Systematic Screening of Human ABCC3 Polymorphisms and Their Effects on MRP3 Expression and Function
Systematic Screening of Human ABCC3 Polymorphisms and Their Effects on MRP3 Expression and Function
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DOI：
10.2133/dmpk.dmpk-10-rg-103
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发表时间：
2011-01-01
影响因子：
2.1
通讯作者：
Ieiri, Ichiro
中科院分区：
文献类型：
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作者：
Sasaki, Tomohiro;Hirota, Takeshi;Ieiri, Ichiro
本研究旨在鉴定多药耐药相关蛋白 3（MRP3，基因名称 ABCC3）的遗传多态性，该蛋白是一种 ATP 结合盒转运蛋白，介导底物穿过基底外侧膜转运到血液中，并研究其对 ABCC3 表达和 MRP3 功能的影响。我们鉴定了 ABCC3 的遗传多态性，并通过 (1) 荧光素酶报告基因测定、(2) 测量 mRNA 水平和 (3) 使用 4-甲基伞形酮葡萄糖醛酸 (4-MUG) 进行人类药物基因组学研究来评估其效果。总体而言，在三个种族人群中发现了 61 种遗传变异；这些变体中有 17 个是新的（7 个是非同义的：61Arg>Cys、132Gln>Stop、221Trp>Stop、270His>Gln、548Leu>Gln、600Lys>Arg 和 1324Arg>His）。然而，这些突变发生的频率非常低（最多 4.7%）。观察到的等位基因频率显示出相当大的种族间差异。报告基因检测表明，与野生型等位基因相比，-1767G>A 等位基因的转录活性显着降低；然而，在人类肝脏样本中并未检测到 ABCC3 mRNA 表达下降。一项人类药代动力学研究表明，启动子区域的 ABCC3 基因型与 MRP3 底物 4-MUG 的药代动力学变化无关。这是第一个评估ABCC3多态性对人体药代动力学影响的研究；然而，还需要进一步调查才能完整了解情况。
The present study was undertaken to identify genetic polymorphisms of multidrug resistance-associated protein 3 (MRP3, gene name ABCC3), an ATP-binding cassette transporter that mediates the transport of substrates across the basolateral membrane into the blood, and to investigate their effects on ABCC3 expression and MRP3 function. We identified genetic polymorphisms of ABCC3 and evaluated the effects by (1) a luciferase reporter gene assay, (2) measuring mRNA levels, and (3) a human pharmacogenomics study with 4-methylumbelliferone glucuronide (4-MUG). Overall, 61 genetic variants were identified in three ethnic populations; of these variants 17 were novel (7 were non-synonymous: 61Arg>Cys, 132Gln>Stop, 221Trp>Stop, 270His>Gln, 548Leu>Gln, 600Lys>Arg, and 1324Arg>His). However, these mutations occurred at very low frequencies (max. 4.7%). The observed allele frequencies showed considerable inter-ethnic differences. The reporter gene assay indicated a significant reduction of transcriptional activity with the -1767G>A allele compared to the wild-type allele; however, a decreased expression of ABCC3 mRNA was not detected in human liver samples. A human pharmacokinetic study showed that the ABCC3 genotype in the promoter region was not associated with changes in the pharmacokinetics of 4-MUG, a substrate of MRP3. This is the first study to assess the effects of ABCC3 polymorphisms on human pharmacokinetics; however, further investigations are needed to complete the picture.