title: PXR-Mediated Upregulation of CYP3A Expression by Herb Compound Praeruptorin C from Peucedanum praeruptorum Dunn.
abstract: We recently reported that Praeruptorin C effectively transactivated the mRNA, protein expression, and catalytic activity of CYP3A4 via the CAR-mediated pathway, but whether and how PC could affect the expression and catalytic activity of CYP3A4 via PXR pathway remains unknown. Therefore, in this study, the effect of PC on the CYP3A gene expression was investigated in mice primary hepatocytes after knockdown of PXR by transient transfection of PXR siRNA, and the gene expression, protein expression, and catalytic activity of CYP3A4 in the LS174T cells with PXR overexpression were determined by real-time PCR, western blot analysis, and LC-MS/MS-based CYP3A4 substrate assay, respectively. We found that the level of CYP3a11 gene expression in mouse primary hepatocytes was significantly increased by praeruptorin C, but such an induction was suppressed after knockdown of pregnane X receptor by its siRNA. In PXR-overexpressed LS174T cells, PC significantly enhanced CYP3A4 mRNA, protein expression, and functional activity through PXR-mediated pathway; conversely, no such increase was found in the untransfected cells. These findings suggest that PC can significantly upregulate CYP3A level via the PXR-mediated pathway, and this should be taken into consideration to predict any potential herb-drug interactions between PC, Qianhu, and the other coadministered drugs.
authors.affiliation: Laboratory of Drug Metabolism and Pharmacokinetics, School of Pharmaceutical Sciences, Sun Yat-sen University, 132 Waihuan Dong Road, Guangzhou 510006, China ; School of Pharmaceutical Sciences, Hainan Medical University, Haikou 571010, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Huang
authors.affiliation: School of Pharmaceutical Sciences, Hainan Medical University, Haikou 571010, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Wu
authors.affiliation: Laboratory of Drug Metabolism and Pharmacokinetics, School of Pharmaceutical Sciences, Sun Yat-sen University, 132 Waihuan Dong Road, Guangzhou 510006, China.
authors.forename: Yu-Hua
authors.initials: YH
authors.lastname: Li
authors.affiliation: Institute of Chinese Medical Sciences, Macau University, Macau 999078, China.
authors.forename: Yi-Tao
authors.initials: YT
authors.lastname: Wang
authors.affiliation: Laboratory of Drug Metabolism and Pharmacokinetics, School of Pharmaceutical Sciences, Sun Yat-sen University, 132 Waihuan Dong Road, Guangzhou 510006, China.
authors.forename: Hui-Chang
authors.initials: HC
authors.lastname: Bi