title: Evaluation of hepatotoxicity and cholestasis in rats treated with EtOH extract of Fructus Psoraleae.
abstract: BACKGROUND
  Fructus Psoraleae (FP) has been widely used to heal skin diseases as well as osteoporosis, osteomalacia, and bone fracture. There also exist many clinical reports about FP-induced hepatotoxicity associated with acute cholestatic hepatic injury. However, the FP-induced hepatotoxicity and the underlying mechanisms remain unclear.
  
  
  OBJECTIVE
  The present study aims to determine the hepatotoxicity of FP in Sprague-Dawley (SD) rats and to investigate the underlying mechanisms.
  
  
  METHODS
  Sprague-Dawley rats of both sexes were intragastrically administered with the EtOH extract of FP (EEFP) at doses of 1.875, 1.25 and 0.625 g/kg for 28 day. Body weight, relative liver weight, biochemical analysis, histopathology, the mRNA and protein expression of Cholesterol 7α-hydroxylase (CYP7A1), farnesoid X receptor (FXR), bile-salt export pump (BSEP), multidrug resistance-associated protein 2 (MRP2), multidrug resistance-associated protein 3 (MRP3) were evaluated to study the EEFP-induced hepatotoxicity and its underlying mechanisms.
  
  
  RESULTS
  Many abnormalities were observed in the EEFP-treated groups including suppression of weight gain and food intake, change of some parameters in serum biochemistry, increased weight of liver, and decreased concentration of bile acid in bile. The mRNA and protein expression of CYP7A1, MRP3, MRP2, BSEP increased and the expression of FXR decreased in EEFP-treated female groups; the mRNA and protein of FXR and CYP7A1 decreased and that of the others remained the same in EEFP-treated male groups.
  
  
  CONCLUSIONS
  In conclusion, we provide evidence for the first time that EEFP can induce sex-related cholestatic hepatotoxicity, and that female rats are more sensitive to EEFP-induced hepatotoxicity, which involves the destruction of the biosynthesis and transportation of bile acid. Further investigation is still needed to uncover the mechanism of the sex-dimorphic EEFP-induced hepatotoxicity.
authors.affiliation: Jiangsu Provincial Center for Drug Screening, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China.
authors.forename: Jiaying
authors.initials: J
authors.lastname: Wang
authors.forename: Zhenzhou
authors.initials: Z
authors.lastname: Jiang
authors.forename: Jinzi
authors.initials: J
authors.lastname: Ji
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Li
authors.forename: Mi
authors.initials: M
authors.lastname: Chen
authors.forename: Yurong
authors.initials: Y
authors.lastname: Wang
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhang
authors.forename: Ting
authors.initials: T
authors.lastname: Tai
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.forename: Luyong
authors.initials: L
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001646:Bile / Q000737:chemistry / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D002779:Cholestasis / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D000431:Ethanol / Q000737:chemistry; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D009929:Organ Size / Q000187:drug effects; D010936:Plant Extracts / Q000494:pharmacology*; D029907:Psoralea; D051381:Rats; D017207:Rats, Sprague-Dawley; D012639:Seeds / Q000737:chemistry; D012737:Sex Factors; D012997:Solvents / Q000737:chemistry; D014969:Xanthine Oxidase / Q000097:blood
chemical_list: D010936:Plant Extracts; D012997:Solvents; D000431:Ethanol; D014969:Xanthine Oxidase