title: Scoparone potentiates transactivation of the bile salt export pump gene and this effect is enhanced by cytochrome P450 metabolism but abolished by a PKC inhibitor.
abstract: OBJECTIVE
  Hyperbilirubinaemia and cholestasis are two major forms of liver abnormality. The Chinese herb Yin Chin has been used for thousands of years to treat liver dysfunctions. In mice, this herb and its principal ingredient scoparone were found to accelerate the clearance of bilirubin accompanied by the induction of uridine diphosphate-5'-glucuronosyltransferase-1A1 (UGT1A1), a bilirubin processing enzyme. The aim of this study was to determine whether scoparone induces the expression of human UGT1A1. In addition, the expression of the bile salt export pump (BSEP), a transporter of bile acids, was determined.
  
  
  METHODS
  Primary human hepatocytes and hepatoma line Huh7 were treated with scoparone, chenodeoxycholic acid (CDCA) or both. The expression of UGT1A1 and BSEP mRNA was determined. The activation of the human BSEP promoter reporter by scoparone was determined in Huh7 cells by transient transfection and in mice by bioluminescent imaging. The metabolism of scoparone was investigated by recombinant CYP enzymes and pooled human liver microsomes.
  
  
  RESULTS
  Scoparone did not enhance the expression of either human BSEP or, surprisingly, UGT1A1. However, scoparone significantly potentiated the expression of BSEP induced by CDCA. Consistent with this, scoparone potentiated the stimulant effect of CDCA on the human BSEP promoter. This potentiation was enhanced by co-transfection of cytochrome P4501A2 but abolished by the PKC inhibitor GF109203X.
  
  
  CONCLUSIONS
  Scoparone and Yin Chin normalize liver function primarily by enhancing the secretion of bile acids, and this effect probably varies depending on the metabolic rate of scoparone.
authors.affiliation: Department of Biomedical Sciences, Center for Pharmacogenomics and Molecular Therapy, University of Rhode Island, Kingston, RI 02881, USA.
authors.forename: Dongfang
authors.initials: D
authors.lastname: Yang
authors.forename: Jian
authors.initials: J
authors.lastname: Yang
authors.forename: Deshi
authors.initials: D
authors.lastname: Shi
authors.forename: Ruitang
authors.initials: R
authors.lastname: Deng
authors.forename: Bingfang
authors.initials: B
authors.lastname: Yan
mesh_terms: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002756:Cholagogues and Choleretics / Q000378:metabolism / Q000494:pharmacology*; D003374:Coumarins / Q000378:metabolism / Q000494:pharmacology*; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004357:Drug Synergism; D017930:Genes, Reporter; D014453:Glucuronosyltransferase / Q000235:genetics; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D011401:Promoter Regions, Genetic; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015533:Transcriptional Activation / Q000187:drug effects*; D014162:Transfection; D000099148:UGT1A1 Enzyme
chemical_list: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D002756:Cholagogues and Choleretics; D003374:Coumarins; D019388:Cytochrome P-450 CYP1A2; D003577:Cytochrome P-450 Enzyme System; D014453:Glucuronosyltransferase; D047428:Protein Kinase Inhibitors; D000099148:UGT1A1 Enzyme; C093491:ABCB11 protein, human; C490549:Abcb11 protein, mouse; C504573:CYP1A2 protein, human; C018145:scoparone