Substrate-dependent effects of human ABCB1 coding polymorphisms
Substrate-dependent effects of human ABCB1 coding polymorphisms
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DOI：
10.1124/jpet.107.135194
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发表时间：
2008-05-01
影响因子：
3.5
通讯作者：
Kroetz, Deanna L.
中科院分区：
文献类型：
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作者：
Gow, Jason M.;Hodges, Laura M.;Kroetz, Deanna L.
有效药物治疗的众多障碍之一是外排转运蛋白P-糖蛋白(P-gp)，它可以限制许多外来物质的血浆和细胞内浓度。药物对P-gp底物的不同反应提示ABCB1的遗传差异可能影响P-gp的转运。目前的研究检测了ABCB1变体如何在体外改变P-gp介导的探针底物的运输。在HEK293T细胞中瞬时表达了等位基因频率为>；=2%的非同义ABCB1突变体和单倍型，并且在没有或存在P-gp抑制剂环孢素A的情况下，钙黄绿素乙氧甲酯和4，4-二氟-4-BORA-3a，4a-二氮-S吲哚(BODIPY-FL)-紫杉醇的转运以底物依赖的方式改变了P-gp的胞内积累。有趣的是，某些变体对环孢素A的抑制表现出不同的敏感性，这也是底物特异性的。这些功能数据表明，ABCB1的非同义多态可能以底物和抑制剂依赖的方式选择性地改变P-gp转运和药物-药物相互作用。
One of the many obstacles to effective drug treatment is the efflux transporter P-glycoprotein P-gp), which can restrict the plasma and intracellular concentrations of numerous xenobiotics. Variable drug response to P-gp substrates suggests that genetic differences in ABCB1 may affect P-gp transport. The current study examined how ABCB1 variants alter the P-gp-mediated transport of probe substrates in vitro. Nonsynonymous ABCB1 variants and haplotypes with an allele frequency >= 2% were transiently expressed in HEK293T cells, and the transport of calcein acetoxymethyl ester and 4,4-difluoro-4-bora-3a, 4a-diaza-s-indacene ( BODIPY-FL)-paclitaxel was measured in the absence or presence of the P-gp inhibitor cyclosporin A. The A893S, A893T, and V1251I variants and the N21D/ 1236C > T/A893S/3435C > T haplotype altered intracellular accumulation compared with reference P-gp in a substrate-dependent manner. It is interesting that certain variants showed altered sensitivity to cyclosporin A inhibition that was also substrate- specific. These functional data demonstrate that nonsynonymous polymorphisms in ABCB1 may selectively alter P-gp transport and drug- drug interactions in a substrate and inhibitor-dependent manner.