Altered expression of small Heterodimer Partner Governs Cytochrome P450 (CYP) 2D6 induction during Pregnancy in CYP2D6-humanized mice

Kwi Hye Koh, Xian Pan, Hong Wu Shen, Samuel L M Arnold, Aiming Yu, Frank J. Gonzalez, Nina Isoherranen, Hyunyoung Jeong

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

Abstract

Background: CYP2D6-mediated drug metabolism is enhanced during pregnancy, but the underlying mechanisms remain unknown. Results: In CYP2D6-humanized mice, CYP2D6 induction during pregnancy was linked to decreased expression of SHP, a repressor of CYP2D6 expression. Conclusion: Decreased SHP expression may account for CYP2D6 induction during pregnancy. Significance: This may provide a mechanistic basis in designing optimal dosage regimens in pregnant women. Substrates of a major drug-metabolizing enzyme CYP2D6 display increased elimination during pregnancy, but the underlying mechanisms are unknown in part 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. In the mouse livers, expression of a known positive regulator of CYP2D6, hepatocyte nuclear factor 4δ (HNF4δ), did not change during pregnancy. However, HNF4δ recruitment to CYP2D6 promoter increased at term pregnancy, accompanied by repressed expression of small heterodimer partner (SHP). In HepG2 cells, SHP repressed HNF4δ transactivation of CYP2D6 promoter. In transgenic (Tg)-CYP2D6 mice, SHP knockdown led to a significant increase in CYP2D6 expression. Retinoic acid, an endogenous compound that induces SHP, exhibited decreased hepatic levels during pregnancy in Tg-CYP2D6 mice. Administration of all-trans-retinoic acid led to a significant decrease in the expression and activity of hepatic CYP2D6 in Tg-CYP2D6 mice. This study provides key insights into mechanisms underlying altered CYP2D6-mediated drug metabolism during pregnancy, laying a foundation for improved drug therapy in pregnant women.

Original languageEnglish (US)
Pages (from-to)3105-3113
Number of pages9
JournalJournal of Biological Chemistry
Volume289
Issue number6
DOIs
StatePublished - Feb 7 2014

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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