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Altered expression of small heterodimer partner governs CYP2D6 induction during pregnancy in CYP2D6‐humanized mice (1141.2)
Author(s) -
Jeong Hyunyoung,
Pan Xian,
Koh Kwihye,
Yu Aiming,
Isoherranen Nina
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.1141.2
Subject(s) - transactivation , drug metabolism , pregnancy , hepatocyte nuclear factor 4 , drug , pharmacology , dosing , hepatocyte nuclear factors , retinoic acid , small heterodimer partner , cyp2d6 , medicine , transcription factor , biology , cancer research , endocrinology , nuclear receptor , metabolism , cytochrome p450 , gene , genetics
Hepatic drug metabolism plays a key role in determining drug response and safety. Over the decades, substantial progresses have been made in our understanding of the regulation of genes encoding drug‐metabolizing enzymes, providing critical information in developing dosing guidelines. However, current knowledge is insufficient to support dosing guidelines for pregnant women. Specifically, 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 mice as an animal model where hepatic CYP2D6 expression is increased during pregnancy. In the mouse livers, small heterodimer partner (SHP) was downregulated during pregnancy. SHP repressed transactivation of the CYP2D6 promoter by hepatocyte nuclear factor (HNF) 4α. Finally, retinoic acid, an endogenous compound that induces SHP, exhibited decreased hepatic levels during pregnancy. 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. Grant Funding Source : Supported by Grant HD065532 and Fellowship K12HK055892