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

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 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.

Pharmacogenomics of human OATP transporters

“…These experiments demonstrated that the K m values for estrone-3-sulfate used as model substrate are in a comparable range for all three OATP2B1 proteins. In addition, no change in the cellular distribution of all different OATP2B1 proteins could be detected (Nozawa et al 2002).…”

“…1), could influence the substrate spectrum whereas the mutation OATP1B1-Leu193Arg totally abolishes the transport function of the protein. Nozawa et al (2002) investigated several polymorphisms in the Japanese population and found that the previously identified OATP1B1*1c allele could not be detected in 267 healthy Japanese subjects, whereas OATP1B1*1b and OATP1B1*5 were present with 54% and 0.7%, respectively. In addition, they identified a novel allele, termed OATP1B1*15 (Table 2), possessing the two SNPs Asn130Asp and Val174Ala simultaneously.…”

“…As for OATP1A2 and OATP1B3, the knowledge of the functional consequences of variations in the SLCO2B1 gene is limited. Nozawa et al (2002) described the two variants OATP2B1*2 (1175C>T; Thr392Ile) and OATP2B1*3 (1457C>T; Ser486Phe) ( Table 2) with an allelic frequency of 30.9% for OATP2B1*3, whereas the OATP2B1*2 allele could not be detected in additional 267 Japanese subjects. The functional consequences of both variations compared to the OATP2B1*1 protein have been analysed in HEK293 cells.…”

Pharmacokinetic interaction between pravastatin and olmesartan in relation to SLCO1B1 polymorphism

“…Previous study has suggested that OATP1B1 is predominantly involved in hepatic uptake of pravastatin in humans (Nakai et al 2001). Several single-nucleotide polymorphisms (SNPs) have been identified in SLCO1B1 (Nozawa et al 2002;Tirona et al 2001), and some are reported to be associated with alterations in the pharmacokinetics of certain substrate drugs, including repaglinide (Niemi et al 2005a), fexofenadine (Niemi et al 2005b), pitavastatin (Chung et al 2005;Ieiri et al 2007), and pravastatin (Mwinyi et al 2004;Niemi et al 2004;Nishizato et al 2003). Particularly subjects having SLCO1B1*15 allele (possessing both 388A [G and 521T[C) showed elevated systemic exposure of pravastatin as compared to subjects without this allele (Niemi et al 2004;Nishizato et al 2003).…”

Pharmacogenetics of Drug Transporters in the Enterohepatic Circulation

“…Very few polymorphisms of SLCO2B1 have been described [60, 61] Two rather frequent polymorphisms were initially shown to be associated with reduced transport activity of OAT2B1 for endogenous substrates (table 2), but one polymorphism was later reported to have increased drug transport activity [148,149]. Pharmacokinetically, the c.935G>A…”