MRP2 haplotypes confer differential susceptibility to toxic liver injury.
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.
Choi
Ji Ha
JH
Department of Pharmacology, Institute of Gastroenterology, Yonsei University College of Medicine, 134 Sinchon-Dong Seoul 120-752, Korea.
Ahn
Byung Min
BM
Yi
Jihyun
J
Lee
Ji Hyun
JH
Lee
Jeong Ho
JH
Nam
Soon Woo
SW
Chon
Chae Yoon
CY
Han
Kwang-Hyub
KH
Ahn
Sang Hoon
SH
Jang
In-Jin
IJ
Cho
Joo-Youn
JY
Suh
Yousin
Y
Cho
Mi-Ook
MO
Lee
Jong-Eun
JE
Kim
Kyung Hwan
KH
Lee
Min Goo
MG
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
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