Cholic acid feeding increases CYP2D6 expression in CYP2D6‐humanized mice

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Cytochrome P450 (CYP) 2D6 is a major drug‐metabolizing enzyme in the liver, but factors involved in the regulation of CYP2D6 expression remain poorly defined. Recent studies have shown that CYP2D6 expression is repressed by small heterodimer partner (SHP), a transcriptional repressor that is upregulated in cholestasis (1,2). The objective of this study was to determine whether cholestasis modulates CYP2D6 expression by upregulating SHP. To this end, CYP2D6‐humanized transgenic mice were fed normal chow (control) or chow supplemented with 1% (w/w) cholic acid (CA) for 2 weeks (n=4/group), and hepatic SHP and CYP2D6 expression was measured. SHP mRNA expression did not differ between the groups while SHP protein expression decreased by 2‐fold. CYP2D6 mRNA and protein expression levels were increased in the CA group by 1.5‐fold. To determine the mechanism for the disconnect between the changes in SHP mRNA and protein levels in CA‐fed mice, an in situ analysis of 3′‐untranslated region of SHP was performed, and a putative binding site for a microRNA, miR142‐3p, was identified. miR142‐3p expression was found to be increased by 5‐fold in the liver of CA‐fed mice. Promoter reporter assays using a luciferase vector harboring the 3′‐untranslated region of SHP revealed that miR142‐3p represses SHP expression by 2‐fold in HEK293T cells. Overall, these results indicate that CA feeding in mice leads to decreased SHP protein levels and increased CYP2D6 expression.Support or Funding InformationThis study was supported by NIH (GM112746 and HD065532).