Genetic variations of the ABC transporter gene ABCC3 in a Japanese population

被引:15
作者
Fukushima-Uesaka, Hirorni
Saito, Yoshiro
Maekawa, Keiko
Hasegawa, Ryuichi
Suzuki, Kazuko
Yanagawa, Tatsuo
Kajio, Hiroshi
Kuzuya, Nobuaki
Noda, Mitsuhiko
Yasuda, Kazuki
Tohkin, Masahiro
Sawada, Jun-ichi
机构
[1] Natl Inst Hlth Sci, Div Biochem & Immunochem, Setagaya Ku, Tokyo 1588501, Japan
[2] Natl Inst Hlth Sci, Project Team Pharmacogenet, Tokyo 158, Japan
[3] Natl Inst Hlth Sci, Div Med Safety Sci, Tokyo 158, Japan
关键词
aBCC3; direct sequencing; novel genetic variation; amino acid change;
D O I
10.2133/dmpk.22.129
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
An ATP-binding cassette transporter, multidrug resistance-related protein 3 (MRP3), is encoded by the ABCC3 gene. The MRP3 protein is expressed in several tissues, and functions as an efflux transporter for conjugated as well as unconjugated substrates. In this study, the 31 ABCC3 exons and their flanking introns were comprehensively screened for genetic variations in 89 Japanese subjects. Forty-six genetic variations, including 21 novel ones, were found: 8 were located in the 5'-flanking region, 14 in the coding exons (8 synonymous and 6 nonsynonymous variations), and 24 in the introns. Of these 46 variations, five novel nonsynonymous variations, 2221C>T (Gln741Stop), 2395G>A (Val799Met), 2798_2799delAG (Gln933ArgfsX64), 3657C>A (Ser1219Arg), and 4217C>T (Thr1406Met), were found as heterozygous variations. The allele frequencies were 0.011 for Ser1219Arg and 0.006 for the other four variations. Gln741Stop induces a stop codon at codon 741. Gln933ArgfsX64 causes a frame-shift at codon 933, resulting in early termination at codon 997. Both variations result in loss of 6 transmembrane helices (from the 12th to 17th helices) in the C-terminus and all regions of nucleotide binding domain 2. Thus, both variant proteins are assumed to be inactive. These data provide fundamental and useful information for pharmacogenetic studies on MRP3-transported drugs in Japanese.
引用
收藏
页码:129 / 135
页数:7
相关论文
共 19 条
[1]   Characterization of MOAT-C and MOAT-D, new members of the MRP/cMOAT subfamily of transporter proteins [J].
Belinsky, MG ;
Bain, LJ ;
Balsara, BB ;
Testa, JR ;
Kruh, GD .
JOURNAL OF THE NATIONAL CANCER INSTITUTE, 1998, 90 (22) :1735-1741
[2]   MRP2 and 3 in health and disease [J].
Borst, P ;
Zelcer, N ;
van de Wetering, K .
CANCER LETTERS, 2006, 234 (01) :51-61
[3]   Transport of glyburide by placental ABC transporters: Implications in fetal drug exposure [J].
Gedeon, C. ;
Behravan, J. ;
Koren, G. ;
Piquette-Miller, M. .
PLACENTA, 2006, 27 (11-12) :1096-1102
[4]   Influence of omeprazole on multidrug resistance protein 3 expression in human liver [J].
Hitzl, M ;
Klein, K ;
Zanger, UM ;
Fritz, P ;
Nüssler, AK ;
Neuhaus, P ;
Fromm, MF .
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2003, 304 (02) :524-530
[5]   Enhanced expression of the human multidrug resistance protein 3 by bile salt in human enterocytes - A transcriptional control of a plausible bile acid transporter [J].
Inokuchi, A ;
Hinoshita, E ;
Iwamoto, Y ;
Kohno, K ;
Kuwano, M ;
Uchiumi, T .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (50) :46822-46829
[6]   cDNA cloning and inducible expression of human multidrug resistance associated protein 3 (MRP3) [J].
Kiuchi, Y ;
Suzuki, H ;
Hirohashi, T ;
Tyson, CA ;
Sugiyama, Y .
FEBS LETTERS, 1998, 433 (1-2) :149-152
[7]   Characterization of the human multidrug resistance protein isoform MRP3 localized to the basolateral hepatocyte membrane [J].
König, J ;
Rost, D ;
Cui, YH ;
Keppler, D .
HEPATOLOGY, 1999, 29 (04) :1156-1163
[8]   MRP3, an organic anion transporter able to transport anti-cancer drugs [J].
Kool, M ;
van der Linden, M ;
de Haas, M ;
Scheffer, GL ;
de Vree, JML ;
Smith, AJ ;
Jansen, G ;
Peters, GJ ;
Ponne, N ;
Scheper, RJ ;
Elferink, RPJO ;
Baas, F ;
Borst, P .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1999, 96 (12) :6914-6919
[9]  
Kool M, 1997, CANCER RES, V57, P3537
[10]   Genetic polymorphisms in the multidrug resistance-associated protein 3 (ABCC3, MRP3) gene and relationship to its mRNA and protein expression in human liver [J].
Lang, T ;
Hitzl, M ;
Burk, O ;
Mornhinweg, E ;
Keil, A ;
Kerb, R ;
Klein, K ;
Zanger, UM ;
Eichelbaum, M ;
Fromm, MF .
PHARMACOGENETICS, 2004, 14 (03) :155-164