title: Reversing effects of silybin on TAA-induced hepatic CYP3A dysfunction through PXR regulation.
abstract: OBJECTIVE
  Silybin (SB), a major constituent of the milk thistle, has been used to treat several liver disorders. However, liver diseases were always accompanied by CYP450 dysfunction. This study was designed to explore the relationship between the hepatoprotective effect and CYP3A regulation of SB during thioacetamide (TAA)-induced rat liver injury.
  
  
  METHODS
  Serum biochemical analysis and histopathological study were taken to evaluate the hepatoprotectinve effect of SB. α-SMA were detected by immunohistochemical analysis and cytokine release in rat liver was determined by ELISA assay. CYP3A and PXR expression were determined by RT-PCR and Western blot analysis, and CYP3A activity was based on the midazolam 4-hydroxylation reaction. Also, siRNA transfection was induced in HepG2 cells to evaluate the effect of PXR on cytotoxicity and CYP3A4 dysregulation caused by TAA.
  
  
  RESULTS
  SB showed powerful hepatoprotective effects, and anti-inflammatory and anti-fibrosis effects, and reversed the loss of CYP3A and PXR in TAA-injured rat liver, and decreased PXR translocation into the cell nucleus. PXR silencing weakened the effect of SB on cytoprotection and CYP3A regulation.
  
  
  CONCLUSIONS
  PXR was a very important factor of CYP3A regulation and might be the target of SB in TAA-induced liver disease. Also, because of the potential interactions of SB and co-administered medicines, it might be necessary to adjust the dosage in the clinical medication of liver disease.
authors.affiliation: Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Xie
authors.affiliation: State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Hai-Ping
authors.initials: HP
authors.lastname: Hao
authors.affiliation: State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.affiliation: School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Zhao-Xian
authors.initials: ZX
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China. Electronic address: guangjiwang@hotmail.com.
authors.forename: Guang-Ji
authors.initials: GJ
authors.lastname: Wang
mesh_terms: D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy* / Q000201:enzymology; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism*; D004365:Drugs, Chinese Herbal / Q000008:administration & dosage*; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008297:Male; D020944:Silybum marianum / Q000737:chemistry*; D000077297:Pregnane X Receptor; D051381:Rats; D017207:Rats, Sprague-Dawley; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D000077385:Silybin; D012838:Silymarin / Q000008:administration & dosage*; D013853:Thioacetamide / Q000009:adverse effects*
chemical_list: D004365:Drugs, Chinese Herbal; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D012838:Silymarin; D013853:Thioacetamide; D000077385:Silybin; D051544:Cytochrome P-450 CYP3A
keywords: CYP3A; Inflammation; Liver injury; PXR; Silybin; Thioacetamide