Polymorphisms in OATP-C -: Identification of multiple allelic variants associated with altered transport activity among European- and African-Americans
Polymorphisms in OATP-C -: Identification of multiple allelic variants associated with altered transport activity among European- and African-Americans
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DOI：
10.1074/jbc.m103792200
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发表时间：
2001-09-21
影响因子：
4.8
通讯作者：
Kim, RB
中科院分区：
文献类型：
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作者：
Tirona, RG;Leake, BF;Kim, RB
人有机阴离子转运多肽-C（OATP-C）（基因SLC 21 A6）是一种肝脏特异性转运蛋白，重要参与肝细胞对多种内源性和外源性化学物质的摄取。在这项研究中，我们证明了存在多个功能相关的单核苷酸多态性（SNPs）在OATP-C在非洲裔和欧洲裔美国人的人口。此外，14个非同义多态性的检查表明，基因型频率依赖于种族。16个OATP-C等位基因的体外功能评估显示，几种变体对OATP-C底物硫酸雌酮和雌二醇17 β-D-葡糖苷酸的摄取显著降低。具体来说，转运的改变与在跨膜结构域内引入氨基酸变化的SNP相关（T217 C（Phe-73 --> Leu），T245 C（瓦尔-82 --> Ala），T521 C（瓦尔-174 --> Ala）和T1058 C（Ile-353 --> Thr））以及修饰细胞外环5的那些（A1294 G（Asn-432 --> Asp）、A1385 G（Asp-462 --> Gly）和A1463 C（Gly-488 --> Ala））。细胞表面生物素化实验表明，一些OATP-C变体的转运活性改变部分是由于质膜表达降低。考虑到欧洲裔美国人中T521 C转换（14%）和非洲裔美国人中G1463 C颠换（9%）的基因型频率相对较高，OATP-C中的SNP可能代表了迄今尚未认识的影响药物处置的因素。
The human organic anion transporting polypeptide-C (OATP-C) (gene SLC21A6) is a liver-specific transporter importantly involved in the hepatocellular uptake of a variety of endogenous and foreign chemicals. In this study, we demonstrate the presence of multiple functionally relevant single-nucleotide polymorphisms (SNPs) in OATP-C in a population of African- and European-Americans. Moreover, examination of 14 nonsynonymous polymorphisms indicated that genotypic frequencies were dependent on race. Functional assessment of 16 OATP-C alleles in vitro revealed that several variants exhibited markedly reduced uptake of the OATP-C substrates estrone sulfate and estradiol 17 beta -D-glucuronide. Specifically, alterations in transport were associated with SNPs that introduce amino acid changes within the transmembrane-spanning domains (T217C (Phe-73 --> Leu), T245C (Val-82 --> Ala), T521C (Val-174 --> Ala), and T1058C (Ile-353 --> Thr)) and also with those that modify extracellular loop 5 (A1294G (Asn-432 --> Asp), A1385G (Asp-462 --> Gly), and A1463C (Gly-488 --> Ala)). Cell surface biotinylation experiments indicated that the altered transport activity of some OATP-C variants was due, in part, to decreased plasma membrane expression. Given the relatively high genotypic frequency of the T521C (14%) transition in European-Americans and the G1463C (9%) transversion in African-Americans, SNPs in OATP-C may represent a heretofore unrecognized factor influencing drug disposition.