Lee Sang Seop, Jeong Hye-Eun, Yi Joo-Mi, Jung Hyun-Ju, Jang Jae-Eun, Kim Eun-Young, Lee Su-Jun, Shin Jae-Gook
Department of Pharmacology, Pharmacogenomics Research Center, College of Medicine, Inje University, 633-165 Gaegum-Dong, Jin-Gu, Busan 614-735, Korea.
Drug Metab Dispos. 2007 Apr;35(4):623-32. doi: 10.1124/dmd.106.012302. Epub 2007 Jan 19.
The breast cancer resistance protein (BCRP) is a member of the ATP-binding cassette transporters. The aim of the present study was to identify genetic variants of BCRP in Koreans and to assess the functional consequences of BCRP polymorphisms. Twenty single nucleotide polymorphisms (SNP), including four nonsynonymous SNP, were identified by DNA sequencing of the BCRP gene in 92 Korean subjects. BCRP V12M, Q141K, P269S, and Q126Stop were detected at frequencies of 23, 28, 0.2, and 1.9%, respectively. These four coding variants were also screened in Chinese and Vietnamese subjects; the allelic frequencies among the three populations were compared; and predictions were made as to the potential frequency of each variant. In vitro functional analyses of the P269S protein and the promoter SNP -19031C>T (mutated in the hypoxia-inducible factor-1alpha binding site) were performed and compared with those of the wild type. P269S exhibited a 35 to 40% decrease in vesicular uptake of [(3)H]estrone-3-sulfate and [(3)H]methotrexate compared with the wild type. The promoter SNP -19031C>T did not affect BCRP promoter activity in either the presence or absence of chemical-induced hypoxic stress. Our results suggest that the P269S variant could be a functionally altered variant. Genotyping of this variant in clinical studies is needed to address its phenotypic role. Genetic polymorphisms of BCRP were found to be very common in Koreans, as well as in other ethnic groups. Comparative analyses among three Asian populations revealed different frequencies for the four functional BCRP variants.
乳腺癌耐药蛋白（BCRP）是ATP结合盒转运体家族的成员。本研究旨在鉴定韩国人群中BCRP的基因变异，并评估BCRP基因多态性的功能后果。通过对92名韩国受试者的BCRP基因进行DNA测序，鉴定出20个单核苷酸多态性（SNP），其中包括4个非同义SNP。BCRP V12M、Q141K、P269S和Q126Stop的检测频率分别为23%、28%、0.2%和1.9%。这四个编码变异也在中国和越南受试者中进行了筛查；比较了三个人群中的等位基因频率；并对每个变异的潜在频率进行了预测。对P269S蛋白和启动子SNP -19031C>T（在缺氧诱导因子-1α结合位点发生突变）进行了体外功能分析，并与野生型进行了比较。与野生型相比，P269S对[³H]雌酮-3-硫酸盐和[³H]甲氨蝶呤的囊泡摄取减少了35%至40%。无论是否存在化学诱导的缺氧应激，启动子SNP -19031C>T均不影响BCRP启动子活性。我们的结果表明，P269S变异可能是一个功能改变的变异。在临床研究中对该变异进行基因分型，以确定其表型作用。研究发现，BCRP的基因多态性在韩国人群以及其他种族群体中非常普遍。对三个亚洲人群的比较分析显示，四种功能性BCRP变异的频率不同。
