title: MRP2 haplotypes confer differential susceptibility to toxic liver injury.
abstract: OBJECTIVE
  Multidrug resistance protein 2 (MRP2, ABCC2) plays an important role in the biliary clearance of a wide variety of endogenous and exogenous toxic compounds. Therefore, polymorphisms and mutations in the MRP2 gene may affect individual susceptibility to hepatotoxic reactions.
  
  
  METHODS
  Associations between genetic variations of MRP2 and toxic hepatitis were investigated using integrated population genetic analysis and functional molecular studies.
  
  
  RESULTS
  Using a gene scanning method, 12 polymorphisms and mutations were found in the MRP2 gene in a Korean population. Individual variation at these sites was analyzed by conventional DNA screening in 110 control subjects and 94 patients with toxic hepatitis induced mostly by herbal remedies. When haplotypes were identified, over 85% of haploid genes belonged to the five most common haplotypes. Among these, a haplotype containing the g.-1774delG polymorphism showed a strong association with cholestatic or mixed-type hepatitis, and a haplotype containing the g.-1549G>A, g.-24C>T, c.334-49C>T, and c.3972C>T variations was associated with hepatocellular-type hepatitis. A comprehensive functional study of these sites revealed that genetic variations in the promoter of this gene are primarily responsible for the susceptibility to toxic liver injuries. The g.-1774delG variation and the combined variation of g.-1549G>A and g.-24C>T decreased MRP2 promoter activity by 36 and 39%, respectively. In addition, the promoter carrying the g.-1774delG allele showed a defect in the bile acid-induced induction of promoter activity.
  
  
  CONCLUSIONS
  These results suggest that genetic variations of MRP2 are an important predisposing factor for herbal-induced or drug-induced toxic liver injuries.
authors.affiliation: Department of Pharmacology, Institute of Gastroenterology, Yonsei University College of Medicine, 134 Sinchon-Dong Seoul 120-752, Korea.
authors.forename: Ji Ha
authors.initials: JH
authors.lastname: Choi
authors.forename: Byung Min
authors.initials: BM
authors.lastname: Ahn
authors.forename: Jihyun
authors.initials: J
authors.lastname: Yi
authors.forename: Ji Hyun
authors.initials: JH
authors.lastname: Lee
authors.forename: Jeong Ho
authors.initials: JH
authors.lastname: Lee
authors.forename: Soon Woo
authors.initials: SW
authors.lastname: Nam
authors.forename: Chae Yoon
authors.initials: CY
authors.lastname: Chon
authors.forename: Kwang-Hyub
authors.initials: KH
authors.lastname: Han
authors.forename: Sang Hoon
authors.initials: SH
authors.lastname: Ahn
authors.forename: In-Jin
authors.initials: IJ
authors.lastname: Jang
authors.forename: Joo-Youn
authors.initials: JY
authors.lastname: Cho
authors.forename: Yousin
authors.initials: Y
authors.lastname: Suh
authors.forename: Mi-Ook
authors.initials: MO
authors.lastname: Cho
authors.forename: Jong-Eun
authors.initials: JE
authors.lastname: Lee
authors.forename: Kyung Hwan
authors.initials: KH
authors.lastname: Kim
authors.forename: Min Goo
authors.initials: MG
authors.lastname: Lee
mesh_terms: D000328:Adult; D000368:Aged; D001483:Base Sequence; D016022:Case-Control Studies; D002460:Cell Line; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000235:genetics*; D017931:DNA Primers / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D007723:Korea; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics*; D008875:Middle Aged; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D009154:Mutation; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D011994:Recombinant Proteins / Q000235:genetics; D014162:Transfection
chemical_list: D017931:DNA Primers; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011994:Recombinant Proteins; C000715087:ABCC2 protein, human