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

TLDR

The study examined allele frequencies of OATP‑C (SLC21A6) and OATP‑B (SLC21A9) variants in a Japanese cohort. Allelic variants were expressed in HEK293 cells and their estrone‑3‑sulfate uptake kinetics were measured. Among 267 subjects, common alleles OATP‑C*1a (35.2 %), OATP‑C*1b (53.7 %), OATP‑C*5 (0.7 %) and OATP‑B*1 (69.1 %) and *3 (30.9 %) were identified, a novel OATP‑C*15 allele (3 %) was found, and functional assays showed that OATP‑B*3 had a 42.5 % reduced Vmax compared to OATP‑B*1 while Km remained similar, indicating a potential impact on drug transport.

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 <i>OATP-C*1a</i>,<i>OATP-C*1b</i> (N130D), <i>OATP-C*1c</i> (R152K and D241N), and <i>OATP-C*5</i> (V174A) were 35.2, 53.7, 0, and 0.7%, respectively, in 267 healthy Japanese subjects. In the<i>OATP-C</i> gene, we found a novel allele called<i>OATP-C*15</i> possessing two single nucleotide polymorphisms (SNPs), N130D and V174A, simultaneously. The allele frequency of<i>OATP-C*15</i> was 3.0%. The allele frequencies of<i>OATP-B*1</i>, <i>OATP-B*2</i> (T392I), and<i>OATP-B*3</i> (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 in<i>K</i>_m or <i>V</i>_max values of [³H]estrone-3-sulfate uptake was observed, even when the <i>V</i>_max values were corrected for the expression levels of OATP-C protein. In contrast,<i>V</i>_max, corrected with the expression level of<i>OATP-B*3</i>, was decreased to 42.5% of<i>OATP-B*1</i>, whereas the <i>K</i>_mvalues were comparable. Since the frequency of the<i>OATP-B*3</i> 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.