Genetic polymorphisms of human organic anion transporters OATP-C (SLC21A6) and OATP-B (SLC21A9): allele frequencies in the Japanese population and functional analysis.
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 [(3)H]estrone-3-sulfate was determined. In the case of OATP-C alleles, no significant alteration in K(m) or V(max) values of [(3)H]estrone-3-sulfate uptake was observed, even when the V(max) values were corrected for the expression levels of OATP-C protein. In contrast, V(max), corrected with the expression level of OATP-B*3, was decreased to 42.5% of OATP-B*1, whereas the K(m) 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.
Division of Molecular Biopharmaceutics, Faculty of Pharmaceutical Sciences, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-0934, Japan.
Takashi
T
Nozawa
Miki
M
Nakajima
Ikumi
I
Tamai
Kumiko
K
Noda
Jun-Ichi
J
Nezu
Yoshimichi
Y
Sai
Akira
A
Tsuji
Tsuyoshi
T
Yokoi
D019943:Amino Acid Substitution; D044466:Asian People / Q000235:genetics; D001483:Base Sequence; D002460:Cell Line; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D007564:Japan; D007668:Kidney; D007700:Kinetics; D027381:Liver-Specific Organic Anion Transporter 1 / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D027361:Organic Anion Transporters / Q000235:genetics* / Q000378:metabolism; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide
D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; C450859:SLCO2B1 protein, human