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Molecular Pharmacology

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Research ArticleArticle

Krüppel-Like Factor 9 Promotes Hepatic Cytochrome P450 2D6 Expression during Pregnancy in CYP2D6-Humanized Mice

Kwi Hye Koh, Xian Pan, Wei Zhang, Alan McLachlan, Raul Urrutia and Hyunyoung Jeong
Molecular Pharmacology December 2014, 86 (6) 727-735; DOI: https://doi.org/10.1124/mol.114.093666
Kwi Hye Koh
Department of Pharmacy Practice (K.H.K., H.J.), Department of Biopharmaceutical Sciences (X.P., H.J.), College of Pharmacy, and Department of Pediatrics (W.Z.) and Department of Microbiology and Immunology (A.M.), College of Medicine, University of Illinois at Chicago, Chicago, Illinois; and Laboratory of Epigenetics and Chromatin Dynamics, and Departments of Biology and Molecular Biology, Epigenomics Translational Program, Mayo Clinic Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota (R.U.)
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Xian Pan
Department of Pharmacy Practice (K.H.K., H.J.), Department of Biopharmaceutical Sciences (X.P., H.J.), College of Pharmacy, and Department of Pediatrics (W.Z.) and Department of Microbiology and Immunology (A.M.), College of Medicine, University of Illinois at Chicago, Chicago, Illinois; and Laboratory of Epigenetics and Chromatin Dynamics, and Departments of Biology and Molecular Biology, Epigenomics Translational Program, Mayo Clinic Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota (R.U.)
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Wei Zhang
Department of Pharmacy Practice (K.H.K., H.J.), Department of Biopharmaceutical Sciences (X.P., H.J.), College of Pharmacy, and Department of Pediatrics (W.Z.) and Department of Microbiology and Immunology (A.M.), College of Medicine, University of Illinois at Chicago, Chicago, Illinois; and Laboratory of Epigenetics and Chromatin Dynamics, and Departments of Biology and Molecular Biology, Epigenomics Translational Program, Mayo Clinic Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota (R.U.)
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Alan McLachlan
Department of Pharmacy Practice (K.H.K., H.J.), Department of Biopharmaceutical Sciences (X.P., H.J.), College of Pharmacy, and Department of Pediatrics (W.Z.) and Department of Microbiology and Immunology (A.M.), College of Medicine, University of Illinois at Chicago, Chicago, Illinois; and Laboratory of Epigenetics and Chromatin Dynamics, and Departments of Biology and Molecular Biology, Epigenomics Translational Program, Mayo Clinic Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota (R.U.)
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Raul Urrutia
Department of Pharmacy Practice (K.H.K., H.J.), Department of Biopharmaceutical Sciences (X.P., H.J.), College of Pharmacy, and Department of Pediatrics (W.Z.) and Department of Microbiology and Immunology (A.M.), College of Medicine, University of Illinois at Chicago, Chicago, Illinois; and Laboratory of Epigenetics and Chromatin Dynamics, and Departments of Biology and Molecular Biology, Epigenomics Translational Program, Mayo Clinic Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota (R.U.)
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Hyunyoung Jeong
Department of Pharmacy Practice (K.H.K., H.J.), Department of Biopharmaceutical Sciences (X.P., H.J.), College of Pharmacy, and Department of Pediatrics (W.Z.) and Department of Microbiology and Immunology (A.M.), College of Medicine, University of Illinois at Chicago, Chicago, Illinois; and Laboratory of Epigenetics and Chromatin Dynamics, and Departments of Biology and Molecular Biology, Epigenomics Translational Program, Mayo Clinic Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota (R.U.)
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Abstract

Cytochrome P450 2D6 (CYP2D6), a major drug-metabolizing enzyme, is responsible for metabolism of approximately 25% of marketed drugs. Clinical evidence indicates that metabolism of CYP2D6 substrates is increased during pregnancy, but the underlying mechanisms remain unclear. To identify transcription factors potentially responsible for CYP2D6 induction during pregnancy, a panel of genes differentially expressed in the livers of pregnant versus nonpregnant CYP2D6-humanized (tg-CYP2D6) mice was compiled via microarray experiments followed by real-time quantitative reverse-transcription polymerase chain reaction(qRT-PCR) verification. As a result, seven transcription factors—activating transcription factor 5 (ATF5), early growth response 1 (EGR1), forkhead box protein A3 (FOXA3), JUNB, Krüppel-like factor 9 (KLF9), KLF10, and REV-ERBα—were found to be up-regulated in liver during pregnancy. Results from transient transfection and promoter reporter gene assays indicate that KLF9 itself is a weak transactivator of CYP2D6 promoter but significantly enhances CYP2D6 promoter transactivation by hepatocyte nuclear factor 4 (HNF4α), a known transcriptional activator of CYP2D6 expression. The results from deletion and mutation analysis of CYP2D6 promoter activity identified a KLF9 putative binding motif at -22/-14 region to be critical in the potentiation of HNF4α-induced transactivation of CYP2D6. Electrophoretic mobility shift assays revealed a direct binding of KLF9 to the putative KLF binding motif. Results from chromatin immunoprecipitation assay showed increased recruitment of KLF9 to CYP2D6 promoter in the livers of tg-CYP2D6 mice during pregnancy. Taken together, our data suggest that increased KLF9 expression is in part responsible for CYP2D6 induction during pregnancy via the potentiation of HNF4α transactivation of CYP2D6.

Footnotes

    • Received May 7, 2014.
    • Accepted September 12, 2014.
  • K.H.K. and X.P. contributed equally to this work.

  • This work was supported by the National Institutes of Health Eunice Kennedy Shriver National Institute of Child Health and Human Development [Grant HD065532], the National Institutes of Health (Grant DK52913) to R.U., and the Mayo Clinic Center for Cell Signaling in Gastroenterology (P30DK084567)

  • dx.doi.org/10.1124/mol.114.093666.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 86 (6)
Molecular Pharmacology
Vol. 86, Issue 6
1 Dec 2014
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Research ArticleArticle

Role of KLF9 in CYP2D6 Induction during Pregnancy

Kwi Hye Koh, Xian Pan, Wei Zhang, Alan McLachlan, Raul Urrutia and Hyunyoung Jeong
Molecular Pharmacology December 1, 2014, 86 (6) 727-735; DOI: https://doi.org/10.1124/mol.114.093666

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Research ArticleArticle

Role of KLF9 in CYP2D6 Induction during Pregnancy

Kwi Hye Koh, Xian Pan, Wei Zhang, Alan McLachlan, Raul Urrutia and Hyunyoung Jeong
Molecular Pharmacology December 1, 2014, 86 (6) 727-735; DOI: https://doi.org/10.1124/mol.114.093666
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