TY - JOUR T1 - New Insights into the Regulation of CYP2C9 Gene Expression: The Role of the Transcription Factor GATA-4 JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 415 LP - 421 DO - 10.1124/dmd.109.029405 VL - 38 IS - 3 AU - Jessica Mwinyi AU - Jana Nekvindová AU - Isa Cavaco AU - Yvonne Hofmann AU - Rasmus Steen Pedersen AU - Ellie Landman AU - Souren Mkrtchian AU - Magnus Ingelman-Sundberg Y1 - 2010/03/01 UR - http://dmd.aspetjournals.org/content/38/3/415.abstract N2 - CYP2C9 is an important drug-metabolizing enzyme that metabolizes, e.g., warfarin, antidiabetics, and antiphlogistics. However, the endogenous regulation of this enzyme is largely unknown. In this study, we examined the role of GATA transcription factors in the gene expression of CYP2C9. We investigated four putative GATA binding sites within the first 200 base pairs of CYP2C9 promoter at the positions I: −173/−170, II: −167/−164, III: −118/−115, and IV: −106/−103. Luciferase activity driven by a wild-type CYP2C9 promoter construct was strongly up-regulated in Huh-7 cells upon cotransfection with expression plasmids for GATA-2 and GATA-4, whereas mutations introduced into GATA binding site III or I and II reduced this induction to a significant extent. Electrophoretic mobility shift assays revealed specific binding of GATA-4 and GATA-6 to the oligonucleotides containing GATA binding sites I and II. Furthermore, the association of GATA-4 with CYP2C9 promoter was confirmed by chromatin immunoprecipitation assays in HepG2 cells. Taken together, these data strongly suggest an involvement of liver-specific transcription factor GATA-4 in the transcriptional regulation of CYP2C9. Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics ER -