Transcriptional Regulation of Cytochrome P450 2D6 by Small Heterodimer Partner

Cytochrome P450 2D6 (CYP2D6) is a major drug-metabolizing enzyme, responsible for eliminating ~20% of marketed drugs. Of note, CYP2D6 activity exhibits large interindividual variability, but the factors leading to this variability remain poorly understood. Accumulating clinical data indicate that CYP2D6-mediated drug metabolism is increased during pregnancy. However, the underlying mechanism was completely unknown in part due to a lack of study models that could recapitulate the clinical finding. Here, we established CYP2D6-humanized transgenic (Tg-CYP2D6) mice as such a model, by showing enhanced CYP2D6 expression at term pregnancy in the mice. Using Tg-CYP2D6 mice, we found that transcription factor small heterodimer partner (SHP) was downregulated in the liver during pregnancy and established SHP as a transcriptional repressor of CYP2D6 expression. Furthermore, we identified that all-trans retinoic acid (atRA), an endogenous compound that induces SHP expression, exhibited decreased hepatic levels during pregnancy in Tg-CYP2D6 mice. Administration of atRA led to a significant decrease in CYP2D6 expression in Tg-CYP2D6 mice. Based on the finding that SHP is a novel transcriptional regulator of CYP2D6 expression, we further examined whether known modulators of SHP expression alter CYP2D6 expression. SHP is a known representative target gene of farnesoid X receptor (FXR), a bile acid sensor. Administration of a synthetic agonist of FXR, GW4064, to Tg-CYP2D6 mice led to significant decreases in CYP2D6 expression in an SHP-dependent manner. Estrogen-induced cholestasis also led to increased SHP and decreased CYP2D6 expression in Tg-CYP2D6 mice. Together, these results suggest that differential levels of SHP modulators may contribute to interindividual variability in CYP2D6 activity. Our study potentially provides a basis to better predict CYP2D6 activity level in humans and thus to enable personalized medicine for CYP2D6 substrates.