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Molecular Pharmacology

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Research ArticleArticle

Aryl Hydrocarbon Receptor Activation and Cytochrome P450 1A Induction by the Mitogen-Activated Protein Kinase Inhibitor U0126 in Hepatocytes

Lise Andrieux, Sophie Langouët, Alain Fautrel, Fréderic Ezan, Joel A. Krauser, Jean F. Savouret, F. Peter Guengerich, Georges Baffet and André Guillouzo
Molecular Pharmacology April 2004, 65 (4) 934-943; DOI: https://doi.org/10.1124/mol.65.4.934
Lise Andrieux
Institut National de la Santé et de la Recherche Médicale U620, Faculté des Sciences Pharmaceutiques et Biologiques, Université de Rennes I, Rennes, France (L.A., S.L., A.F., A.G.); Institut National de la Santé et de la Recherche Médicale U522, Hôpital Pontchaillou, Rennes, France (F.E., G.B.); Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee (J.A.K., F.P.G.); and Institut National de la Santé et de la Recherche Médicale U530, Université René Descartes, Paris, France (J.F.S.)
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Sophie Langouët
Institut National de la Santé et de la Recherche Médicale U620, Faculté des Sciences Pharmaceutiques et Biologiques, Université de Rennes I, Rennes, France (L.A., S.L., A.F., A.G.); Institut National de la Santé et de la Recherche Médicale U522, Hôpital Pontchaillou, Rennes, France (F.E., G.B.); Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee (J.A.K., F.P.G.); and Institut National de la Santé et de la Recherche Médicale U530, Université René Descartes, Paris, France (J.F.S.)
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Alain Fautrel
Institut National de la Santé et de la Recherche Médicale U620, Faculté des Sciences Pharmaceutiques et Biologiques, Université de Rennes I, Rennes, France (L.A., S.L., A.F., A.G.); Institut National de la Santé et de la Recherche Médicale U522, Hôpital Pontchaillou, Rennes, France (F.E., G.B.); Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee (J.A.K., F.P.G.); and Institut National de la Santé et de la Recherche Médicale U530, Université René Descartes, Paris, France (J.F.S.)
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Fréderic Ezan
Institut National de la Santé et de la Recherche Médicale U620, Faculté des Sciences Pharmaceutiques et Biologiques, Université de Rennes I, Rennes, France (L.A., S.L., A.F., A.G.); Institut National de la Santé et de la Recherche Médicale U522, Hôpital Pontchaillou, Rennes, France (F.E., G.B.); Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee (J.A.K., F.P.G.); and Institut National de la Santé et de la Recherche Médicale U530, Université René Descartes, Paris, France (J.F.S.)
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Joel A. Krauser
Institut National de la Santé et de la Recherche Médicale U620, Faculté des Sciences Pharmaceutiques et Biologiques, Université de Rennes I, Rennes, France (L.A., S.L., A.F., A.G.); Institut National de la Santé et de la Recherche Médicale U522, Hôpital Pontchaillou, Rennes, France (F.E., G.B.); Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee (J.A.K., F.P.G.); and Institut National de la Santé et de la Recherche Médicale U530, Université René Descartes, Paris, France (J.F.S.)
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Jean F. Savouret
Institut National de la Santé et de la Recherche Médicale U620, Faculté des Sciences Pharmaceutiques et Biologiques, Université de Rennes I, Rennes, France (L.A., S.L., A.F., A.G.); Institut National de la Santé et de la Recherche Médicale U522, Hôpital Pontchaillou, Rennes, France (F.E., G.B.); Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee (J.A.K., F.P.G.); and Institut National de la Santé et de la Recherche Médicale U530, Université René Descartes, Paris, France (J.F.S.)
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F. Peter Guengerich
Institut National de la Santé et de la Recherche Médicale U620, Faculté des Sciences Pharmaceutiques et Biologiques, Université de Rennes I, Rennes, France (L.A., S.L., A.F., A.G.); Institut National de la Santé et de la Recherche Médicale U522, Hôpital Pontchaillou, Rennes, France (F.E., G.B.); Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee (J.A.K., F.P.G.); and Institut National de la Santé et de la Recherche Médicale U530, Université René Descartes, Paris, France (J.F.S.)
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Georges Baffet
Institut National de la Santé et de la Recherche Médicale U620, Faculté des Sciences Pharmaceutiques et Biologiques, Université de Rennes I, Rennes, France (L.A., S.L., A.F., A.G.); Institut National de la Santé et de la Recherche Médicale U522, Hôpital Pontchaillou, Rennes, France (F.E., G.B.); Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee (J.A.K., F.P.G.); and Institut National de la Santé et de la Recherche Médicale U530, Université René Descartes, Paris, France (J.F.S.)
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André Guillouzo
Institut National de la Santé et de la Recherche Médicale U620, Faculté des Sciences Pharmaceutiques et Biologiques, Université de Rennes I, Rennes, France (L.A., S.L., A.F., A.G.); Institut National de la Santé et de la Recherche Médicale U522, Hôpital Pontchaillou, Rennes, France (F.E., G.B.); Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee (J.A.K., F.P.G.); and Institut National de la Santé et de la Recherche Médicale U530, Université René Descartes, Paris, France (J.F.S.)
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Abstract

The aryl hydrocarbon receptor (AhR) is involved in various processes such as cytochrome P450 (P450) 1A induction after xenobiotic exposure. It is also considered to play a major role in cell proliferation and differentiation. Recent evidences have suggested a cross-talk between AhR functions and the mitogen-activated protein kinase (MAPK) cascade. We now report that 1,4-diamino-2,3-dicyano-1,4-bis[2-aminophenylthio]butadiene (U0126), a specific inhibitor of MAPK kinase (MEK) MEK1/2, elicits a marked increase in CYP1A1 expression at both mRNA and protein levels associated with a significant increase of enzyme activity in primary rat hepatocytes and a human hepatoma cell line. This induction occurred independently of MEK/extracellular signal-regulated kinase (ERK) activation and in the absence of ERK1 and ERK2 expression. The effect of U0126 was mediated by its ability to transactivate xenobiotic responsive element (XRE)-driven genes, as demonstrated by transfection assays with an XRE-driven luciferase construct in the human B16A2 hepatoma cell line. CYP1A1 modulation was abolished by a cotreatment with resveratrol, an established AhR antagonist, arguing for AhR activation by U0126. Such an effect was demonstrated by direct in vitro ligand binding competition assays using rabbit liver cytosol, showing that this compound binds AhR with an EC50 = 25 × 10-6 M. Moreover, we demonstrated that U0126 is a substrate for several P450s including human CYP1A2, -1A1, and -1B1. We conclude that the widely used specific inhibitor of MEK/ERK, U0126, also acts as a potent AhR activator and an inducer of related genes. Such effects on the AhR may have an impact on biological functions attributed previously to MAPK inhibition.

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Molecular Pharmacology: 65 (4)
Molecular Pharmacology
Vol. 65, Issue 4
1 Apr 2004
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Research ArticleArticle

Aryl Hydrocarbon Receptor Activation and Cytochrome P450 1A Induction by the Mitogen-Activated Protein Kinase Inhibitor U0126 in Hepatocytes

Lise Andrieux, Sophie Langouët, Alain Fautrel, Fréderic Ezan, Joel A. Krauser, Jean F. Savouret, F. Peter Guengerich, Georges Baffet and André Guillouzo
Molecular Pharmacology April 1, 2004, 65 (4) 934-943; DOI: https://doi.org/10.1124/mol.65.4.934

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Research ArticleArticle

Aryl Hydrocarbon Receptor Activation and Cytochrome P450 1A Induction by the Mitogen-Activated Protein Kinase Inhibitor U0126 in Hepatocytes

Lise Andrieux, Sophie Langouët, Alain Fautrel, Fréderic Ezan, Joel A. Krauser, Jean F. Savouret, F. Peter Guengerich, Georges Baffet and André Guillouzo
Molecular Pharmacology April 1, 2004, 65 (4) 934-943; DOI: https://doi.org/10.1124/mol.65.4.934
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