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Transcriptional Regulation of Cytochrome P450 2D6 by Small Heterodimer Partner
thesisposted on 2015-10-21, 00:00 authored by Xian Pan
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.
AdvisorJeong, HyunyoungHe, XiaolongMcLachlan, AlanBurdette, Joanna E.
Degree GrantorUniversity of Illinois at Chicago
Committee MemberLee, Hyunwoo He, Xiaolong McLachlan, Alan Burdette, Joanna E.