%0 Journal Article
%A Albert Braeuning
%A Albrecht Buchmann
%T 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
%D 2009
%R 10.1124/dmd.109.027821
%J Drug Metabolism and Disposition
%P 1576-1580
%V 37
%N 8
%X 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 3β (GSK3β), is frequently used to activate β-catenin signaling by mimicking the action of Wnt molecules. β-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 β-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 GSK3β and the β-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.
%U https://dmd.aspetjournals.org/content/dmd/37/8/1576.full.pdf