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Functional association of hepatocyte nuclear factor 4 alpha (HNF4α) and Krüppel‐like factor 9 (KLF9) in cytochrome P450 2D6 (CYP2D6) regulation during pregnancy
Author(s) -
Koh Kwi Hye,
Pan Xian,
Yu Aiming,
Jeong Hyunyoung
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.1102.2
Subject(s) - transactivation , hepatocyte nuclear factor 4 , transcription factor , hepatocyte nuclear factors , cyp2d6 , microbiology and biotechnology , biology , endocrinology , cytochrome p450 , gene , genetics , metabolism , nuclear receptor
CYP2D6 is responsible for metabolism of ~25% of marketed drugs. Clinical data indicate that pregnancy increases CYP2D6‐mediated drug metabolism. Previously, we have found humanized CYP2D6 transgenic mice (tg‐ CYP2D6 ) as a potential model to study CYP2D6 induction during pregnancy. To elucidate the mechanisms underlying CYP2D6 regulation during pregnancy, we obtained a list of genes differentially expressed in livers of pregnant vs. nonpregnant tg‐ CYP2D6 mice through microarray experiments. The results revealed that 430 and 225 genes were up‐or down‐regulated, respectively, during pregnancy. The upregulated genes included the following 11 transcription factors: Ar, Ascl1, Atf5, Ddit, Egr1, Foxa3, Junb, Klf9, Klf10, Mafk and Rev‐erbα . Most of these transcription factors, when individually transfected into HepG2 cells, did not significantly increase promoter activities of CYP2D6. However, when co‐transfected with a known transcriptional activator of CYP2D6 (i.e., HNF4α), KLF9 significantly increased HNF4α transactivation of CYP2D6; HNF4α alone enhanced CYP2D6 promoter activity by 1.7‐fold, whereas co‐transfection of HNF4α and KLF9 enhanced the activity by 12.6‐fold. Together, our results suggest that the increased expression of KLF9 may be in part responsible for CYP2D6 induction during pregnancy by potentiating HNF4α transactivation. This study is supported by NIH (R01HD065532).