Mifepristone(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·kg-1·d-1,i.p.)treatment for 5 days significantly induced hepatomegaly with enlarged hepatocytes and promoted proliferation,but low dose of Mif(5 mg·kg-1·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(100mg·kg-1·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.

Xin-peng Yao;Ting-ying Jiao;Yi-ming Jiang;Shi-cheng Fan;Ying-yuan Zhao;Xiao Yang;Yue Gao;Fei Li;Yan-ying Zhou;Pan-pan Chen;Min Huang;Hui-chang Bi

Guangdong Provincial Key Laboratory of New Drug Design and Evaluation,School of Pharmaceutical Sciences,Sun Yat-sen University,Guangzhou 510006,China;Kunming Institute of Botany,Chinese Academy of Sciences,Kunming 650201,China;School of Pharmacy,Southern Medical University,Guangzhou 510515,China

中国药理学报（英文版）

[1]Xin-peng Yao;Ting-ying Jiao;Yi-ming Jiang;Shi-cheng Fan;Ying-yuan Zhao;Xiao Yang;Yue Gao;Fei Li;Yan-ying Zhou;Pan-pan Chen;Min Huang;Hui-chang Bi-.PXR mediates mifepristone-induced hepatomegaly in mice)[J].中国药理学报（英文版）,2022(01):146-156

hepatomegaly,Mif,antiprogesterone,Pxr,CYP3A11,CYP2B10,ANKRD

PXR,mediates,mifepristone,induced,mice,Mifepristone,effective,synthetic,steroidal,drug,widely,used,medical,abortion,pregnancy,prevention,Due,its,glucocorticoid,high,dose,also,Cushing,syndrome,was,reported,active,pregnane,receptor,vitro,via,activation,interaction,yes,associated,YAP,pathway,High,rats,but,underlying,mechanism,remains,unclear,Here,role,studied,C57BL,knockout,results,demonstrated,that,treatment,days,significantly,enlarged,hepatocytes,promoted,proliferation,low,cannot,dual,luciferase,reporter,assays,showed,activate,human,concentration,dependent,manner,In,addition,could,nuclear,translocation,expression,their,target,proteins,such,UGT1A1,CTGF,However,100mg,failed,well,enlargement,further,indicating,summary,this,study,mediated,probably,This,provides,new,insights,novel,evidence,crucial,function,liver,regeneration

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