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Krüppel-like factor 9 promotes hepatic cytochrome P450 2D6 expression during pregnancy in CYP2D6-humanized mice. Mol Pharmacol 2014 Dec;86(6):727-35 PMID: 25217496 PMCID: PMC4244597

Pubmed ID

25217496

DOI

10.1124/mol.114.093666

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.

Author List

Koh KH, Pan X, Zhang W, McLachlan A, Urrutia R, Jeong H

Author

Raul A. Urrutia MD Center Director, Professor in the Surgery department at Medical College of Wisconsin




Scopus

2-s2.0-84964698054   12 Citations

MESH terms used to index this publication - Major topics in bold

Animals
Cytochrome P-450 CYP2D6
Female
HEK293 Cells
Hepatocyte Nuclear Factor 4
Humans
Kruppel-Like Transcription Factors
Liver
Male
Mice
Pregnancy
Pregnancy, Animal
Promoter Regions, Genetic
jenkins-FCD Prod-310 bff9d975ec7f2d302586822146c2801dd4449aad