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MRP2 haplotypes confer differential susceptibility to toxic liver injury

 Ji Ha Choi  ;  Byung Min Ahn  ;  Min Goo Lee  ;  Kyung Hwan Kim  ;  Jong-Eun Lee  ;  Mi-Ook Cho  ;  Yousin Suh  ;  Joo-Youn Cho  ;  In-Jin Jang  ;  Sang Hoon Ahn  ;  Kwang-Hyub Han  ;  Chae Yoon Chon  ;  Soon Woo Nam  ;  Jeong Ho Lee  ;  Ji Hyun Lee  ;  Jihyun Yi 
 Pharmacogenetics and Genomics, Vol.17(6) : 403-415, 2007 
Journal Title
 Pharmacogenetics and Genomics 
Issue Date
OBJECTIVES: 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.
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1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
김경환(Kim, Kyung Hwan)
안상훈(Ahn, Sang Hoon) ORCID logo https://orcid.org/0000-0002-3629-4624
이민구(Lee, Min Goo) ORCID logo https://orcid.org/0000-0001-7436-012X
이정호(Lee, Jeong Ho)
이지현(Lee, Ji Hyun)
전재윤(Chon, Chae Yoon)
최지하(Choi, Ji Ha)
한광협(Han, Kwang-Hyub) ORCID logo https://orcid.org/0000-0003-3960-6539
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