Stimulation of AMP-activated protein kinase is essential for the induction of drug metabolizing enzymes by phenobarbital in human and mouse liver

Franck Rencurel, Marc Foretz, Michel R Kaufmann, Deborah Stroka, Renate Looser, Isabelle Leclerc, Gabriela da Silva Xavier, Guy A Rutter, Benoit Viollet, Urs A Meyer

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79 Citations (Scopus)

Abstract

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-beta-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 alpha1 and alpha2 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 alpha1 and alpha2 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.

Original languageEnglish
Pages (from-to)1925-34
Number of pages10
JournalMolecular Pharmacology
Volume70
Issue number6
DOIs
Publication statusPublished - Dec 2006

Keywords

  • AMP-Activated Protein Kinases/metabolism
  • Adenosine Triphosphate/metabolism
  • Aminoimidazole Carboxamide/analogs & derivatives
  • Animals
  • Base Sequence
  • Cells, Cultured
  • DNA Primers
  • Dose-Response Relationship, Drug
  • Enzyme Activation
  • Enzyme Induction
  • Hepatocytes/drug effects
  • Humans
  • Immunohistochemistry
  • Metformin/pharmacology
  • Mice
  • Multienzyme Complexes/metabolism
  • Phenobarbital/pharmacology
  • Protein-Serine-Threonine Kinases/metabolism
  • Ribonucleotides/pharmacology

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