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

被引:12
|
作者
Pan, Xian [2 ]
Kent, Rebecca [2 ]
Won, Kyoung-Jae [1 ]
Jeong, Hyunyoung [1 ,2 ]
机构
[1] Univ Illinois, Coll Pharm, Dept Pharm Practice, 900 South Ashland Ave,MC 870, Chicago, IL 60607 USA
[2] Univ Illinois, Coll Pharm, Dept Biopharmaceut Sci, 900 South Ashland Ave,MC 870, Chicago, IL 60607 USA
基金
美国国家卫生研究院;
关键词
SMALL HETERODIMER PARTNER; BACTERIAL TRANSLOCATION; INDUCED CHOLESTASIS; IN-VIVO; BILE; LIVER; SHP; METABOLISM; REPRESSION; BIOSYNTHESIS;
D O I
10.1124/dmd.116.074013
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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 (similar to 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.
引用
收藏
页码:346 / 352
页数:7
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