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Vol. 302, Issue 2, 804-813, August 2002

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

Takashi Nozawa, Miki Nakajima, Ikumi Tamai , Kumiko Noda, Jun-ichi Nezu, Yoshimichi Sai , Akira Tsuji and Tsuyoshi Yokoi

Division of Molecular Biopharmaceutics (T.N., I.T., Y.S., A.T.) and Drug Metabolism (M.N., K.N., T.Y.), Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, Japan; Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation (I.T., Y.S., A.T.), Kawaguchi, Japan; and Chugai Pharmaceutical Company, Ltd. (J.N.), Ibaraki, Japan.

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 the OATP-C gene, we found a novel allele called OATP-C*15 possessing two single nucleotide polymorphisms (SNPs), N130D and V174A, simultaneously. The allele frequency of OATP-C*15 was 3.0%. The allele frequencies of OATP-B*1, OATP-B*2 (T392I), and OATP-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 in Km 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 of OATP-B*3, was decreased to 42.5% of OATP-B*1, whereas the Km values were comparable. Since the frequency of the OATP-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.

0022-3565/02/3022-0804$07.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics


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