title: Danning tablets attenuates α-naphthylisothiocyanate-induced cholestasis by modulating the expression of transporters and metabolic enzymes.
abstract: BACKGROUND
  The Danning tablets (DNts) is commonly prescribed in China as a cholagogic formula. Our previous studies showed that DNts exerted the protective effect on α-naphthylisothiocyanate (ANIT)-induced liver injury with cholestasis in a dose-dependent mannar. However, the detailed molecular mechanisms of DNts against ANIT-induced cholestasis are still not fully explored.
  
  
  METHODS
  Danning tablet (3 g/kg body weight/day) was administered orally to experimental rats for seven days before they were treated with ANIT (60 mg/kg daily via gastrogavage) which caused cholestasis. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total bilirubin (T-Bil), direct bilirubin (D-Bil) and total bile acid (TBA) were measured to evaluate the protective effect of Danning tablet at 12, 24 and 48h after ANIT treatment. Meanwhile, total bilirubin or total bile acid in the bile, urine and liver were also measured at 48h after ANIT treatment. Furthermore, the hepatic or renal mRNA and protein levels of metabolic enzymes and transports were investigated to elucidate the protective mechanisms of Danning tablet against ANIT-induced cholestasis.
  
  
  RESULTS
  In this study, we found that DNts significantly attenuated translocation of multidrug resistance-associated protein 2 (Mrp2) from the canalicular membrane into an intracellular and up-regulated the hepatic mRNA and protein expressions of metabolic enzymes including cytochrome P450 2b1(Cyp2b1) and uridine diphosphate-5¢- glucuronosyltransferase (Ugt1a1)) and transporters including bile salt export pump (Bsep) and multidrug resistance protein 2 (Mdr2)) as well as renal organic solute transporter beta (Ostβ), accompanied by further increase in urinary and biliary excretion of bile acid and bilirubin.
  
  
  CONCLUSIONS
  DNts might promote bile acid and bilirubin elimination by regulating the expressions of hepatic and renal transporters as well as hepatic metabolic enzymes.
authors.forename: Lili
authors.initials: L
authors.lastname: Ding
authors.forename: Binfeng
authors.initials: B
authors.lastname: Zhang
authors.forename: Changsen
authors.initials: C
authors.lastname: Zhan
authors.affiliation: The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, Institute of Traditional Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. yangli7951@hotmail.com.
authors.forename: Li
authors.initials: L
authors.lastname: Yang
authors.forename: Zhengtao
authors.initials: Z
authors.lastname: Wang
mesh_terms: D015058:1-Naphthylisothiocyanate / Q000633:toxicity*; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001647:Bile Acids and Salts / Q000378:metabolism; D001663:Bilirubin / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D002779:Cholestasis / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism*; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000096:biosynthesis*; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar
chemical_list: D015058:1-Naphthylisothiocyanate; D000410:Alanine Transaminase; D001219:Aspartate Aminotransferases; D001647:Bile Acids and Salts; D001663:Bilirubin; D004365:Drugs, Chinese Herbal; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins