Received for publication April 3, 2009.
Revised May 5, 2009.
Accepted for publication May 15, 2009.

The glycogen synthase kinase inhibitor SB216763 is a partial agonist of the aryl hydrocarbon receptor

Abstract

Kinase inhibitors are frequently used tools in signal transduction research. SB216763 (3-(2,4-Dichlorophenyl)-4-(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione), a potent inhibitor of glycogen synthase kinase 3 (GSK3), is frequently used to activate -catenin signaling by mimicking the action of Wnt molecules. -catenin is a crucial player in the regulation of hepatic drug metabolism. It is thus of particular importance to know whether the tools employed to study the effects of -catenin signaling may affect the respective drug-metabolizing target enzymes in an unwanted manner. Here 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 GSK3 and the -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.

Key words: Ah receptor, CYP expression, CYP induction, CYP1A, cytochrome P450