title: Up-regulatation of CYP3A expression through pregnent X receptor by praeruptorin D isolated from Peucedanum praeruptorum Dunn.
abstract: BACKGROUND
  Qianhu, the dried roots of Peucedanum praeruptorum DUNN (Umbelliferae), is a well-known traditional Chinese medicinal herb which was officially listed in the Chinese Pharmacopoeia. Praeruptorin D (PD) is one of the major active constituents of Peucedanum praeruptorum Dunn (Qianhu). The Pregnane X receptor (PXR) is an orphan nuclear receptor and plays a pivotal role in the activation of human cytochrome P450 3A4 (CYP3A4) gene.
  
  
  OBJECTIVE
  The purpose of this study was to investigate the effect of PD on the PXR-mediated transactivation of CYP3A4, and thus to predict potential herb-drug interactions between PD, Qianhu, and the other co-administered drugs that metabolized by CYP3A4.
  
  
  METHODS
  The effect of PD on the Cyp3a11, mPXR mRNA expression in mice primary hepatocytes was measured using real-time PCR. The gene expression, protein expression, and catalytic activity of CYP3A4 in the LS174T cells after transfected with PXR expression plasmids were determined by real-time PCR, Western blot analysis, and LC-MS/MS based CYP3A4 substrate assay.
  
  
  RESULTS
  The results revealed that the level of Cyp3a11 gene expression in mice primary hepatocytes was significantly increased by PD, but PD cannot induce the mPXR gene expression. On the other hand, CYP3A4 mRNA, protein expression and functional activity in PXR-over-expression LS174T cells were significantly increased by PD through PXR-mediated pathway; conversely, no significant change was found in the untransfected cells.
  
  
  CONCLUSIONS
  These findings suggest that PD can significantly up-regulate CYP3A4 expression and activity via the PXR-mediated pathway and this should be taken into consideration to predict any potential herb-drug interactions when PD and Peucedanum praeruptorum Dunn are co-administered with other drugs.
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, 132# Waihuan Dong Road, University City, Guangzhou 510006, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Huang
authors.forename: Min
authors.initials: M
authors.lastname: Huang
authors.forename: Yu-Hua
authors.initials: YH
authors.lastname: Li
authors.forename: Rui-Ming
authors.initials: RM
authors.lastname: Li
authors.forename: Yu
authors.initials: Y
authors.lastname: Zeng
authors.forename: Shao-Yi
authors.initials: SY
authors.lastname: Kuang
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Yi-Tao
authors.initials: YT
authors.lastname: Wang
authors.forename: Hui-Chang
authors.initials: HC
authors.lastname: Bi
mesh_terms: D000818:Animals; D019661:Apiaceae / Q000737:chemistry*; D002460:Cell Line; D003374:Coumarins / Q000737:chemistry / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis* / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D041743:Herb-Drug Interactions; D006801:Humans; D008297:Male; D008516:Medicine, Chinese Traditional / Q000379:methods; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology*; D000077297:Pregnane X Receptor; D012333:RNA, Messenger / Q000235:genetics; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D003374:Coumarins; D008565:Membrane Proteins; D010936:Plant Extracts; D000077297:Pregnane X Receptor; D012333:RNA, Messenger; D011987:Receptors, Steroid; C496508:Cyp3a11 protein, mouse; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human