Unknown,Transcriptomics,Genomics,Proteomics

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Effects of pregnancy on hepatic gene expression in CYP2D6-humanized mice

ABSTRACT: Hepatic drug metabolism plays a key role in determining drug response and safety. Studies of drug metabolism generate valuable information about regulation of genes encoding drug-metabolizing enzymes and enzyme functions that are critical in developing dosing guideline. However, current knowledge is insufficient to support dosing guideline for pregnant women. Specifically, substrates of a major drug-metabolizing enzyme CYP2D6 show increased elimination during pregnancy, but the underlying mechanisms are completely unknown largely due to a lack of experimental models. Here, we introduce CYP2D6-humanized (Tg-CYP2D6) mice as an animal model where hepatic CYP2D6 expression is increased during pregnancy, recapitulating the clinically reported changes in CYP2D6-mediated drug metabolism. In these mice, pregnancy had minimal effects on the expression of hepatocyte nuclear factor (HNF) 4a, the transcription factor controlling basal CYP2D6 expression. KrÃ¼ppel-like factor (KLF) 9 and small heterodimer partner (SHP) were found up- and down-regulated in Tg-CYP2D6 mouse livers during pregnancy, respectively. KLF9 enhanced HNF4a-mediated transactivation of the CYP2D6 promoter whereas SHP repressed it. Retinoic acid (RA), an endogenous compound that induces SHP, exhibited decreased hepatic levels during pregnancy. These results indicate that interplay among hepatic transcription factors HNF4a, SHP, and KLF9 underlies CYP2D6 induction during pregnancy, and that retinoic acid is a potential trigger. This is the first report on the mechanisms underlying CYP2D6 induction and illustrates the utility of humanized mice as an in vivo model to study altered drug disposition during pregnancy. Livers collected at pre-pregnancy, 21 days of pregnancy, and 7 days postpartum from CYP2D6-humanized mice.

ORGANISM(S): Mus musculus

SUBMITTER: Wei Zhang

PROVIDER: E-GEOD-50166 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Krüppel-like factor 9 promotes hepatic cytochrome P450 2D6 expression during pregnancy in CYP2D6-humanized mice.

Koh Kwi Hye KH Pan Xian X Zhang Wei W McLachlan Alan A Urrutia Raul R Jeong Hyunyoung H

Molecular pharmacology 20140912 6

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 co ...[more]

PMID: 25217496

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Project description:The transcriptional regulation of drug-metabolizing enzymes and transporters (here collectively referred to as DMEs) in the developing proximal tubule is not well understood. As in the liver, DME regulation in the PT may be mediated through nuclear receptors which are thought to “sense” deviations from homeostasis by being activated by ligands, some of which are handled by DMEs, including drug transporters. Systems analysis of transcriptomic data during kidney development predicted a set of upstream transcription factors, including Hnf4a and Hnf1a, as well as Nr3c1 (Gr), Nfe2l2 (Nrf2), Ppara, and Tp53. Motif analysis of cis-regulatory further suggested that Hnf4a and Hnf1a are the main transcriptional regulators in the PT. Available expression data from tissue-specific Hnf4a KO tissues revealed that distinct subsets of DMEs were regulated by Hnf4a in a tissue-specific manner. ChIP-seq was performed to characterize the PT-specific binding sites of Hnf4a in rat kidneys at three developmental stages (prenatal, immature, adult), which further supported a major role for Hnf4a in regulating PT gene expression, including DMEs. In ex vivo kidney organ culture, an antagonist of Hnf4a (but not a similar inactive compound) led to predicted changes in DME expression, including among others Fmo1, Cyp2d2, Cyp2d4, Nqo2, as well as organic cation transporters and organic anion transporters Slc22a1(Oct1), Slc22a2 (Oct2), Slc22a6 (Oat1), Slc22a8(Oat3), and Slc47a1(Mate1). Conversely, overexpression of Hnf1a and Hnf4a in primary mouse embryonic fibroblasts (MEFs), sometimes considered a surrogate for mesenchymal stem cells, induced expression of several of these proximal tubule DMEs, as well as epithelial markers and a PT-specific brush border marker Ggt1. These cells had organic anion transporter function. Taken together, the data strongly supports a critical role for HNF4a and Hnf1a in the tissue-specific regulation of drug handling and differentiation toward a PT cellular identity. Hnf4a binding was examined in rat kidneys at three timepoints (E20, P13 and Adult) and p300 binding was examined in adult rat kidney cortex tissue using ChIP-seq. Four corresponding input DNA samples were used as controls for peak calling.

Dataset Information

Effects of pregnancy on hepatic gene expression in CYP2D6-humanized mice

Publications

Krüppel-like factor 9 promotes hepatic cytochrome P450 2D6 expression during pregnancy in CYP2D6-humanized mice.

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