title: Monoammonium glycyrrhizinate protects rifampicin- and isoniazid-induced hepatotoxicity via regulating the expression of transporter Mrp2, Ntcp, and Oatp1a4 in liver.
abstract: BACKGROUND
  Drug-induced liver injury (DILI) is associated with altering expression of hepatobiliary membrane transporters. Monoammonium glycyrrhizin (MAG) is commonly used for hepatic protection and may have a correlation with the inhibition effect of multidrug resistance-associated protein 2 (Mrp2).
  
  
  OBJECTIVE
  This study evaluates the dynamic protective effect of MAG on rifampicin (RIF)- and isoniazid (INH)-induced hepatotoxicity in rats.
  
  
  METHODS
  Male Wistar rats were randomly divided into four groups of 15 rats. Liver injury was induced by co-treatment with RIF (60 mg/kg) and INH (60 mg/kg) by gavage administration; MAG was orally pretreated at the doses of 45 or 90 mg/kg 3 h before RIF and INH. Rats in each group were sacrificed at 7, 14, and 21 d time points after drug administration.
  
  
  RESULTS
  Liver function, histopathological analysis, and oxidative stress factors were significantly altered in each group. The expression of Mrp2 was significantly increased 230, 760, and 990% at 7, 14, and 21 time points, respectively, in RIF- and INH-treated rats. Compared with the RIF and INH groups, Mrp2 was reduced and Ntcp was significantly elevated by 180, 140, and 160% in the MAG high-dose group at the three time points, respectively. The immunoreaction intensity of Oatp1a4 was increased 170, 190, and 370% in the MAG low-dose group and 160, 290, and 420% in the MAG high-dose group at the three time points, respectively, compared with the RIF and INH groups.
  
  
  CONCLUSIONS
  These results indicated that MAG has a protective effects against RIF- and INH-induced hepatotoxicity. The underlying mechanism may have correlation with its effect on regulating the expression of hepatobiliary membrane transporters.
authors.affiliation: a Department of Pharmacy , the First Hospital of Lanzhou University , Lanzhou , China .
authors.forename: Liting
authors.initials: L
authors.lastname: Zhou
authors.affiliation: b Department of Pharmacy , the First Hospital of Jilin University , Changchun , China , and.
authors.forename: Yanqing
authors.initials: Y
authors.lastname: Song
authors.affiliation: c College of Pharmaceutical Science, Lanzhou University , Lanzhou , China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.affiliation: a Department of Pharmacy , the First Hospital of Lanzhou University , Lanzhou , China .
authors.forename: Hongyan
authors.initials: H
authors.lastname: Qin
authors.affiliation: a Department of Pharmacy , the First Hospital of Lanzhou University , Lanzhou , China .
authors.forename: Guoqiang
authors.initials: G
authors.lastname: Zhang
authors.affiliation: a Department of Pharmacy , the First Hospital of Lanzhou University , Lanzhou , China .
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: a Department of Pharmacy , the First Hospital of Lanzhou University , Lanzhou , China .
authors.forename: Xin'an
authors.initials: X
authors.lastname: Wu
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000284:Administration, Oral; D000818:Animals; D000995:Antitubercular Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005786:Gene Expression Regulation / Q000187:drug effects*; D019695:Glycyrrhizic Acid / Q000008:administration & dosage / Q000627:therapeutic use*; D007538:Isoniazid / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity; D008297:Male; D027361:Organic Anion Transporters / Q000235:genetics*; D029363:Organic Anion Transporters, Sodium-Dependent / Q000235:genetics*; D017208:Rats, Wistar; D012293:Rifampin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity; D027981:Symporters / Q000235:genetics*
chemical_list: D018528:ATP-Binding Cassette Transporters; C423013:Abcc2 protein, rat; D000995:Antitubercular Agents; D027361:Organic Anion Transporters; D029363:Organic Anion Transporters, Sodium-Dependent; C503597:Slco1a4 protein, rat; D027981:Symporters; C071908:sodium-bile acid cotransporter; D019695:Glycyrrhizic Acid; D007538:Isoniazid; D012293:Rifampin
keywords: Anti-tuberculosis agent; glycyrrhizin acid; hepatoprotective; liver injury