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  2. Cholic Acid Feeding Leads to Increased CYP2D6 Expression in CYP2D6-Humanized Mice

Cholic Acid Feeding Leads to Increased CYP2D6 Expression in CYP2D6-Humanized Mice

  • Drug Metab Dispos. 2017 Apr;45(4):346-352. doi: 10.1124/dmd.116.074013.
Xian Pan 1 Rebecca Kent 1 Kyoung-Jae Won 1 Hyunyoung Jeong 2
Affiliations

Affiliations

  • 1 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.
  • 2 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.
Abstract

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.

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