title: The feline bile salt export pump: a structural and functional comparison with canine and human Bsep/BSEP.
abstract: BACKGROUND
  The bile salt export pump (BSEP/ABCB11) is the primary transporter for the excretion of bile acids from hepatocytes into bile. In human, inhibition of BSEP by drugs has been related to drug-induced cholestasis and subsequent cytotoxic effects. The role of BSEP in canine and feline liver diseases has not been studied in detail, but the same mechanism of inhibition by drugs as in humans could play a role in veterinary medicine. The aim of this study was to investigate the functional characteristics of feline Bsep in comparison with canine and human Bsep/BSEP with respect to substrate affinities and inhibitory potential of model drugs. Orthologs of all three species were cloned and cell membrane vesicles overexpressing feline, canine and human Bsep/BSEP were prepared for functional analyses.
  
  
  RESULTS
  The cDNA sequences of the open reading frames of feline, canine and human Bsep/BSEP showed a high similarity between the species. Functional studies demonstrated for all species a tendency to a higher affinity of BSEP/Bsep for the conjugated bile acid taurocholic acid (TCA) than glycocholic acid (GCA), and a higher affinity for GCA than for the unconjugated cholic acid (CA). The inhibitory potency of the model inhibitors cyclosporine A, troglitazone and ketoconazole was characterized against TCA uptake into BSEP/Bsep containing membrane vesicles. All three substances potently inhibited TCA uptake without significant species differences.
  
  
  CONCLUSIONS
  Structure and functional characteristics of cat, dog and human Bsep/BSEP appeared to be very similar, indicating that the properties of this transporter have been highly preserved among the different species. Therefore, inhibition of BSEP by drugs could also be a mechanism in cholestasis and liver disease in veterinary relevant animal species. This model could be used to predict drug-induced liver injury caused by BSEP inhibition at an early stage in veterinary drug development.
authors.forename: Cyrina D
authors.initials: CD
authors.lastname: van Beusekom
authors.forename: Jeroen J M W
authors.initials: JJ
authors.lastname: van den Heuvel
authors.forename: Jan B
authors.initials: JB
authors.lastname: Koenderink
authors.affiliation: Veterinary Pharmacology, Pharmacotherapy and Toxicology, Institute for Risk Assessment Sciences, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 104, Utrecht 3584 CM, The Netherlands. J.A.Schrickx@uu.nl.
authors.forename: Johannes A
authors.initials: JA
authors.lastname: Schrickx
authors.forename: Frans G M
authors.initials: FG
authors.lastname: Russel
mesh_terms: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001647:Bile Acids and Salts / Q000378:metabolism*; D002415:Cats; D003001:Cloning, Molecular; D004285:Dogs; D057809:HEK293 Cells; D006801:Humans; D008099:Liver / Q000378:metabolism; D008107:Liver Diseases / Q000378:metabolism / Q000503:physiopathology / Q000662:veterinary; D008969:Molecular Sequence Data
chemical_list: C093491:ABCB11 protein, human; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D001647:Bile Acids and Salts