MRP2 haplotypes confer differential susceptibility to toxic liver injury

被引:108
作者
Choi, Ji Ha
Ahn, Byung Min
Yi, Jihyun
Lee, Ji Hyun
Lee, Jeong Ho
Nam, Soon Woo
Chon, Chae Yoon
Han, Kwang-Hyub
Ahn, Sang Hoon
Jang, In-Jin
Cho, Joo-Youn
Suh, Yousin
Cho, Mi-Ook
Lee, Jong-Eun
Kim, Kyung Hwan
Lee, Min Goo
机构
[1] Yonsei Univ, Coll Med, Dept Pharmacol, Inst Gastroenterol, Seoul 120752, South Korea
[2] Yonsei Univ, Coll Med, Dept Internal Med, Seoul 120752, South Korea
[3] Seoul Natl Univ, Coll Med, Dept Pharmacol, Seoul, South Korea
[4] DNA Link Inc, Seoul, South Korea
[5] Catholic Univ, Daejeon St Marys Hosp, Coll Med, Dept Internal Med, Taejon, South Korea
[6] Univ Texas, Hlth Sci Ctr, Inst Biotechnol, Dept Mol Med, San Antonio, TX USA
关键词
haplotype; hepatotoxicity; MRP2; susceptibility;
D O I
10.1097/01.fpc.0000236337.41799.b3
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
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. - 1 774delG allele showed a defect in the bile acid-induced induction of promoter activity. Conclusions These results suggest that genetic variations of IVIRP2 are an important predisposing factor for herbal-induced or drug-induced toxic liver injuries.
引用
收藏
页码:403 / 415
页数:13
相关论文
共 37 条
[1]   Haploview: analysis and visualization of LD and haplotype maps [J].
Barrett, JC ;
Fry, B ;
Maller, J ;
Daly, MJ .
BIOINFORMATICS, 2005, 21 (02) :263-265
[2]   Tauroursodeoxycholic acid inserts the apical conjugate export pump, Mrp2, into canalicular membranes and stimulates organic anion secretion by protein kinase C-dependent mechanisms in cholestatic rat liver [J].
Beuers, U ;
Bilzer, M ;
Chittattu, A ;
Kullak-Ublick, GA ;
Keppler, D ;
Paumgartner, G ;
Dombrowski, F .
HEPATOLOGY, 2001, 33 (05) :1206-1216
[3]   Mechanisms of hepatic transport of drugs: Implications for cholestatic drug reactions [J].
Bohan, A ;
Boyer, JL .
SEMINARS IN LIVER DISEASE, 2002, 22 (02) :123-136
[4]   Cholestasis and regulation of genes related to drug metabolism and biliary transport in rat liver following treatment with cyclosporine A and sirolimus (Rapamycin) [J].
Bramow, S ;
Ott, P ;
Nielsen, FT ;
Bangert, K ;
Tygstrup, N ;
Dalhoff, K .
PHARMACOLOGY & TOXICOLOGY, 2001, 89 (03) :133-139
[5]   Polymorphisms of MRP1 (ABCC1) and related ATP-dependent drug transporters [J].
Conseil, G ;
Deeley, RG ;
Cole, SPC .
PHARMACOGENETICS AND GENOMICS, 2005, 15 (08) :523-533
[6]  
Cui YH, 1999, MOL PHARMACOL, V55, P929
[7]   CAUSALITY ASSESSMENT OF ADVERSE REACTIONS TO DRUGS .1. A NOVEL METHOD BASED ON THE CONCLUSIONS OF INTERNATIONAL CONSENSUS MEETINGS - APPLICATION TO DRUG-INDUCED LIVER INJURIES [J].
DANAN, G ;
BENICHOU, C .
JOURNAL OF CLINICAL EPIDEMIOLOGY, 1993, 46 (11) :1323-1330
[8]   HEPATOBILIARY TRANSPORT OF GLUTATHIONE AND GLUTATHIONE CONJUGATE IN RATS WITH HEREDITARY HYPERBILIRUBINEMIA [J].
ELFERINK, RPJ ;
OTTENHOFF, R ;
LIEFTING, W ;
DEHAAN, J ;
JANSEN, PLM .
JOURNAL OF CLINICAL INVESTIGATION, 1989, 84 (02) :476-483
[9]   Drug therapy - Pharmacogenomics - Drug disposition, drug targets, and side effects [J].
Evans, WE ;
McLeod, HL .
NEW ENGLAND JOURNAL OF MEDICINE, 2003, 348 (06) :538-549
[10]   Effects of ursodeoxycholic and cholic acid feeding on hepatocellular transporter expression in mouse liver [J].
Fickert, P ;
Zollner, G ;
Fuchsbichler, A ;
Stumptner, C ;
Pojer, C ;
Zenz, R ;
Lammert, F ;
Stieger, B ;
Meier, PJ ;
Zatloukal, K ;
Denk, H ;
Trauner, M .
GASTROENTEROLOGY, 2001, 121 (01) :170-183