Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-32349
Mwinyi, J; Nekvindová, J; Cavaco, I; Hofmann, Y; Pedersen, R S; Landman, E; Mkrtchian, S; Ingelman-Sundberg, M (2010). New insights into the regulation of CYP2C9 gene expression: the role of the transcription factor GATA-4. Drug Metabolism and Disposition, 38(3):415-421.
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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.
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|Item Type:||Journal Article, refereed, original work|
|Communities & Collections:||04 Faculty of Medicine > University Hospital Zurich > Clinic for Clinical Pharmacology and Toxicology|
|DDC:||610 Medicine & health|
|Deposited On:||26 Mar 2010 07:47|
|Last Modified:||28 Nov 2013 02:01|
|Publisher:||American Society for Pharmacology and Experimental Therapeutics|
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