The glycogen synthase kinase inhibitor 3-(2,4-dichlorophenyl)-4-(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione (SB216763) is a partial agonist of the aryl hydrocarbon receptor

Drug Metab Dispos. 2009 Aug;37(8):1576-80. doi: 10.1124/dmd.109.027821. Epub 2009 May 15.

Abstract

Kinase inhibitors are frequently used tools in signal transduction research. 3-(2,4-Dichlorophenyl)-4-(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione (SB216763), a potent inhibitor of glycogen synthase kinase 3beta (GSK3beta), is frequently used to activate beta-catenin signaling by mimicking the action of Wnt molecules. beta-Catenin is a crucial player in the regulation of hepatic drug metabolism. Thus, it is of particular importance to know whether the tools used to study the effects of beta-catenin signaling may affect the respective drug-metabolizing target enzymes in an unwanted manner. In this study, we show that SB216763 is able to induce cytochrome P450 1a1 (Cyp1a1) expression in a dose-dependent manner in mouse hepatoma cells. Moreover, SB216763 is able to inhibit Cyp1a1 induction by the prototype aryl hydrocarbon receptor (AhR) ligand 2,3,7,8-tetrachloro-p-dibenzodioxin. Cyp1a1 induction by SB216763 is independent of GSK3beta and the beta-catenin pathway. Instead, SB216763 induces Cyp1a1 by activation of AhR-mediated transcription. The present results suggest that SB216763 acts as a partial agonist of the AhR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aryl Hydrocarbon Receptor Nuclear Translocator / metabolism
  • Basic Helix-Loop-Helix Transcription Factors
  • Cell Line, Tumor
  • Cytochrome P-450 CYP1A1 / biosynthesis*
  • Cytochrome P-450 CYP1A1 / genetics
  • Dose-Response Relationship, Drug
  • Drug Partial Agonism
  • Enzyme Induction
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors*
  • Glycogen Synthase Kinase 3 beta
  • Hepatocytes / drug effects*
  • Hepatocytes / enzymology
  • Indoles / pharmacology*
  • Male
  • Maleimides / pharmacology*
  • Mice
  • Mice, Inbred C3H
  • Mice, Knockout
  • Polychlorinated Dibenzodioxins / pharmacology
  • Promoter Regions, Genetic / drug effects
  • Protein Kinase Inhibitors / pharmacology*
  • RNA, Messenger / biosynthesis
  • Receptors, Aryl Hydrocarbon / agonists*
  • Receptors, Aryl Hydrocarbon / genetics
  • Receptors, Aryl Hydrocarbon / metabolism
  • Signal Transduction / drug effects
  • Transcriptional Activation / drug effects
  • Wnt Proteins / metabolism
  • Wnt3 Protein
  • beta Catenin / genetics
  • beta Catenin / metabolism

Substances

  • Ahr protein, mouse
  • Arnt protein, mouse
  • Basic Helix-Loop-Helix Transcription Factors
  • CTNNB1 protein, mouse
  • Indoles
  • Maleimides
  • Polychlorinated Dibenzodioxins
  • Protein Kinase Inhibitors
  • RNA, Messenger
  • Receptors, Aryl Hydrocarbon
  • SB 216763
  • Wnt Proteins
  • Wnt3 Protein
  • beta Catenin
  • Aryl Hydrocarbon Receptor Nuclear Translocator
  • Cytochrome P-450 CYP1A1
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, mouse
  • Glycogen Synthase Kinase 3