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Division of Pharmacology-Neurobiology of the Biozentrum, University of Basel, Basel, Switzerland (F.R., M.R.K., R.L., U.A.M.); Departments of Visceral Surgery and Clinical Research, University of Bern, Bern, Switzerland (D.S.); Institut Cochin, Département Endocrinologie Métabolisme et Cancer, Paris, France (M.F., B.V.); Institut National de la Santé et de la Recherche Médicale, U567, Paris, France (M.F., B.V.); Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104, Paris, France (M.F., B.V.); Université Paris 5, Facultéde Médecine René Descartes, UM 3, Paris, France (M.F., B.V.); Department of Biochemistry, School of Medical Sciences, University of Bristol, Bristol, United Kingdom (I.L., G.X., G.A.R.); and Department of Cell Biology, Division of Medicine, Imperial College, London, United Kingdom (I.L., G.X., G.A.R.)
Our previous studies have suggested a role for AMP-activated protein kinase (AMPK) in the induction of CYP2B6 by phenobarbital (PB) in hepatoma-derived cells (Rencurel et al., 2005). In this study, we showed in primary human hepatocytes that: 1) 5'-phosphoribosyl-5-aminoimidazol-4-carboxamide 1-
-D-ribofuranoside and the biguanide metformin, known activators of AMPK, dose-dependently increase the expression of CYP2B6 and CYP3A4 to an extent similar to that of PB. 2) PB, but not the human nuclear receptor constitutive active/androstane receptor (CAR) ligand 6-(4-chlorophenyl)imidazol[2,1-6][1,3]thiazole-5-carbaldehyde, dose-dependently increase AMPK activity. 3) Pharmacological inhibition of AMPK activity with compound C or dominant-negative forms of AMPK blunt the inductive response to phenobarbital. Furthermore, in transgenic mice with a liver-specific deletion of both the 
1 and 2 AMPK catalytic subunits, basal levels of Cyp2b10 and Cyp3a11 mRNA were increased but not in primary culture of mouse hepatocytes. However, phenobarbital or 1,4 bis[2-(3,5-dichloropyridyloxy)]benzene, a mouse CAR ligand, failed to induce the expression of these genes in the liver or cultured hepatocytes from mice lacking hepatic expression of the 1 and 2 subunits of AMPK. The distribution of CAR between the nucleus and cytosol was not altered in hepatocytes from mice lacking both AMPK catalytic subunits. These data highlight the essential role of AMPK in the CAR-mediated signal transduction pathway.
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