title: Geniposidic acid protected against ANIT-induced hepatotoxity and acute intrahepatic cholestasis, due to Fxr-mediated regulation of Bsep and Mrp2.
abstract: BACKGROUND
  Geniposidic acid (GPA) is the main constituent of Gardenia jasminoides Ellis (Rubiaceae), which has long been used to treat inflammation, jaundice and hepatic disorders. The cholagogic effect of Gardenia jasminoides Ellis (Rubiaceae) and GPA have been widely reported, but the underlying occurrence mechanism remains unclear.
  
  
  OBJECTIVE
  This investigation was designed to evaluate the hepatoprotection effect and potential mechanisms of GPA derived from Gardenia jasminoides Ellis (Rubiaceae) on fighting against α-naphthylisothiocyanate (ANIT) caused liver injury with acute intrahepatic cholestasis.
  
  
  METHODS
  Sprague-Dawley (SD) rats were intragastrically (i.g.) administered with the GPA (100, 50 and 25mg/kg B.W. every 24h) for seven consecutive days, and then they were treated with ANIT (i.g. 65mg/kg once in the 5th day) which induced liver injury with acute intrahepatic cholestasis. Serum and bile biochemical analysis, bile flow rate and liver histopathology were measured to evaluate the protective effect of GPA fight against ANIT treatment. The protein and mRNA expression levels of farnesoid X receptor (Fxr), bile-salt export pump (Bsep), multidrug resistance associated protein2 (Mrp2), were evaluated to study the effect of liver protection about GPA against ANIT induced hepatotoxicity and underlying mechanisms.
  
  
  RESULTS
  Some abnormalities were observed on ANIT treated rats including weight loss, reduced food intake and hair turned yellow. Obtained results demonstrated that at dose 100 and 50mg/kg B.W. (P<0.01) and 25mg/kg B.W. (P<0.05) of GPA pretreated dramatically prevented ANIT induced decreased in bile flow rate. Compared with ANIT treated group, the results of bile biochemical parameters about total bile acid (TBA) was increased by GPA at groups with any dose (P<0.01), glutathione (GSH) was increased significantly at high dose (P<0.01) and medium dose (P<0.05), total bilirubin (TB) was increased at high and medium dose (P<0.05), direct bilirubin (DB) was only increased at high dose (P<0.01). Serum levels of glutamic-Oxalacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), γ-glutamyltranspeptidase (γ-GT), TB, DB and TBA in comparison with ANIT treated group (P<0.01) were reduced by GPA (between 100 and 50mg/kg B.W.) pretreatment. Histopathology of the liver tissue showed that pathological damages and hepatic portal area filled with bile were relieved after GPA pretreatment compared with ANIT treated group. The protein and mRNA expression of Fxr, Bsep and Mrp2 were decreased in ANIT treated group. On the contrary, the protein and mRNA of Fxr, Bsep and Mrp2 were up regulated significantly pretreatment by GPA at dose of high and medium groups. On protein level of Bsep and Mrp2 the result shown no statistical difference in GPA (25mg/kg B.W.), but it was not same shown in mRNA level.
  
  
  CONCLUSIONS
  The results of this investigation have demonstrated that the GPA exerts a dose dependent hepatoprotection effect on ANIT induced liver damage with acute intrahepatic cholestasis in rats, which may due to Fxr mediated regulation of bile transporters like Bsep and Mrp2.
authors.affiliation: Institute of Clinical Pharmacology Biochemical Pharmacology Laboratory Guangzhou University of Chinese Medicine, Jichang Road 12, Guangzhou 510405, Guangdong Province, PR China.
authors.forename: Hao
authors.initials: H
authors.lastname: Chen
authors.affiliation: Institute of Clinical Pharmacology Biochemical Pharmacology Laboratory Guangzhou University of Chinese Medicine, Jichang Road 12, Guangzhou 510405, Guangdong Province, PR China.
authors.forename: Xiaotao
authors.initials: X
authors.lastname: Huang
authors.affiliation: Institute of Clinical Pharmacology Biochemical Pharmacology Laboratory Guangzhou University of Chinese Medicine, Jichang Road 12, Guangzhou 510405, Guangdong Province, PR China.
authors.forename: Jianbin
authors.initials: J
authors.lastname: Min
authors.affiliation: Institute of Clinical Pharmacology Biochemical Pharmacology Laboratory Guangzhou University of Chinese Medicine, Jichang Road 12, Guangzhou 510405, Guangdong Province, PR China.
authors.forename: Weirong
authors.initials: W
authors.lastname: Li
authors.affiliation: Institute of Clinical Pharmacology Biochemical Pharmacology Laboratory Guangzhou University of Chinese Medicine, Jichang Road 12, Guangzhou 510405, Guangdong Province, PR China.
authors.forename: Rong
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Institute of Clinical Pharmacology Biochemical Pharmacology Laboratory Guangzhou University of Chinese Medicine, Jichang Road 12, Guangzhou 510405, Guangdong Province, PR China. Electronic address: athena_zw@126.com.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Institute of Clinical Pharmacology Biochemical Pharmacology Laboratory Guangzhou University of Chinese Medicine, Jichang Road 12, Guangzhou 510405, Guangdong Province, PR China. Electronic address: realliuch@126.com.
authors.forename: Changhui
authors.initials: C
authors.lastname: Liu
authors.affiliation: Institute of Clinical Pharmacology Biochemical Pharmacology Laboratory Guangzhou University of Chinese Medicine, Jichang Road 12, Guangzhou 510405, Guangdong Province, PR China.
authors.forename: Lang
authors.initials: L
authors.lastname: Yi
authors.affiliation: Institute of Clinical Pharmacology Biochemical Pharmacology Laboratory Guangzhou University of Chinese Medicine, Jichang Road 12, Guangzhou 510405, Guangdong Province, PR China.
authors.forename: Suiqing
authors.initials: S
authors.lastname: Mi
authors.affiliation: Institute of Clinical Pharmacology Biochemical Pharmacology Laboratory Guangzhou University of Chinese Medicine, Jichang Road 12, Guangzhou 510405, Guangdong Province, PR China.
authors.forename: Ningsheng
authors.initials: N
authors.lastname: Wang
authors.affiliation: Institute of Clinical Pharmacology Biochemical Pharmacology Laboratory Guangzhou University of Chinese Medicine, Jichang Road 12, Guangzhou 510405, Guangdong Province, PR China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Institute of Clinical Pharmacology Biochemical Pharmacology Laboratory Guangzhou University of Chinese Medicine, Jichang Road 12, Guangzhou 510405, Guangdong Province, PR China.
authors.forename: Chenchen
authors.initials: C
authors.lastname: Zhu
mesh_terms: D015058:1-Naphthylisothiocyanate / Q000633:toxicity; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D001646:Bile / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy* / Q000473:pathology; D002780:Cholestasis, Intrahepatic / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D057888:Iridoid Glucosides / Q000494:pharmacology* / Q000627:therapeutic use*; D008297:Male; D020011:Protective Agents / Q000494:pharmacology; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D015058:1-Naphthylisothiocyanate; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D057888:Iridoid Glucosides; D020011:Protective Agents; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C490548:Abcb11 protein, rat; C423013:Abcc2 protein, rat; C058966:geniposidic acid
keywords: Acute intrahepatic cholestasis; Bile salt export pump; Farnesoid X receptor; Geniposidic acid; Keywords:; Multidrug resistance protein 2; α-naphthylisothiocyanate