title: Hepatobiliary transporters in drug-induced cholestasis: a perspective on the current identifying tools.
abstract: BACKGROUND
  Impaired bile formation leads to the accumulation of cytotoxic bile salts in hepatocytes and, consequently, cholestasis and severe liver disease. Knowledge of the role of hepatobiliary transporters, especially the bile salt export pump (BSEP), in the pathogenesis of cholestasis is continuously increasing.
  
  
  METHODS
  This review provides an introduction into the role of these transport proteins in bile formation. It addresses the clinical relevance and pathophysiologic consequences of altered functions of these transporters by genetic mutations and drugs. In particular, the current practical aspects of identification and mitigation of drug candidates with liver liabilities employed during drug development, with an emphasis on preclinical screening for BSEP interaction, are discussed.
  
  
  CONCLUSIONS
  Within the potential pathogenetic mechanisms of acquired cholestasis, the inhibition of BSEP by drugs is well established. Interference of a new compound with BSEP transport activity should raise a warning sign to conduct follow-up experiments and to monitor liver function during clinical development. A combination of in vitro screening for transport interaction, in silico predicting models, and consideration of physicochemical and metabolic properties should lead to a more efficient screening of potential liver liability.
authors.affiliation: Faculdade de Farmácia - UFMG, Departamento de Análises Clínicas e Toxicológicas, Av. Antônio Carlos, 6.627 - Pampulha, 31270-901 - Belo Horizonte - MG , Brazil +55 31 3547 3462 ; mtoccafondo@yahoo.com.
authors.forename: Manuela
authors.initials: M
authors.lastname: de Lima Toccafondo Vieira
authors.forename: Carlos Alberto
authors.initials: CA
authors.lastname: Tagliati
mesh_terms: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D001647:Bile Acids and Salts / Q000378:metabolism; D001652:Bile Ducts / Q000166:cytology / Q000378:metabolism*; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism*; D002779:Cholestasis / Q000139:chemically induced / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism*; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D027361:Organic Anion Transporters / Q000378:metabolism; D029363:Organic Anion Transporters, Sodium-Dependent / Q000378:metabolism; D027981:Symporters / Q000378:metabolism
chemical_list: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D001647:Bile Acids and Salts; D026901:Membrane Transport Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D027361:Organic Anion Transporters; D029363:Organic Anion Transporters, Sodium-Dependent; D027981:Symporters; C093491:ABCB11 protein, human; C071908:sodium-bile acid cotransporter