title: Multifaceted interaction of the traditional Chinese medicinal herb Schisandra chinensis with cytochrome P450-mediated drug metabolism in rats.
abstract: BACKGROUND
  Schisandra chinensis (SC), officially listed as a sedative and tonic in the Chinese Pharmacopoeia, has been used as a common component in various prescriptions in Traditional Chinese Medicine (TCM) and more recently in western medicine for its antihepatotoxic effect. To assess the possible herb-drug interaction, effects of SC extracts on hepatic cytochrome P450 (P450, CYP) enzymes were studied.
  
  
  METHODS
  Effects of SC extracts on rat hepatic CYP450 enzymes in vitro and in vivo were investigated by probe substrates method, real-time RT-PCR assay and Western blotting analysis. Furthermore, the effects of SC alcoholic extract on the PK of four SC lignans and the drugs possibly co-administrated in vivo were studied in male Sprague-Dawley rat.
  
  
  RESULTS
  SC aqueous extract and alcoholic extract showed significant inhibitory effect on the activities of rat liver microsomal CYP1A2, 2C6, 2C11, 2D2, 2E1 and 3A1/2 in vitro. Multiple administrations of SC aqueous extract (1.5g/kg, qd×7d) and alcoholic extract (1.5g/kg, qd×7d) increased the activities, mRNA and protein expressions of CYP2E1 and CYP3A1/2, and meanwhile, inhibited the activities and mRNA expression of CYP2D2 in vivo. The in vivo metabolism of four SC lignans, such as schisandrin, schisantherin A, deoxyshisandrin and γ-schisandrin, and chlorzoxazone was significantly accelerated, exhibited by the reduced AUC and increased CLz/F, by 7-day pretreatment with SC alcoholic extract. However, both single and multiple dosing treatments of SC alcoholic extract remarkably decreased the in vivo metabolism of tacrolimus indicated by the enhanced AUC (7-12 fold) and elevated Cmax (10 fold).
  
  
  CONCLUSIONS
  These results revealed that the SC extracts exhibited multifaceted effects on rat hepatic CYP450 enzymes. Herb-drug interaction should be paid intense attention between SC components and drugs metabolized by different CYP450 enzymes.
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, No.1 Xiannongtan Street, Beijing 100050, China. Electronic address: wangbaolian@imm.ac.cn.
authors.forename: Baolian
authors.initials: B
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, No.1 Xiannongtan Street, Beijing 100050, China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, No.1 Xiannongtan Street, Beijing 100050, China.
authors.forename: Jinping
authors.initials: J
authors.lastname: Hu
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, No.1 Xiannongtan Street, Beijing 100050, China. Electronic address: yanli@imm.ac.cn.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000097:blood / Q000493:pharmacokinetics; D002753:Chlorzoxazone / Q000097:blood / Q000493:pharmacokinetics; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D041743:Herb-Drug Interactions; D007166:Immunosuppressive Agents / Q000097:blood / Q000493:pharmacokinetics; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D017705:Lignans / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D008516:Medicine, Chinese Traditional; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D009125:Muscle Relaxants, Central / Q000097:blood / Q000493:pharmacokinetics; D010936:Plant Extracts / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D032141:Schisandra; D020280:Sertraline / Q000097:blood / Q000493:pharmacokinetics; D016559:Tacrolimus / Q000097:blood / Q000493:pharmacokinetics
chemical_list: D000928:Antidepressive Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D007166:Immunosuppressive Agents; D007527:Isoenzymes; D017705:Lignans; D009125:Muscle Relaxants, Central; D010936:Plant Extracts; D012333:RNA, Messenger; D003577:Cytochrome P-450 Enzyme System; D002753:Chlorzoxazone; D020280:Sertraline; D016559:Tacrolimus
keywords: CYP450; Chlorzoxazone (PubChem CID:2733); Deoxyshisandrin (PubChem CID:155256); Herb–drug interaction; Induction; Inhibition; Schisandra chinensis; Schisandrin (PubChem CID: 3001664); Schisantherin A (PubChem CID:151529); Sertraline(PubChem CID:68617); Tacrolimus(PubChem CID: 5282315); γ-schisandrin (PubChem CID: 108130)