Farnesoid X Receptor Agonist Represses Cytochrome P450 2D6 Expression by Upregulating Small Heterodimer Partner.
Cytochrome P450 2D6 (CYP2D6) is a major drug-metabolizing enzyme responsible for eliminating approximately 20% of marketed drugs. Studies have shown that differential transcriptional regulation of CYP2D6 may contribute to large interindividual variability in CYP2D6-mediated drug metabolism. However, the factors governing CYP2D6 transcription are largely unknown. We previously demonstrated small heterodimer partner (SHP) as a novel transcriptional repressor of CYP2D6 expression. SHP is a representative target gene of the farnesoid X receptor (FXR). The objective of this study is to investigate whether an agonist of FXR, 3-(2,6-dichlorophenyl)-4-(3'-carboxy-2-chlorostilben-4-yl)oxymethyl-5-isopropylisoxazole (GW4064), alters CYP2D6 expression and activity. In CYP2D6-humanized transgenic mice, GW4064 decreased hepatic CYP2D6 expression and activity (by 2-fold) while increasing SHP expression (by 2-fold) and SHP recruitment to the CYP2D6 promoter. CYP2D6 repression by GW4064 was abrogated in Shp(-/-);CYP2D6 mice, indicating a critical role of SHP in CYP2D6 regulation by GW4064. Also, GW4064 decreased CYP2D6 expression (by 2-fold) in primary human hepatocytes, suggesting that the results obtained in CYP2D6-humanized transgenic mice can be translated to humans. This proof of concept study provides evidence for CYP2D6 regulation by an inducer of SHP expression, namely, the FXR agonist GW4064.
Departments of Pharmacy Practice (H.J.) and Biopharmaceutical Sciences (X.P., H.J.), College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois; and Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio (Y.K.L.).
Xian
X
Pan
Departments of Pharmacy Practice (H.J.) and Biopharmaceutical Sciences (X.P., H.J.), College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois; and Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio (Y.K.L.).
Yoon-Kwang
YK
Lee
Departments of Pharmacy Practice (H.J.) and Biopharmaceutical Sciences (X.P., H.J.), College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois; and Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio (Y.K.L.) yjeong@uic.edu.
Hyunyoung
H
Jeong
D000818:Animals; D019389:Cytochrome P-450 CYP2D6 / Q000096:biosynthesis*; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D057809:HEK293 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics; D000099150:Receptor, Farnesoid X-Activated
D019389:Cytochrome P-450 CYP2D6; D065607:Cytochrome P-450 Enzyme Inhibitors; D007555:Isoxazoles; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C412815:GW 4064