PXR mediates mifepristone-induced hepatomegaly in mice

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 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.

Automated summary

This study demonstrated that high-dose Mifepristone can induce hepatomegaly in mice through PXR-mediated activation of the YAP pathway. The results showed that Mifepristone can activate human PXR in a concentration-dependent manner and promote the nuclear translocation of PXR and YAP, leading to the expression of their target proteins. High-dose Mifepristone failed to induce hepatomegaly in Pxr-knockout mice, highlighting the crucial role of PXR in Mifepristone-induced hepatomegaly.