RT Journal Article
SR Electronic
T1 Kruppel-like Factor 9 (KLF9) Promotes Cytochrome P450 (CYP) 2D6 Expression during Pregnancy in CYP2D6-humanized Mice
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.114.093666
DO 10.1124/mol.114.093666
A1 Kwi Hye Koh
A1 Xian Pan
A1 Wei Zhang
A1 Alan McLachlan
A1 Raul Urrutia
A1 Hyunyoung Jeong
YR 2014
UL http://molpharm.aspetjournals.org/content/early/2014/09/12/mol.114.093666.abstract
AB 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 vs. nonpregnant CYP2D6-humanized (tg-CYP2D6) mice was compiled via microarray experiments followed by qRT-PCR verification. As a result, seven transcription factors (ATF5, EGR1, FOXA3, JUNB, KLF9, KLF10, and REV-ERBα) were found to be upregulated 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 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.