Polymorphisms in OATP-C: identification of multiple allelic variants associated with altered transport activity among European- and African-Americans.

Tirona RG, Leake BF, Merino G, Kim RB
J Biol Chem. 2001 276 (38): 35669-75

PMID: 11477075 · DOI:10.1074/jbc.M103792200

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 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 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.

MeSH Terms (17)

African Continental Ancestry Group Alleles Amino Acid Sequence Anion Transport Proteins Base Sequence Carrier Proteins DNA Primers Europe European Continental Ancestry Group Genetic Variation Haplotypes HeLa Cells Humans Ion Transport Molecular Sequence Data Mutagenesis, Site-Directed Polymorphism, Genetic

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