title: Mutations and polymorphisms in the bile salt export pump and the multidrug resistance protein 3 associated with drug-induced liver injury.
abstract: OBJECTIVE
  Increasing evidence suggests that a genetically determined functional impairment of the hepatocellular efflux transporters bile salt export pump (BSEP, ABCB11) and multidrug resistance protein 3 (MDR3, ABCB4) play a pathophysiological role in the development of drug-induced liver injury. The aim of this study was therefore to describe the extent of genetic variability in ABCB11 and ABCB4 in patients with drug-induced liver injury and to in vitro functionally characterize newly detected ABCB11 mutations and polymorphisms.
  
  
  METHODS
  ABCB11 and ABCB4 were sequenced in 23 patients with drug-induced cholestasis and 13 patients with drug-induced hepatocellular injury. Ninety-five healthy Caucasians served as the control group. Reference and mutant BSEP were expressed in Sf9 cells and ATP-dependent transport of [H]-taurocholate was measured in a rapid filtration assay.
  
  
  RESULTS
  Four highly conserved nonsynonymous mutations were specific for drug-induced liver injury [ABCB11: D676Y (drug-induced cholestasis) and G855R (drug-induced cholestasis); ABCB4: I764L (drug-induced cholestasis) and L1082Q (drug-induced hepatocellular injury)]. Furthermore, a polymorphism in exon 13 of ABCB11 (V444A), which is associated with decreased hepatic BSEP expression was significantly more frequent in drug-induced cholestasis patients than in drug-induced hepatocellular injury patients and healthy controls (76 versus 50 and 59% in drug-induced cholestasis patients, drug-induced hepatocellular injury patients and healthy controls, respectively; P<0.05). The in-vitro transport activity of the V444A and the D676Y BSEP constructs was similar, whereas the G855R mutation was nonfunctional.
  
  
  CONCLUSIONS
  In summary, our data support a role of ABCB11 and ABCB4 mutations and polymorphisms in drug-induced cholestasis. Genotyping of selected patients with acquired cholestasis might help to identify individuals with a genetic predisposition.
authors.affiliation: Division of Clinical Pharmacology and Toxicology, University Hospital Zurich, Switzerland.
authors.forename: Carmen
authors.initials: C
authors.lastname: Lang
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Meier
authors.forename: Bruno
authors.initials: B
authors.lastname: Stieger
authors.forename: Ulrich
authors.initials: U
authors.lastname: Beuers
authors.forename: Thomas
authors.initials: T
authors.lastname: Lang
authors.forename: Reinhold
authors.initials: R
authors.lastname: Kerb
authors.forename: Gerd A
authors.initials: GA
authors.lastname: Kullak-Ublick
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Meier
authors.forename: Christiane
authors.initials: C
authors.lastname: Pauli-Magnus
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics*; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D056486:Chemical and Drug Induced Liver Injury; D002779:Cholestasis / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008107:Liver Diseases / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D011110:Polymorphism, Genetic; D017433:Protein Structure, Secondary; D013656:Taurocholic Acid / Q000378:metabolism; D044465:White People
chemical_list: C093491:ABCB11 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D013656:Taurocholic Acid; C095122:multidrug resistance protein 3