title: Alterations of canalicular ATP-binding cassette transporter expression in drug-induced liver injury.
abstract: BACKGROUND
  Drug-induced liver injury (DILI) is a major clinical problem and its pathogenesis is poorly understood. The association of DILI with polymorphisms in hepatobiliary transport systems suggests a role for transport proteins in the pathogenesis of DILI.
  
  
  OBJECTIVE
  To investigate expression and tissue distribution of hepatobiliary transport systems in DILI.
  
  
  METHODS
  Expression of the canalicular bile salt export pump BSEP (ABCC11), phospholipid flippase MDR3 (ABCB4) and bilirubin export pump MRP2 (ABCC2) was assessed immunohistochemically in liver biopsies from 23 patients with DILI.
  
  
  RESULTS
  Of 12 patients with cholestatic DILI (mostly due to antibiotics), 8 displayed a marked reduction of MRP2, MDR3 and BSEP expression. Transporter staining was normal in 4 patients with cholestatic DILI. In 11 patients with necroinflammatory hepatocellular injury (most frequently caused by NSAIDs), transporter staining was normal in areas where hepatocyte morphology was preserved. Due to hepatocyte necrosis and the reduction of the hepatocyte number, overall transporter expression was reduced without a reduction in transporter expression at the single hepatocyte level.
  
  
  CONCLUSIONS
  Canalicular ABC transporter expression is profoundly disturbed in most cases of cholestatic DILI. Drug-induced hepatitis does not lead to repression of transporter expression but to hepatocyte drop-outs with a numerical loss of bile canaliculi.
authors.affiliation: Laboratory of Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria.
authors.forename: Gernot
authors.initials: G
authors.lastname: Zollner
authors.forename: Andrea
authors.initials: A
authors.lastname: Thueringer
authors.forename: Carolin
authors.initials: C
authors.lastname: Lackner
authors.forename: Peter
authors.initials: P
authors.lastname: Fickert
authors.forename: Michael
authors.initials: M
authors.lastname: Trauner
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001648:Bile Canaliculi / Q000378:metabolism*; D056486:Chemical and Drug Induced Liver Injury / Q000175:diagnosis / Q000378:metabolism*; D005260:Female; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C093491:ABCB11 protein, human; C000715087:ABCC2 protein, human; C095122:multidrug resistance protein 3