title: Genetic variations of bile salt transporters as predisposing factors for drug-induced cholestasis, intrahepatic cholestasis of pregnancy and therapeutic response of viral hepatitis.
abstract: BACKGROUND
  Drug-induced cholestasis, intrahepatic cholestasis of pregnancy and viral hepatitis are acquired forms of liver disease. Cholestasis is a pathophysiologic state with impaired bile formation and subsequent accumulation of bile salts in hepatocytes. The bile salt export pump (BSEP) (ABCB11) is the key export system for bile salts from hepatocytes.
  
  
  METHODS
  This article provides an introduction into the physiology of bile formation followed by a summary of the current knowledge on the key bile salt transporters, namely, the sodium-taurocholate co-transporting polypeptide NTCP, the organic anion transporting polypeptides (OATPs), BSEP and the multi-drug resistance protein 3. The pathophysiologic consequences of altered functions of these transporters, with an emphasis on molecular and genetic aspects, are then discussed.
  
  
  CONCLUSIONS
  Knowledge of the role of hepatocellullar transporters, especially BSEP, in acquired cholestasis is continuously increasing. A common variant of BSEP (p.V444A) is now a well-established susceptibility factor for acquired cholestasis and recent evidence suggests that the same variant also influences the therapeutic response and disease progression of viral hepatitis C. Studies in large independent cohorts are now needed to confirm the relevance of p.V444A. Genome-wide association studies should lead to the identification of additional genetic factors underlying cholestatic liver disease.
authors.affiliation: University Hospital Zurich, Division of Clinical Pharmacology and Toxicology, 8091 Zurich, Switzerland. bstieger@kpt.uzh.ch
authors.forename: Bruno
authors.initials: B
authors.lastname: Stieger
authors.forename: Andreas
authors.initials: A
authors.lastname: Geier
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D001647:Bile Acids and Salts / Q000378:metabolism; D001692:Biological Transport; D002780:Cholestasis, Intrahepatic / Q000139:chemically induced / Q000150:complications / Q000235:genetics / Q000503:physiopathology; D002986:Clinical Trials as Topic; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006526:Hepatitis C / Q000188:drug therapy / Q000235:genetics*; D022781:Hepatocytes / Q000187:drug effects; D006801:Humans; D008107:Liver Diseases / Q000150:complications / Q000378:metabolism; D029363:Organic Anion Transporters, Sodium-Dependent / Q000235:genetics; D010597:Pharmacogenetics; D011247:Pregnancy; D011248:Pregnancy Complications / Q000139:chemically induced / Q000235:genetics / Q000503:physiopathology; D027981:Symporters / Q000235:genetics
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D001647:Bile Acids and Salts; D029363:Organic Anion Transporters, Sodium-Dependent; D027981:Symporters; C071908:sodium-bile acid cotransporter; C095122:multidrug resistance protein 3