Cholic Acid Feeding Leads to Increased CYP2D6 Expression in CYP2D6-Humanized Mice.
Cytochrome P450 2D6 (CYP2D6) is a major drug-metabolizing enzyme, but the factors governing transcriptional regulation of its expression remain poorly understood. Based on previous reports of small heterodimer partner (SHP) playing an important role as a transcriptional repressor of CYP2D6 expression, here we investigated how a known upstream regulator of SHP expression, namely cholestasis triggered by cholic acid (CA) feeding in mice, can lead to altered CYP2D6 expression. To this end, CYP2D6-humanized (Tg-CYP2D6) mice were fed with a CA-supplemented or control diet for 14 days, and hepatic expression of multiple genes was examined. Unexpectedly, CA feeding led to insignificant changes in SHP mRNA but also to significant (2.8-fold) decreases in SHP protein levels. In silico analysis of the SHP gene regulatory region revealed a putative binding site for a microRNA, miR-142-3p. Results from luciferase reporter assays suggest that miR-142-3p targets the SHP gene. Hepatic expression of miR-142-3p was significantly increased in CA-fed mice (∼5-fold), suggesting a potential role of miR-142-3p in the regulation of SHP expression in cholestasis. The decreased SHP protein levels were accompanied by increased expression and activity of CYP2D6 in the liver of CA-fed mice. These results suggest potential roles of differential hepatic levels of bile acids in the transcriptional regulation of CYP2D6 expression.
Department of Pharmacy Practice (K.-J.W., H.J.) and Department of Biopharmaceutical Sciences (X.P., R.K., H.J.), College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois.
Xian
X
Pan
Department of Pharmacy Practice (K.-J.W., H.J.) and Department of Biopharmaceutical Sciences (X.P., R.K., H.J.), College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois.
Rebecca
R
Kent
Department of Pharmacy Practice (K.-J.W., H.J.) and Department of Biopharmaceutical Sciences (X.P., R.K., H.J.), College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois.
Kyoung-Jae
KJ
Won
Department of Pharmacy Practice (K.-J.W., H.J.) and Department of Biopharmaceutical Sciences (X.P., R.K., H.J.), College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois yjeong@uic.edu.
Hyunyoung
H
Jeong
D000818:Animals; D001665:Binding Sites; D002779:Cholestasis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D019826:Cholic Acid / Q000633:toxicity; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D008099:Liver / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*
D035683:MicroRNAs; C529102:Mirn142 microRNA, mouse; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; C099713:nuclear receptor subfamily 0, group B, member 2; D019389:Cytochrome P-450 CYP2D6; D019826:Cholic Acid