- 著者
-
Keiko MAEKAWA
Masaya ITODA
Kimie SAI
Yoshiro SAITO
Nahoko KANIWA
Kuniaki SHIRAO
Tetsuya HAMAGUCHI
Hideo KUNITOH
Noboru YAMAMOTO
Tomohide TAMURA
Hironobu MINAMI
Kaoru KUBOTA
Atsushi OHTSU
Teruhiko YOSHIDA
Nagahiro SAIJO
Naoyuki KAMATANI
Shogo OZAWA
Jun-ichi SAWADA
- 出版者
- The Japanese Society for the Study of Xenobiotics
- 雑誌
- Drug Metabolism and Pharmacokinetics (ISSN:13474367)
- 巻号頁・発行日
- vol.21, no.2, pp.109-121, 2006 (Released:2006-05-10)
- 参考文献数
- 35
- 被引用文献数
-
36
The ATP-binding cassette transporter, ABCG2, which is expressed at high levels in the intestine and liver, functions as an efflux transporter for many drugs, including clinically used anticancer agents such as topotecan and the active metabolite of irinotecan (SN-38). In this study, to elucidate the linkage disequilibrium (LD) profiles and haplotype structures of ABCG2, we have comprehensively searched for genetic variations in the putative promoter region, all the exons, and their flanking introns of ABCG2 from 177 Japanese cancer patients treated with irinotecan. Forty-three genetic variations, including 11 novel ones, were found: 5 in the 5′-flanking region, 13 in the coding exons, and 25 in the introns. In addition to 9 previously reported nonsynonymous single nucleotide polymorphisms (SNPs), 2 novel nonsynonymous SNPs, 38C>T (Ser13Leu) and 1060G>A (Gly354Arg), were found with minor allele frequencies of 0.3%. Based on the LD profiles between the SNPs and the estimated past recombination events, the region analyzed was divided into three blocks (Block -1, 1, and 2), each of which spans at least 0.2 kb, 46 kb, and 13 kb and contains 2, 24, and 17 variations, respectively. The two, eight, and five common haplotypes detected in 10 or more patients accounted for most (>90%) of the haplotypes inferred in Block -1, Block 1, and Block 2, respectively. The SNP and haplotype distributions in Japanese were different from those reported previously in Caucasians. This study provides fundamental information for the pharmacogenetic studies investigating the relationship between the genetic variations in ABCG2 and pharmacokinetic/pharmacodynamic parameters.