title: Geniposide attenuates ANIT-induced cholestasis through regulation of transporters and enzymes involved in bile acids homeostasis in rats.
abstract: BACKGROUND
  Geniposide (GE) is one of the major iridoid glycosides isolated from the fruit of Gardenia jasminoides Ellis that has been used to treat hepatic disorders including cholestasis. However, the underlying mechanisms for GE ameliorating the reduction in bile acids accumulation by α-naphthylisothiocyanate (ANIT) remain unclear.
  
  
  OBJECTIVE
  The purpose of this study is to characterize the efficacy of GE in regulation of bile acids uptake, synthesis, metabolism, and transport in ANIT-induced rats.
  
  
  METHODS
  Sprague-Dawley rats were orally administrated with vehicle, GE (25, 50, and 100mg/kg), and ursodeoxycholic acid (UDCA) (60mg/kg) once daily for seven days. On the fifth day, a single dose of ANIT (75mg/kg) was administrated via oral gavage. Blood biochemical determination, bile flow rate and liver histopathology were measured to evaluate the protective effect of GE. The mRNA expressions and protein levels of transporters and enzymes involved in bile acids homeostasis were determined by quantitative real-time polymerase chain reaction (PCR) and western blot to study the underlying mechanism of GE against ANIT-induced rats.
  
  
  RESULTS
  GE (25, 50, and 100mg/kg, po) dose-dependently prevented ANIT-induced changes in serum markers for liver injury. GE treatment reduced basolateral bile acids uptake via repression of OATP2 (P<0.05). Bile acids biosynthesis was decreased through down-regulation of CYP7A1, CYP8B1, and CYP27A1 (P<0.05). GE significantly increased canalicular bile acids secretion via BSEP (P<0.05), subsequently stimulating bile flow during cholestasis. GE also markedly enhanced mRNA level of basolateral transporter OSTβ (P<0.01). Bile acids transported to the plasma were cleared into the urine, resulting in down-regulation of plasma bile acids. However, GE did not alter the mRNA levels of CYP3A2, UGT1A1 and SULT2A1. Furthermore, the gene and protein expression analysis demonstrated activation of FXR, PXR, and SHP after GE administration.
  
  
  CONCLUSIONS
  GE attenuates ANIT-induced hepatotoxicity and cholestasis in rats, due to regulation enzymes and transporters responsible for bile acids homeostasis.
authors.affiliation: School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, PR China.
authors.forename: Lingling
authors.initials: L
authors.lastname: Wang
authors.affiliation: School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, PR China.
authors.forename: Guixin
authors.initials: G
authors.lastname: Wu
authors.affiliation: School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, PR China.
authors.forename: Feihua
authors.initials: F
authors.lastname: Wu
authors.affiliation: School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, PR China.
authors.forename: Nan
authors.initials: N
authors.lastname: Jiang
authors.affiliation: School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, PR China. Electronic address: cpuzyzj246@163.com.
authors.forename: Yining
authors.initials: Y
authors.lastname: Lin
mesh_terms: D015058:1-Naphthylisothiocyanate; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D002779:Cholestasis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D014453:Glucuronosyltransferase / Q000235:genetics; D006706:Homeostasis; D039823:Iridoids / Q000494:pharmacology / Q000627:therapeutic use*; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D027361:Organic Anion Transporters / Q000235:genetics; D000077297:Pregnane X Receptor; D020011:Protective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism; D015238:Sulfotransferases / Q000235:genetics; D000099150:Receptor, Farnesoid X-Activated; D000099148:UGT1A1 Enzyme
chemical_list: D015058:1-Naphthylisothiocyanate; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D001647:Bile Acids and Salts; D003577:Cytochrome P-450 Enzyme System; D014453:Glucuronosyltransferase; D039823:Iridoids; D027361:Organic Anion Transporters; D000077297:Pregnane X Receptor; D020011:Protective Agents; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D015238:Sulfotransferases; D000099150:Receptor, Farnesoid X-Activated; C490548:Abcb11 protein, rat; C503597:Slco1a4 protein, rat; C499946:Ugt1a1 protein, rat; D000099148:UGT1A1 Enzyme; C099713:nuclear receptor subfamily 0, group B, member 2; C007835:geniposide; C028152:alcohol sulfotransferase
keywords: Bile acids; Cholestasis; Enzymes; Geniposide; Transporters; α-Naphthylisothiocyanate