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 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.
Footnotes
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This work was supported by the Deutsche Forschungsgemeinschaft [Grant SFB 773].
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.109.027821.
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ABBREVIATIONS: AhR, aryl hydrocarbon receptor; Arnt, AhR nuclear translocator; DRE, dioxin response element; U0126, 1,4-diamino-2,3-dicyano-1,4-bis(2-aminophynyltio)butadiene; PD98059, 2′-amino-3′-methoxyflavone; SP600125, 1,9-pyrazoloanthrone; GSK3β, glycogen synthase kinase 3β; SB216763, 3-(2,4-dichlorophenyl)-4-(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione; TCF, T cell factor; P450, cytochrome P450; TCDD, 2,3,7,8-tetrachloro-p-dibenzodioxin; PCR, polymerase chain reaction; RT, reverse transcription.
- Accepted May 15, 2009.
- Received April 3, 2009.
- The American Society for Pharmacology and Experimental Therapeutics
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