title: Induction of human CYP3A4 by huperzine A, ligustrazine and oridonin through pregnane X receptor-mediated pathways.
abstract: The pregnane X receptor (PXR) is a key regulator of CYP3A4, which is involved in catalyzing the metabolic conversion of a number of endogenous substrates. In this study, we screened 22 compounds isolated from traditional Chinese herbal medicines using luciferase reporter gene assays for inspecting their capabilities in inducing PXR-mediated transactivation of CYP3A4 expression. In addition, the mRNA and protein expressions of CYP3A4 and PXR as well as the enzymatic activites of CYP3A4 were analyzed by real-time PCR, Western blot analysis and UPLC-MS/MS-based metabolite assay in LS174T cells. Huperzine A, ligustrazine and oridonin were identified to be the inducers of CYP3A4. These compounds induced the CYP3A4 reporter luciferase activity, and up-regulated CYP3A4 mRNA and protein levels significantly. Besides, huperzine A, ligustrazine and oridonin significantly up-regulated enzymatic activities of CYP3A4. However, the three compounds showed no effects on PXR mRNA and protein expression. To our knowledge, it is the first identification of these three compounds as PXR activators to induce CYP3A4. These results indicate that huperzine A, ligustrazine and oridonin induced CYP3A4 expression and activation via PXR dependent pathways, and might contribute to drug-drug interactions.
authors: Yi-Wen
authors: YW
authors: Zhang
authors: Mei-Hua
authors: MH
authors: Bao
authors: Guo
authors: G
authors: Wang
authors: Qiang
authors: Q
authors: Qu
authors: Hong-Hao
authors: HH
authors: Zhou
mesh_terms: D000470:Alkaloids / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D015153:Blotting, Western; D002460:Cell Line; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis*; D045786:Diterpenes, Kaurane / Q000494:pharmacology*; D004790:Enzyme Induction / Q000187:drug effects; D017930:Genes, Reporter / Q000235:genetics; D006801:Humans; D010957:Plasmids / Q000235:genetics; D000077297:Pregnane X Receptor; D011719:Pyrazines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D011987:Receptors, Steroid / Q000187:drug effects*; D012717:Sesquiterpenes / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection
chemical_list: D000470:Alkaloids; D000972:Antineoplastic Agents, Phytogenic; D002800:Cholinesterase Inhibitors; D045786:Diterpenes, Kaurane; D000077297:Pregnane X Receptor; D011719:Pyrazines; D012333:RNA, Messenger; D011987:Receptors, Steroid; D012717:Sesquiterpenes; C050426:huperzine A; C011959:oridonin; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C017953:tetramethylpyrazine