title: The Chinese herbal medicine Sophora flavescens activates pregnane X receptor.
abstract: Sophora flavescens (SF) is an herbal medicine widely used for the treatment of viral hepatitis, cancer, viral myocarditis, gastrointestinal hemorrhage, and skin diseases. It was recently reported that SF up-regulates CYP3A expression. The mechanism of SF-induced CYP3A expression is unknown. In the current study, we tested the hypothesis that SF-induced CYP3A expression is mediated by the activation of pregnane X receptor (PXR). We used two cell lines, DPX2 and HepaRG, to investigate the role of PXR in SF-induced CYP3A expression. The DPX2 cell line is derived from HepG2 cells with the stable transfection of human PXR and a luciferase reporter gene linked with a human PXR response element identified in the CYP3A4 gene promoter. In DPX2 cells, SF activated PXR in a concentration-dependent manner. We used a metabolomic approach to identify the chemical constituents in SF, which were further analyzed for their effect on PXR activation and CYP3A regulation. One chemical in SF, N-methylcytisine, was identified as an individual chemical that activated PXR. HepaRG is a highly differentiated hepatoma cell line that mimics human hepatocytes. In HepaRG cells, N-methylcytisine significantly induced CYP3A4 expression, and this induction was suppressed by the PXR antagonist sulforaphane. These results suggest that SF induces CYP3A expression via the activation of PXR.
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA.
authors.forename: Laiyou
authors.initials: L
authors.lastname: Wang
authors.forename: Feng
authors.initials: F
authors.lastname: Li
authors.forename: Jie
authors.initials: J
authors.lastname: Lu
authors.forename: Guodong
authors.initials: G
authors.lastname: Li
authors.forename: Dan
authors.initials: D
authors.lastname: Li
authors.forename: Xiao-bo
authors.initials: XB
authors.lastname: Zhong
authors.forename: Grace L
authors.initials: GL
authors.lastname: Guo
authors.forename: Xiaochao
authors.initials: X
authors.lastname: Ma
mesh_terms: D000470:Alkaloids / Q000494:pharmacology; D002460:Cell Line; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis* / Q000235:genetics; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D004790:Enzyme Induction / Q000187:drug effects; D041743:Herb-Drug Interactions; D006801:Humans; D000077297:Pregnane X Receptor; D011807:Quinolizines / Q000494:pharmacology; D011987:Receptors, Steroid / Q000378:metabolism*; D029909:Sophora; D000093843:Quinolizidine Alkaloids
chemical_list: D000470:Alkaloids; D051544:Cytochrome P-450 CYP3A; D004365:Drugs, Chinese Herbal; D000077297:Pregnane X Receptor; D011807:Quinolizines; D011987:Receptors, Steroid; C510163:CYP3A4 protein, human; C034245:N-methylcytisine; D000093843:Quinolizidine Alkaloids