title: Hepatocyte nuclear factor (HNF) 4α transactivation of cytochrome P450 (Cyp) 2d40 promoter is enhanced during pregnancy in mice.
abstract: We have recently reported that transactivation of cytochrome P450 (CYP) 2D6 promoter by hepatocyte nuclear factor (HNF) 4α is enhanced during pregnancy, and this is triggered in part by altered expression of small heterodimer partner (SHP) and Krüppel-like factor 9 (KLF9). The objective of this study is to determine whether this is conserved for mouse endogenous Cyp2d gene(s). Among the eight Cyp2d homologs of mouse we examined, only Cyp2d40 expression was found induced (by 6-fold) at term pregnancy as compared to pre-pregnancy level. In mice where hepatic Hnf4α was knocked-down, the pregnancy-mediated increase in Cyp2d40 expression was abrogated. Results from transient transfection, promoter reporter assays, and electrophoretic mobility shift assays indicated that HNF4α transactivates Cyp2d40 promoter via direct binding to -117/-105 of the gene. Chromatin immunoprecipitation assay showed a 2.3-fold increase in HNF4α recruitment to Cyp2d40 promoter during pregnancy. Results from mice treated with an SHP inducer (i.e., GW4064) and HepG2 cells co-transfected with KLF9 suggest that neither SHP nor KLF9 is involved in the increased HNF4α transactivation of Cyp2d40 promoter during pregnancy. Together, our results indicate that while the underlying molecular mechanism is different from that for CYP2D6, Cyp2d40 is induced during pregnancy through enhanced transactivation by HNF4α.
authors.affiliation: Department of Biopharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, 833 S. Wood St. (MC 865), Chicago, IL 60612, USA. Electronic address: mning2@uic.edu.
authors.forename: Miaoran
authors.initials: M
authors.lastname: Ning
authors.affiliation: Department of Pharmacy Practice, College of Pharmacy, University of Illinois at Chicago, 833 S. Wood St. (MC 886), Chicago, IL 60612, USA. Electronic address: noble.koh@gmail.com.
authors.forename: Kwi Hye
authors.initials: KH
authors.lastname: Koh
authors.affiliation: Department of Biopharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, 833 S. Wood St. (MC 865), Chicago, IL 60612, USA. Electronic address: xpan9@uic.edu.
authors.forename: Xian
authors.initials: X
authors.lastname: Pan
authors.affiliation: Department of Biopharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, 833 S. Wood St. (MC 865), Chicago, IL 60612, USA; Department of Pharmacy Practice, College of Pharmacy, University of Illinois at Chicago, 833 S. Wood St. (MC 886), Chicago, IL 60612, USA. Electronic address: yjeong@uic.edu.
authors.forename: Hyunyoung
authors.initials: H
authors.lastname: Jeong
mesh_terms: D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D005260:Female; D017930:Genes, Reporter; D057809:HEK293 Cells; D056945:Hep G2 Cells; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D007555:Isoxazoles / Q000494:pharmacology; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D011247:Pregnancy; D011401:Promoter Regions, Genetic; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D015533:Transcriptional Activation
chemical_list: D051557:Hepatocyte Nuclear Factor 4; C496593:Hnf4a protein, mouse; D007527:Isoenzymes; D007555:Isoxazoles; C489675:Klf9 protein, mouse; D051741:Kruppel-Like Transcription Factors; D018160:Receptors, Cytoplasmic and Nuclear; C099713:nuclear receptor subfamily 0, group B, member 2; D003577:Cytochrome P-450 Enzyme System; D008156:Luciferases; C412815:GW 4064
keywords: Cyp2d40; HNF4α; Pregnancy; Regulation