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Induction of CYP2D6 Expression during Pregnancy Is Associated with an Increased Activity of Hepatocyte Nuclear Factor 4α
Author(s) -
PAN XIAN,
Koh Kwihye,
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.1102.3
Subject(s) - hepatocyte nuclear factor 4 , hepatocyte nuclear factors , biology , messenger rna , gene expression , pregnancy , microbiology and biotechnology , activator (genetics) , cyp2d6 , endocrinology , transcription factor , gene , medicine , cytochrome p450 , metabolism , genetics , nuclear receptor
Clinical evidence indicates increased metabolism of CYP2D6 substrates during pregnancy; the underlying mechanisms are unknown. The objectives of this study were (1) to evaluate the utility of CYP2D6‐humanized transgenic (Tg‐ CYP2D6 ) mouse as a model for CYP2D6 induction during pregnancy, and (2) to investigate the role of hepatocyte nuclear factor 4α (HNF4α), a known transcriptional activator of CYP2D6, in CYP2D6 induction. The genome of Tg‐ CYP2D6 mouse harbors human CYP2D6 gene with its 2.5‐kb upstream regulatory region. qRT‐PCR and western blot results revealed that CYP2D6 mRNA and protein expressions was 2–3 fold higher in Tg‐ CYP2D6 mice during pregnancy than pre‐pregnancy, consistent with an elevated CYP2D6 metabolism shown in pregnant women. In contrast, mRNA expression of Cyp2d22 , the mouse homologue of human CYP2D6 , did not increase during pregnancy. While hepatic HNF4α mRNA or protein levels were not altered in Tg‐ CYP2D6 mice at pregnancy, ChIP‐qPCR study demonstrated an increased recruitment of HNF4α (and RNA polymerase II) onto CYP2D6 promoter region (~3 fold) in livers of pregnant mouse vs. those of virgin or postpartum mice. An increased recruitment was also shown for another HNF4α target gene, ApoC2. Our results suggest that CYP2D6 induction during pregnancy may be due to the increase of HNF4α activity that enhances transcription expression of CYP2D6. This study is supported by NIH (R01HD065532).