【摘 要】
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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 activ
【机 构】
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Guangdong Provincial Key Laboratory of New Drug Design and Evaluation,School of Pharmaceutical Scien
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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.
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