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

Citation
Rg. Tirona et al., Polymorphisms in OATP-C - Identification of multiple allelic variants associated with altered transport activity among European- and African-Americans, J BIOL CHEM, 276(38), 2001, pp. 35669-35675
Citations number
22
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Biochemistry & Biophysics
Journal title
JOURNAL OF BIOLOGICAL CHEMISTRY
ISSN journal
0021-9258 → ACNP
Volume
276
Issue
38
Year of publication
2001
Pages
35669 - 35675
Database
ISI
SICI code
0021-9258(20010921)276:38<35669:PIO-IO>2.0.ZU;2-D
Abstract
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-nucleotid e polymorphisms (SNPs) in OATP-C in a population of African- and European-A mericans. Moreover, examination of 14 nonsynonymous polymorphisms indicated that genotypic frequencies were dependent on race. Functional assessment o f 16 OATP-C alleles in vitro revealed that several variants exhibited marke dly reduced uptake of the OATP-C substrates estrone sulfate and estradiol 1 7 beta -D-glucuronide. Specifically, alterations in transport were associat ed with SNPs that introduce amino acid changes within the transmembrane-spa nning domains (T217C (Phe-73 --> Leu), T245C (Val-82 --> Ala), T521C (Val-1 74 --> Ala), and T1058C (Ile-353 --> Thr)) and also with those that modify extracellular loop 5 (A1294G (Asn-432 --> Asp), A1385G (Asp-462 --> Gly), a nd A1463C (Gly-488 --> Ala)). Cell surface biotinylation experiments indica ted that the altered transport activity of some OATP-C variants was due, in part, to decreased plasma membrane expression. Given the relatively high g enotypic frequency of the T521C (14%) transition in European-Americans and the G1463C (9%) transversion in African-Americans, SNPs in OATP-C may repre sent a heretofore unrecognized factor influencing drug disposition.