
<ArticleTitle>Polymorphisms in <prot>OATP-C</prot>: identification of multiple allelic variants associated with altered transport activity among European- and African-Americans.</ArticleTitle>
<AbstractText>The human organic anion transporting <prot>polypeptide-C</prot> (<prot>OATP-C</prot>) (gene <prot>SLC21A6</prot>) 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 <prot>OATP-C</prot> 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 <prot>OATP-C</prot> alleles in vitro revealed that several variants exhibited markedly reduced uptake of the <prot>OATP-C</prot> substrates estrone sulfate and estradiol 17beta-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 <prot>OATP-C</prot> 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 <prot>OATP-C</prot> may represent a heretofore unrecognized factor influencing drug disposition.</AbstractText>
