PT - JOURNAL ARTICLE AU - Jessica Mwinyi AU - Isa Cavaco AU - Rasmus Steen Pedersen AU - Anna Persson AU - Sabrina Burkhardt AU - Souren Mkrtchian AU - Magnus Ingelman-Sundberg TI - Regulation of CYP2C19 expression by estrogen receptor alpha. Implications for estrogen dependent inhibition of drug metabolism AID - 10.1124/mol.110.065540 DP - 2010 Jul 30 TA - Molecular Pharmacology PG - mol.110.065540 4099 - http://molpharm.aspetjournals.org/content/early/2010/07/30/mol.110.065540.short 4100 - http://molpharm.aspetjournals.org/content/early/2010/07/30/mol.110.065540.full AB - Cytochrome P4502C19 (CYP2C19) is an important drug metabolizing enzyme involved in the biotransformation of e.g. proton pump inhibitors and antidepressants. Several in vivo studies have shown that the CYP2C19 activity is inhibited by oral contraceptives which can cause important drug interactions. The underlying molecular mechanism has been suggested to be competitive inhibition. However, the results presented here indicate that estradiol derivatives downregulate CYP2C19 expression via estrogen receptor α (ERα) which interacts with the newly identified ER-binding half site (ERE) at the position -151/-147 in the CYP2C19 promoter. In gene reporter experiments in Huh-7 hepatoma cells the activity of the luciferase construct carrying a 1.6 kb long CYP2C19 promoter fragment co-transfected with ERα was down regulated upon treatment with 17β-estradiol (EE) or 17α-ethinylestradiol (ETE) at half maximum concentrations of 10-7 M and 10-8 M, respectively. Mutations introduced into the ERE half site -151/-147 significantly inhibited these ligand dependent effects. Electrophoretic mobility shift assays and quantitative chromatin immunoprecipitation experiments revealed that estrogen receptor α binds to this element. A significant suppression of CYP2C19 transcription by female sex steroids was confirmed by RT PCR after hormonal treatment of human hepatocytes. Inhibition experiments using a stable HEK293 CYP2C19 cell line revealed competitive inhibition at much higher concentrations of EE and ETE as compared to those required for transcriptional inhibition. These results indicate that both EE and ETE inhibit CYP2C19 expression via an ERα-dependent regulatory pathway, thus providing a new insight into the molecular mechanism behind the inhibitory effect of oral contraceptives on CYP2C19 activity.