The relative expression of PXR (A), CAR (B), CYP2B6 (C), or CYP3A4 (D) mRNA was measured by qPCR and normalized to RPLP0. Results are expressed relative to not treated siCT-transfected PHHs (UT) in medium without EGF. PHHs from Liv16 were transfected with siCT, siCAR and/or siPXR siRNAs. Then, they were incubated with 0.5 mM PB or DMSO for 24 hours, in the presence of 10 ng/ml EGF (from D0). The relative expression of CAR and PXR (E), CYP2B6, CYP3A4, TSKU, CYP2C8, CYP2A6, CYP2A7, CYP3A43 (F) mRNA was measured by qPCR and normalized to RPLP0 expression level. Results are expressed relative to not treated siCT-transfected PHHs in medium with EGF (white bars). *P < 0.05; **P < 0.01; ***P < 0.001 relative to control in the same treatment group.

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    Fig. 8.

    PHHs from eight donors (Liv3–7 and 13–15, Table 1) were incubated with 0.5 mM PB, 1 µM CITCO, or DMSO (UT) for 24 hours in the presence or not of 10 ng/ml EGF (from D0). The relative expression of CYP2B6 was measured by qPCR and normalized to RPLP0 in the absence (A) or presence (C) of EGF. PXR/CAR mRNA expression ratio in the absence (B) or presence (D) of EGF (expressed as LOG10). PHHs from two donors (Liv13 and Liv15, Table 1) (E and F) were transfected with control (siCT), CAR-targeting (siCAR), or PXR-targeting (siPXR) siRNAs. They were then incubated with 0.5 mM PB, 1 µM CITCO, or DMSO (UT) for 24 hours in the presence or not of 10 ng/ml EGF (from D0). The relative expression of CYP2B6 was measured by qPCR and normalized to RPLP0 in the absence or presence of EGF. Results are expressed relative to not treated siCT-transfected PHHs (UT) in medium without EGF. *P < 0.05; **P < 0.01; ***P < 0.001.

Tables

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    TABLE 1 

    Liver donor data

    LiverOriginAge (yr)SexPathology
    Liv1Donor41MAnoxia
    Liv2Biopredic Intl78FHepatocellular carcinoma
    Liv3Resection66FMetastasis from colon cancer
    Liv4Donor69FRenal cyst
    Liv5Donor53MStroke
    Liv6Resection76MMetastasis from colon cancer
    Liv7Resection45FPolycystic liver disease
    Liv10Biopredic Intl72MHepatocellular carcinoma
    Liv12Resection78FCholangiocarcinoma
    Liv13Donor59MMeningeal hemorrhage
    Liv14Donor60MStroke
    Liv15Donor55MStroke
    Liv16Resection67FMetastasis from colon cancer
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    TABLE 2 

    Primer sequences

    GeneForward PrimerReverse Primer
    ALAS1GATGTCAGCCACCTCAGAGAACCATCCACGAAGGTGATTGCTCC
    CARTGCTGCCTCTGGTCACACACCCCGCAGAGGAAGTTTTGTG
    CPEB3GGTGTTTGTTGGAGGACTTCCTCCCTCTTGGAACAGCAGAAAGGC
    CYP2A6GTCAATCTCCTCATGGACCTTGGCCTGGTGATGACCACGTTGAAC
    CYP2A7CGCTATGGCTTCTTGCTGCTCACTCCATGTAGGGCATCTTGGTC
    CYP2B6ATGGGGCACTGAAAAAGACTGAAGAGGCGGGGACACTGAATGAC
    CYP2C8GAGACAACAAGCACCACTCTGAGCAGTGTAAGGCATGTGGCTCCT
    CYP2C9TCCTATCATTGATTACTTCCCGAACTGCAGTGTTTTCCAAGC
    CYP3A4GCCTGGTGCTCCTCTATCTAGGTGTTGACCATCATAAAG
    CYP3A43CTGCCTATGACACAACTAGCACCTACCAGGGCATCGTAGGTGACA
    CYP3A7AAGTCTGGGGTATTTATGACTCGCTGGTGAATGTTGGAGAC
    EPHX1GTTTTCCACCTGGACCAATACGGTGGTGCCTGTTGTCCAGTAGAG
    PORACTCTGCTCTCGTCAACCAGCTTGGGTGCTTCTTGTTGGACTCC
    PXRGGACCAGCTGCAGGAGCAATCATGAGGGGCGTAGCAAAGG
    RDH16TATGGCGTGGAAGCCTTCTCTGGGTCCCAAATCTCCAGGAAGCT
    RPLP0TCGACAATGGCAGCATCTACGCCTTGACCTTTTCAGCAAG
    STEAP2CCTCTGCTTACCGATGAGAAGGCAGGAGGGAAAGTAAGCCAAGG
    TAGLNTCCAGGTCTGGCTGAAGAATGGCTGCTCCATCTGCTTGAAGACC
    TSKUAGTCGCTTGACCTCAGCCACAATCGTGAAGGCAGACACTGAGAC
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    TABLE 3 

    Enriched biologic processes after incubation of PHHs with CITCO

    GO NumberBiologic ProcessCountP ValueGenes
    Deregulated by CITCO in the absence of EGF only
    GO.0042738Exogenous drug catabolic process61.09e−05CYP1A2, CYP2A7, CYP2C19, CYP2C8, CYP2C9, CYP3A4
    GO.0016098Monoterpenoid metabolic process44.66e−05CYP1A2, CYP2C19, CYP2C9, CYP3A4
    GO.0019373Epoxygenase P450 pathway50.000103CYP1A2, CYP2A7, CYP2C19, CYP2C8, CYP2C9
    GO.0042221Response to chemical410.000103ADCY2, AKR1B1, ANXA3, CA3, CPEB3, CREB3L3, CTGF, CXCL5, CYP1A2, CYP2A7, CYP2C19, CYP2C8, CYP2C9, CYP3A4, CYP3A43, CYP3A7, EPHX1, ETV1, F2R, GSTA1, IL18, ITGA2, KCNA5, KRT19, MATN2, MICALL1, MRC1, MYL9, OR1C1, OR51B4, PANX1, PF4V1, POR, SERPINE1, SLC23A1, SOCS2, SOX2, TGFB2, TMEM67, TNFSF11, WNT6
    GO.0050896Response to stimulus580.000166ADCY2, AK7, AMOTL1, ANO1, BOC, CA3, CPE, CPEB3, CRIM1, CXCL5, CYP1A2, CYP2A7, CYP2C19, CYP2C8, CYP2C9, CYP3A4, CYP3A43, CYP3A7, DKK3, DST, EPHX1, ETV1, F2R, GSTA1, HRH4, IL18, ITGA2, KCNA5, KRT19, LRRN4, MAP4K5, MATN2, MCTP2, MICALL1, MRC1, MYL9, NABP1, OR1C1, OR51B4, PF4V1, PLK2, PNMA1, POR, RASEF, RRAD, RRM1, SERPINE1, SLC23A1, SOCS2, STK17A, SUSD4, TACSTD2, TGFB2, TMEM67, TNC, TNFSF11, VSIG4, WNT6
    GO.0097267Omega hydroxylase P450 pathway40.000166CYP1A2, CYP2C19, CYP2C8, CYP2C9
    GO.0006805Xenobiotic metabolic process90.000299CYP1A2, CYP2A7, CYP2C19, CYP2C8, CYP2C9, CYP3A4, CYP3A43, CYP3A7, GSTA1
    GO.0071466Cellular response to xenobiotic stimulus90.00033CYP1A2, CYP2A7, CYP2C19, CYP2C8, CYP2C9, CYP3A4, CYP3A43, CYP3A7, GSTA1
    GO.0070989Oxidative demethylation40.00102CYP1A2, CYP2C8, CYP2C9, CYP3A4
    GO.1901700Response to oxygen-containing compound200.00389ADCY2, AKR1B1, CA3, CPEB3, CTGF, CXCL5, CYP1A2, F2R, IGFBP1, IL18, KCNA5, MRC1, PANX1, PAX2, PF4V1, POR, SERPINE1, SOCS2, TGFB2, WNT6
    Deregulated by CITCO in the presence of EGF only
    GO.0006397mRNA processing90.00486DHX9, HNRNPC, MBNL2, RBM22, RBM27, SON, SRRM2, SYNCRIP, THRAP3
    GO.0048255mRNA stabilization40.00486DHX9, HNRNPC, SYNCRIP, THRAP3
    GO.0016071mRNA metabolic process100.00533DHX9, EIF4G1, HNRNPC, MBNL2, RBM22, RBM27, SON, SRRM2, SYNCRIP, THRAP3
    GO.0008380RNA splicing80.0061DHX9, HNRNPC, MBNL2, RBM22, SON, SRRM2, SYNCRIP, THRAP3
    • IGF, insulin-like growth factor.

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    TABLE 4 

    Enriched biologic processes following incubation of PHHs with PB

    GO NumberBiologic ProcessCountP ValueGenes
    Deregulated by PB only in medium without EGF
    GO.0008202Steroid metabolic process100.00081ABCG1, AKR1B1, AKR1B10, CYP1A2, DHCR24, HMGCS1, HSD17B2, NSDHL, SLC27A2, TM7SF2
    GO.0033993Response to lipid170.00081ABCG1, ANKRD1, ANXA3, BAX, CDO1, CTGF, CXCL5, CYP1A2, HMGCS1, HSD17B2, INHBA, KLF4, KRAS, KRT19, MRC1, PELI1, SOCS3
    GO.0006694Steroid biosynthetic process70.00273AKR1B1, DHCR24, HMGCS1, HSD17B2, NSDHL, SLC27A2, TM7SF2
    GO.0006629Lipid metabolic process180.0028ABCG1, AKR1B1, AKR1B10, ANKRD1, BAX, CAV1, CTGF, CYP1A2, CYP2A7, DHCR24, ELOVL6, FADS1, HSD17B2, ME1, NSDHL, PNPLA3, RDH16, TM7SF2
    GO.0044281Small molecule metabolic process260.0028ABCG1, AKR1B10, ANKRD1, CAV1, CTGF, CTPS1, CYP1A2, CYP2A7, DHCR24, ELOVL6, ENTPD5, FADS1, GCAT, GLYAT, GSTA1, GSTA3, HMGCS1, HOGA1, MAT1A, ME1, NSDHL, PNPLA3, SLC23A1, SLC25A15, TM7SF2, UGT1A6
    GO.0009725Response to hormone160.00289ABCG1, AKR1B1, ANXA3, BAX, CAV1, CDO1, CTGF, CYP1A2, DHCR24, HMGCS1, IGFBP1, INHBA, KRT19, ME1, STEAP2, UGT1A6
    GO.0042221Response to chemical350.00529ABCG1, AKR1B1, ANKRD1, ANXA3, CAV1, CCL16, CDO1, CPEB3, CTGF, CTPS1, CUX2, CXCL5, CYP1A2, CYP2A7, DHCR24, FSTL3, GLYAT, GSTA1, GSTA3, HMGCS1, HSD17B2, KLF4, KRT19, MAT1A, MATN2, ME1, MRC1, MT1M, MYL9, NTN4, PELI1, SLC23A1, SLC47A1, STEAP2, UGT1A6
    Deregulated by PB only in medium with EGF
    GO.0048255mRNA stabilization40.00728DHX9, HNRNPC, SYNCRIP, THRAP3
    Deregulated by PB in the presence and absence of EGF
    GO.0006805Xenobiotic metabolic process131.5e−13CYP2A6, CYP2B6, CYP2C19, CYP2C8, CYP2C9, CYP3A4, CYP3A43, CYP3A5, CYP3A7, CYP4A11, SULT2A1, UGT1A1, UGT1A8
    GO.0071466Cellular response to xenobiotic stimulus131.5e−13CYP2A6, CYP2B6, CYP2C19, CYP2C8, CYP2C9, CYP3A4, CYP3A43, CYP3A5, CYP3A7, CYP4A11, SULT2A1, UGT1A1, UGT1A8
    GO.0017144Drug metabolic process99.51e−13CYP2A6, CYP2B6, CYP2C19, CYP2C8, CYP2C9, CYP3A4, CYP3A5, UGT1A1, UGT1A8
    GO.0042737Drug catabolic process78.5e−11CYP2A6, CYP2B6, CYP2C19, CYP2C8, CYP2C9, CYP3A4, CYP3A5
    GO.0019373Epoxygenase P450 pathway64.24e−09CYP2A6, CYP2B6, CYP2C19, CYP2C8, CYP2C9, CYP4A11
    GO.0042738Exogenous drug catabolic process67.24e−09CYP2A6, CYP2B6, CYP2C19, CYP2C8, CYP2C9, CYP3A4
    GO.0032787Monocarboxylic acid metabolic process139.67e−09AKR1D1, CYP2A6, CYP2B6, CYP2C19, CYP2C8, CYP2C9, CYP4A11, FASN, PDK4, POR, SULT2A1, UGT1A1, UGT1A8
    GO.0044281Small molecule metabolic process221.24e−08ABCB1, AKR1D1, ALAS1, CYB5A, CYP2A6, CYP2B6, CYP2C19, CYP2C8, CYP2C9, CYP3A4, CYP3A43, CYP3A5, CYP3A7, CYP4A11, DIO1, FASN, PDK4, POR, PRODH2, SULT2A1, UGT1A1, UGT1A8
    GO.0019752Carboxylic acid metabolic process152.28e−08AKR1D1, CYB5A, CYP2A6, CYP2B6, CYP2C19, CYP2C8, CYP2C9, CYP4A11, FASN, PDK4, POR, PRODH2, SULT2A1, UGT1A1, UGT1A8
    GO.0008202Steroid metabolic process104.36e−08AKR1D1, CYP2A6, CYP2B6, CYP2C19, CYP2C9, CYP3A4, CYP3A5, SULT2A1, UGT1A1, UGT1A8
    • View popup
    TABLE 5 

    List of genes differentially regulated by CITCO and PB in a CAR-dependent manner

    siCTsiCAR
    −EGF+EGF−EGF+EGF
    CITCOPBCITCOPBCITCOPBCITCOPB
    FCq-valueFCq-valueFCq-valueFCq-valueFC*q-valueFC**q-valueFC*q-valueFC**q-value
    TAGLN0.60.00.60.01.47.51.1N.S.1.40.0N.S.N.S.N.S.
    RDH161.30.01.40,00.9N.S.1.1N.S.0.70.0N.S.N.S.N.S.
    ALAS11.40.03.30.01.1N.S.2.30.00.70.0N.S.N.S.N.S.
    POR1.50.02.60.01.1N.S.2.40.00.70.0N.S.N.S.N.S.
    CYP2C91.50.01.80.01.1N.S.1.80.00.70.0N.S.0.75.3N.S.
    CPEB31.60.02.70.01.0N.S.1.3N.S.0.70.0N.S.N.S.N.S.
    CYP2C81.70.02.30.01.1N.S.3.70.00.70.0N.S.N.S.N.S.
    CYP3A431.90.05.40.01.0N.S.2.30.70.60.0N.S.N.S.N.S.
    EPHX12.10.02.30.01.3N.S.1.70.40.60.0N.S.N.S.N.S.
    TSKU2.40.03.80.01.2N.S.3.10.00.50.0N.S.N.S.N.S.
    CYP3A72.40.06.00.00.9N.S.11.41.00.50.0N.S.N.S.N.S.
    CYP2A73.50.03.60.01.1N.S.1.3N.S.0.50.00.60.0N.S.N.S.
    CYP3A43.80.014.40.01.1N.S.23.80.00.40.0N.S.N.S.N.S.
    CYP2B610.50.010.70.02.11.35.60.00.30.00.50.00.75.3N.S.
    CYP2A614.80.015.40.01.40.71.90.00.20.00.30.00.75.3N.S.
    STEAP20.8N.S.0.60.00.9N.S.0.8N.S.N.S.1.42.4N.S.N.S.
    • FC, fold change (siCT-CITCO/siCT-DMSO or siCT-PB/siCT-DMSO); N.S., not significant; siCT, control siRNA; siCAR, anti-CAR siRNA.

    • ↵* siCAR-CITCO/siCT-CITCO;

    • ↵** siCAR-PB/siCT-PB.

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Drug Metabolism and Disposition: 46 (3)
Drug Metabolism and Disposition
Vol. 46, Issue 3
1 Mar 2018
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Switch from CAR to PXR in the Presence of EGF

Hugues de Boussac, Claire Gondeau, Philippe Briolotti, Cédric Duret, Fridolin Treindl, Michael Römer, Jean-Michel Fabre, Astrid Herrero, Jeanne Ramos, Patrick Maurel, Markus Templin, Sabine Gerbal-Chaloin and Martine Daujat-Chavanieu
Drug Metabolism and Disposition March 1, 2018, 46 (3) 223-236; DOI: https://doi.org/10.1124/dmd.117.078683

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Research ArticleArticles

Switch from CAR to PXR in the Presence of EGF

Hugues de Boussac, Claire Gondeau, Philippe Briolotti, Cédric Duret, Fridolin Treindl, Michael Römer, Jean-Michel Fabre, Astrid Herrero, Jeanne Ramos, Patrick Maurel, Markus Templin, Sabine Gerbal-Chaloin and Martine Daujat-Chavanieu
Drug Metabolism and Disposition March 1, 2018, 46 (3) 223-236; DOI: https://doi.org/10.1124/dmd.117.078683
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