Genetic Polymorphisms of Human Organic Anion Transporters OATP-C (SLC21A6) and OATP-B (SLC21A9): Allele Frequencies in the Japanese Population and Functional Analysis

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Abstract
Genetic polymorphisms of human organic anion transporting polypeptides OATP-C (SLC21A6) and OATP-B (SLC21A9) in the Japanese population were analyzed. The allele frequencies of OATP-C*1a,OATP-C*1b (N130D), OATP-C*1c (R152K and D241N), and OATP-C*5 (V174A) were 35.2, 53.7, 0, and 0.7%, respectively, in 267 healthy Japanese subjects. In theOATP-C gene, we found a novel allele calledOATP-C*15 possessing two single nucleotide polymorphisms (SNPs), N130D and V174A, simultaneously. The allele frequency ofOATP-C*15 was 3.0%. The allele frequencies ofOATP-B*1, OATP-B*2 (T392I), andOATP-B*3 (S486F) were 69.1, 0, and 30.9%, respectively. For functional analysis, each OATP-C and OATP-B allele was expressed in human embryonic kidney (HEK293) cells, and the kinetics of uptake of [3H]estrone-3-sulfate was determined. In the case of OATP-C alleles, no significant alteration inKm or Vmax values of [3H]estrone-3-sulfate uptake was observed, even when the Vmax values were corrected for the expression levels of OATP-C protein. In contrast,Vmax, corrected with the expression level ofOATP-B*3, was decreased to 42.5% ofOATP-B*1, whereas the Kmvalues were comparable. Since the frequency of theOATP-B*3 allele was high (30.9%) in our subjects, the SNP of S486F may affect the physiological function and/or pharmacological effects of OATP-B substrates in vivo.

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