MRP2 haplotypes confer differential susceptibility to toxic liver injury

Ji Ha Choi, Byung Min Ahn, Jihyun Yi, Ji Hyun Lee, Jeong Ho Lee, Soon Woo Nam, Chae Yoon Chon, Kwang Hyub Han, Sang Hoon Ahn, In Jin Jang, Joo Youn Cho, Yousin Suh, Mi Ook Cho, Jong Eun Lee, Kyung Hwan Kim, Min Goo Lee

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119 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)403-415
Number of pages13
JournalPharmacogenetics and Genomics
Volume17
Issue number6
DOIs
StatePublished - Jun 1 2007

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Keywords

  • Haplotype
  • Hepatotoxicity
  • MRP2
  • Susceptibility

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Choi, J. H., Ahn, B. M., Yi, J., Lee, J. H., Lee, J. H., Nam, S. W., Chon, C. Y., Han, K. H., Ahn, S. H., Jang, I. J., Cho, J. Y., Suh, Y., Cho, M. O., Lee, J. E., Kim, K. H., & Lee, M. G. (2007). MRP2 haplotypes confer differential susceptibility to toxic liver injury. Pharmacogenetics and Genomics, 17(6), 403-415. https://doi.org/10.1097/01.fpc.0000236337.41799.b3