Polymorphisms in OATP-C: identification of multiple allelic variants associated with altered transport activity among European- and African-Americans.
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.
Tirona
R G
RG
Division of Clinical Pharmacology, Departments of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-6602, USA.
Leake
B F
BF
Merino
G
G
Kim
R B
RB
D000483:Alleles; D000595:Amino Acid Sequence; D027321:Anion Transport Proteins; D001483:Base Sequence; D044383:Black People / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D017931:DNA Primers; D005060:Europe; D014644:Genetic Variation; D006239:Haplotypes; D006367:HeLa Cells; D006801:Humans; D017136:Ion Transport / Q000235:genetics; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D011110:Polymorphism, Genetic; D044465:White People / Q000235:genetics*; D001741:Black or African American
D027321:Anion Transport Proteins; D002352:Carrier Proteins; D017931:DNA Primers