From the Department of Pharmacy Practice and.
J Biol Chem. 2014 Feb 7;289(6):3105-13. doi: 10.1074/jbc.M113.526798. Epub 2013 Dec 6.
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 4α (HNF4α), did not change during pregnancy. However, HNF4α recruitment to CYP2D6 promoter increased at term pregnancy, accompanied by repressed expression of small heterodimer partner (SHP). In HepG2 cells, SHP repressed HNF4α 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.
主要药物代谢酶 CYP2D6 的底物在怀孕期间的消除率增加，但部分原因是缺乏实验模型，其潜在机制尚不清楚。在这里，我们引入 CYP2D6 人源化（Tg-CYP2D6）小鼠作为一种动物模型，其中肝 CYP2D6 的表达在怀孕期间增加。在小鼠肝脏中，已知 CYP2D6 的正向调控因子肝细胞核因子 4α（HNF4α）的表达在怀孕期间没有变化。然而，HNF4α 募集到 CYP2D6 启动子的增加在妊娠末期，伴随着小异二聚体伴侣（SHP）的表达受抑制。在 HepG2 细胞中，SHP 抑制 HNF4α 对 CYP2D6 启动子的转录激活。在转基因（Tg）-CYP2D6 小鼠中，SHP 的敲低导致 CYP2D6 表达显著增加。视黄酸是一种诱导 SHP 的内源性化合物，在 Tg-CYP2D6 小鼠中，其在怀孕期间肝脏中的水平降低。全反式视黄酸的给药导致 Tg-CYP2D6 小鼠肝 CYP2D6 的表达和活性显著降低。这项研究为理解怀孕期间 CYP2D6 介导的药物代谢改变的机制提供了重要的见解，为改善孕妇的药物治疗奠定了基础。
