Polymorphisms in human organic anion-transporting polypeptide 1A2 (OATP1A2) - Implications for altered drug disposition and central nervous system drug entry
Polymorphisms in human organic anion-transporting polypeptide 1A2 (OATP1A2) - Implications for altered drug disposition and central nervous system drug entry
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DOI：
10.1074/jbc.m411092200
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发表时间：
2005-03-11
影响因子：
4.8
通讯作者：
Kim, RB
中科院分区：
文献类型：
--
作者：
Lee, W;Glaeser, H;Kim, RB
有机阴离子转运多肽1A 2（OATP 1A 2）是一种具有广泛底物特异性的药物摄取转运蛋白，包括许多临床应用的药物。因此，SLCO 1A 2的遗传变异可能对底物药物的处置和组织渗透具有重要意义。在本研究中，我们证明OATP 1A 2蛋白表达在人脑毛细血管和肾脏远端肾单位使用免疫组织化学。我们还通过分析种族定义的基因组DNA样本（非洲裔、中国裔、欧洲裔和西班牙裔美国人各95例）确定了SLCO 1A 2单核苷酸多态性的程度。我们在SLCO 1A 2编码区发现了6个非同义多态性（T38 C（I13 T）、A516 C（E172 D）、G559 A（A187 T）、A382 T（N128 Y）、A404 T（N135 I）和C2003 G（T668 S）），其等位基因频率似乎与种族有关。体外功能评估显示，A516 C和A404 T变体介导OATP 1A 2底物、雌酮3-硫酸盐和两种δ阿片受体激动剂、deltorphin II和[D-青霉胺2，5]脑啡肽的细胞摄取的能力显著降低。另一方面，G559 A和C2003 G变体似乎具有转运活性的底物依赖性变化。细胞表面生物素化和免疫荧光共聚焦显微镜表明，改变质膜表达的转运蛋白可能有助于减少运输活动与A516 C，A404 T，和C2003 G的变体。A404 T（N135 I）变体也显示出表观分子大小的变化，表明糖基化状态的改变。总之，这些数据表明，SLCO 1A 2多态性可能是一个重要的，但尚未认识到的贡献者个体间变异的药物处置和中枢神经系统进入的底物药物。
Organic anion- transporting polypeptide 1A2 ( OATP1A2) is a drug uptake transporter known for broad substrate specificity, including many drugs in clinical use. Therefore, genetic variation in SLCO1A2 may have important implications to the disposition and tissue penetration of substrate drugs. In the present study, we demonstrate OATP1A2 protein expression in human brain capillary and renal distal nephron using immunohistochemistry. We also determined the extent of single nucleotide polymorphisms in SLCO1A2 upon analyses of ethnically defined genomic DNA samples ( n = 95 each for African-, Chinese-, European-, and Hispanic- Americans). We identified six nonsynonymous polymorphisms within the coding region of SLCO1A2 ( T38C ( I13T), A516C ( E172D), G559A ( A187T), A382T ( N128Y), A404T ( N135I), and C2003G ( T668S)), the allelic frequencies of which appeared to be ethnicity dependent. In vitro functional assessment revealed that the A516C and A404T variants had markedly reduced capacity for mediating the cellular uptake of OATP1A2 substrates, estrone 3-sulfate and two delta-opioid receptor agonists, deltorphin II, and [D-penicillamine2,5]enkephalin. On the other hand, the G559A and C2003G variants appeared to have substrate- dependent changes in transport activity. Cell surface biotinylation and immunofluorescence confocal microscopy suggested that altered plasma membrane expression of the transporter may contribute to reduced transport activity associated with the A516C, A404T, and C2003G variants. The A404T ( N135I) variant also showed a shift in the apparent molecular size, indicative of alterations in glycosylation status. Taken together, these data suggest that SLCO1A2 polymorphisms may be an important yet unrecognized contributor to interindividual variability in drug disposition and central nervous system entry of substrate drugs.