PXR mediates mifepristone-induced hepatomegaly in mice
Yao,Xin-peng; Jiao,Ting-ying; Jiang,Yi-ming; Fan,Shi-cheng; Zhao,Ying-yuan; Yang,Xiao; Gao,Yue; Li,Fei; Zhou,Yan-ying; Chen,Pan-pan; Huang,Min; Bi,Hui-chang
AbstractMifepristone (Mif), an effective synthetic steroidal antiprogesterone drug, is widely used for medical abortion and pregnancy prevention. Due to its anti-glucocorticoid effect, high-dose Mif is also used to treat Cushing's syndrome. Mif was reported to active pregnane X receptor (PXR) in vitro and PXR can induce hepatomegaly via activation and interaction with yes-associated protein (YAP) pathway. High-dose Mif was reported to induce hepatomegaly in rats and mice, but the underlying mechanism remains unclear. Here, the role of PXR was studied in Mif-induced hepatomegaly in C57BL/6 mice and Pxr-knockout mice. The results demonstrated that high-dose Mif (100 mg center dot kg(-1) center dot d(-1), i.p.) treatment for 5 days significantly induced hepatomegaly with enlarged hepatocytes and promoted proliferation, but low dose of Mif (5 mg center dot kg(-1) center dot d(-1), i.p.) cannot induce hepatomegaly. The dual-luciferase reporter gene assays showed that Mif can activate human PXR in a concentration-dependent manner. In addition, Mif could promote nuclear translocation of PXR and YAP, and significantly induced the expression of PXR, YAP, and their target proteins such as CYP3A11, CYP2B10, UGT1A1, ANKRD, and CTGF. However, Mif (100 mg center dot kg(-1) center dot d(-1), i.p.) failed to induce hepatomegaly in Pxr-knockout mice, as well as hepatocyte enlargement and proliferation, further indicating that Mif-induced hepatomegaly is PXR-dependent. In summary, this study demonstrated that PXR-mediated Mif-induced hepatomegaly in mice probably via activation of YAP pathway. This study provides new insights in Mif-induced hepatomegaly, and provides novel evidence on the crucial function of PXR in liver enlargement and regeneration.
Keywordmifepristone hepatomegaly pregnane X receptor (PXR) yes-associated protein (YAP)
WOS IDWOS:000634685300001
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Document Type期刊论文
Affiliation1.Sun Yat Sen Univ, Sch Pharmaceut Sci, Guangdong Prov Key Lab New Drug Design & Evaluat, Guangzhou 510006, Peoples R China
2.Chinese Acad Sci, Kunming Inst Bot, Kunming 650201, Yunnan, Peoples R China
3.Southern Med Univ, Sch Pharm, Guangzhou 510515, Peoples R China
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GB/T 7714
Yao,Xin-peng,Jiao,Ting-ying,Jiang,Yi-ming,et al. PXR mediates mifepristone-induced hepatomegaly in mice[J]. ACTA PHARMACOLOGICA SINICA,2022,43(1):146-156.
APA Yao,Xin-peng.,Jiao,Ting-ying.,Jiang,Yi-ming.,Fan,Shi-cheng.,Zhao,Ying-yuan.,...&Bi,Hui-chang.(2022).PXR mediates mifepristone-induced hepatomegaly in mice.ACTA PHARMACOLOGICA SINICA,43(1),146-156.
MLA Yao,Xin-peng,et al."PXR mediates mifepristone-induced hepatomegaly in mice".ACTA PHARMACOLOGICA SINICA 43.1(2022):146-156.
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