Re-evaluation and functional classification of non-synonymous single nucleotide polymorphisms of the human ATP-binding cassette transporter ABCG2

被引:103
|
作者
Tamura, Ai
Wakabayashi, Kanako
Onishi, Yuko
Takeda, Misako
Ikegami, Yoji
Sawada, Seigo
Tsuji, Masahisa
Matsuda, Yoichi
Ishikawa, Toshihisa [1 ]
机构
[1] Tokyo Inst Technol, Grad Sch Biosci & Biotechnol, Dept Biomol Engn, Yokohama, Kanagawa 2268501, Japan
[2] Meiji Pharmaceut univ, Dept Drug Metab & Disposit, Tokyo 2048588, Japan
[3] Yakult Cent Inst Microbiol Res, Tokyo 1860011, Japan
[4] Chromosome Sci Lab, Sapporo, Hokkaido 0030022, Japan
[5] Hokkaido Univ, Creat Res Initiat Sousei, Lab Anim Cytogenet, Sapporo, Hokkaido 0010021, Japan
关键词
D O I
10.1111/j.1349-7006.2006.00371.x
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Impacts of genetic polymorphisms of the ATP-binding cassette (ABC) transporter BCRP/MXR1/ABCP (ABCG2) on drug response have been implicated; however, the hitherto reported data involve some inconsistencies. To re-evaluate the effect of single nucleotide polymorphisms (SNP) of ABCG2 in vitro, we created a total of seven variant cDNAs (V12M, Q141K, F208S, S248P, F431L, S441N and F489L) by site-directed mutagenesis and stably expressed each of them in Flp-In-293 cells using the Flp recombinase system. Multicolor fluorescence in situ hybridization mapping analysis revealed that one single copy of ABCG2 cDNA was incorporated into the telomeric region of chromosome 12p. It was proven that mRNAs of those integrated ABCG2 variants were expressed evenly in Flp-In-293 cells. However, the protein expression levels varied among those variants. In particular, expression of the F208S and S441N variants was markedly low, suggesting the instability of these variant proteins. Drug resistance profiles of Flp-In-293 cells expressing two major SNP variants (V12M and Q141K) toward the drug SN-38 demonstrated that the IC50 value (drug concentrations producing a 50% reduction of cell growth) for Q141K was approximately 50% of that for wild type. The contributions of the minor SNP variants (F208S, S248P, F431L, S441N and F489L) to drug resistance toward SN-38, mitoxantrone, doxorubicin, daunorubicin or etoposide were significantly lower than wild type. Based on our functional validation, the above-mentioned non-synonymous polymorphisms as well as acquired mutants (R482G and R482T) of ABCG2 were classified into four groups. Furthermore, new camptothecin analogs synthesized by our research group had potent effects in circumventing ABCG2-mediated drug resistance without any influence from major non-synonymous polymorphisms.
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收藏
页码:231 / 239
页数:9
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