Aryl Hydrocarbon Receptor Activation and Cytochrome P450 1A Induction by the Mitogen-Activated Protein Kinase Inhibitor U0126 in Hepatocytes
| Autor: | Sophie Langouët, Frédéric Ezan, F. Peter Guengerich, Alain Fautrel, André Guillouzo, Lise Andrieux, Jean F. Savouret, Georges Baffet, Joel A. Krauser |
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| Rok vydání: | 2004 |
| Předmět: |
Male
MAPK/ERK pathway Time Factors MAP Kinase Signaling System Mitogen-activated protein kinase kinase Rats Sprague-Dawley Nitriles Butadienes Cytochrome P-450 CYP1A1 Animals Humans Enzyme Inhibitors Enzyme inducer Protein kinase A Cells Cultured Mitogen-Activated Protein Kinase Kinases Pharmacology Dose-Response Relationship Drug biology Kinase Mitogen-Activated Protein Kinase Inhibitor Aryl hydrocarbon receptor Molecular biology Rats Receptors Aryl Hydrocarbon Enzyme Induction Hepatocytes biology.protein Molecular Medicine Mitogen-Activated Protein Kinases Signal transduction Signal Transduction |
| Zdroj: | Molecular Pharmacology. 65:934-943 |
| ISSN: | 1521-0111 0026-895X |
| DOI: | 10.1124/mol.65.4.934 |
| Popis: | 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 EC(50) = 25 x 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. |
| Databáze: | OpenAIRE |
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