Abstract
In the present study, we analyzed the function of a novel mutation (c.1628T>G, p.Leu543Trp) in the solute carrier organic anion transporter (SLCO) 1B1 gene, encoding organic anion transporting polypeptide (OATP) 1B1, which was identified in a patient with pravastatin-induced myopathy. OATP1B1 variants carrying the mutation (OATP1B1*1a+c.1628T>G or *1b+c.1628T>G) showed a reduced transporting activity toward typical substrates and pravastatin compared with the activity of the references (OATP1B1*1a or *1b). This was due to reduction in Vmax values of the variants, not due to change in their Km values. OATP1B1*1b+c.1628T>G was normally expressed on the plasma membrane of HEK293 cells at the same level as that of OATP1B1*1b. Taken together, our results suggest that the mutation c.1628T>G (p.Leu543Trp) reduced the function of OATP1B1 probably due to decrease in turnover rate of one OATP1B1 molecule rather than impairment of protein sorting to the plasma membrane.
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Abbreviations
- BSP:
-
bromosulfophthalein
- E217βG:
-
estradiol-17β glucuronide
- E13S:
-
estrone-3-sulfate
- OATP:
-
organic anion transporting polypeptide
- SLCO:
-
solute carrier organic anion transporter
- SNP:
-
single nucleotide polymorphism
References
Hsiang B, Zhu Y, Wang Z, Wu Y, Sasseville V, Yang WP et al. A novel human hepatic organic anion transporting polypeptide (OATP2). Identification of a liver-specific human organic anion transporting polypeptide and identification of rat and human hydroxymethylglutaryl-CoA reductase inhibitor transporters. J Biol Chem 1999; 274: 37161–37168.
Abe T, Kakyo M, Tokui T, Nakagomi R, Nishio T, Nakai D et al. Identification of a novel gene family encoding human liver-specific organic anion transporter LST-1. J Biol Chem 1999; 274: 17159–17163.
Konig J, Cui Y, Nies AT, Keppler D . A novel human organic anion transporting polypeptide localized to the basolateral hepatocyte membrane. Am J Physiol Gastrointest Liver Physiol 2000; 278: G156–G164.
Nozawa T, Minami H, Sugiura S, Tsuji A, Tamai I . Role of organic anion transporter OATP1B1 (OATP-C) in hepatic uptake of irinotecan and its active metabolite, 7-ethyl-10-hydroxycamptothecin: in vitro evidence and effect of single nucleotide polymorphisms. Drug Metab Dispos 2005; 33: 434–439.
Tirona RG, Leake BF, Wolkoff AW, Kim RB . Human organic anion transporting polypeptide-C (SLC21A6) is a major determinant of rifampin-mediated pregnane X receptor activation. J Pharmacol Exp Ther 2003; 304: 223–228.
Nishizato Y, Ieiri I, Suzuki H, Kimura M, Kawabata K, Hirota T et al. Polymorphisms of OATP-C (SLC21A6) and OAT3 (SLC22A8) genes: consequences for pravastatin pharmacokinetics. Clin Pharmacol Ther 2003; 73: 554–565.
Niemi M, Schaeffeler E, Lang T, Fromm MF, Neuvonen M, Kyrklund C et al. High plasma pravastatin concentrations are associated with single nucleotide polymorphisms and haplotypes of organic anion transporting polypeptide-C (OATP-C, SLCO1B1). Pharmacogenetics 2004; 14: 429–440.
Mwinyi J, Johne A, Bauer S, Roots I, Gerloff T . Evidence for inverse effects of OATP-C (SLC21A6) 5 and 1b haplotypes on pravastatin kinetics. Clin Pharmacol Ther 2004; 75: 415–421.
Niemi M, Backman JT, Kajosaari LI, Leathart JB, Neuvonen M, Daly AK et al. Polymorphic organic anion transporting polypeptide 1B1 is a major determinant of repaglinide pharmacokinetics. Clin Pharmacol Ther 2005; 77: 468–478.
Pasanen MK, Neuvonen M, Neuvonen PJ, Niemi M . SLCO1B1 polymorphism markedly affects the pharmacokinetics of simvastatin acid. Pharmacogenet Genomics 2006; 16: 873–879.
Takane H, Miyata M, Burioka N, Kurai J, Fukuoka Y, Suyama H et al. Severe toxicities after irinotecan-based chemotherapy in a patient with lung cancer: a homozygote for the SLCO1B1*15 allele. Ther Drug Monit 2007; 29: 666–668.
Kameyama Y, Yamashita K, Kobayashi K, Hosokawa M, Chiba K . Functional characterization of SLCO1B1 (OATP-C) variants, SLCO1B1*5, SLCO1B1*15 and SLCO1B1*15+C1007G, by using transient expression systems of HeLa and HEK293 cells. Pharmacogenet Genomics 2005; 15: 513–522.
Tirona RG, Leake BF, Merino G, Kim RB . Polymorphisms in OATP-C: identification of multiple allelic variants associated with altered transport activity among European- and African-Americans. J Biol Chem 2001; 276: 35669–35675.
Michalski C, Cui Y, Nies AT, Nuessler AK, Neuhaus P, Zanger UM et al. A naturally occurring mutation in the SLC21A6 gene causing impaired membrane localization of the hepatocyte uptake transporter. J Biol Chem 2002; 277: 43058–43063.
Morimoto K, Oishi T, Ueda S, Ueda M, Hosokawa M, Chiba K . A novel variant allele of OATP-C (SLCO1B1) found in a Japanese patient with pravastatin-induced myopathy. Drug Metab Pharmacokinet 2004; 19: 453–455.
Seithel A, Klein K, Zanger UM, Fromm MF, König J . Non-synonymous polymorphisms in the human SLCO1B1 gene: an in vitro analysis of SNP c.1929A>C. Mol Genet Genomics 2008; 279: 149–157.
Hagenbuch B, Meier PJ . The superfamily of organic anion transporting polypeptides. Biochim Biophys Acta 2003; 1609: 1–18.
Noe J, Portmann R, Brun ME, Funk C . Substrate-dependent drug-drug interactions between gemfibrozil, fluvastatin and other organic anion-transporting peptide (OATP) substrates on OATP1B1, OATP2B1, and OATP1B3. Drug Metab Dispos 2007; 35: 1308–1314.
Tamai I, Nozawa T, Koshida M, Nezu J, Sai Y, Tsuji A . Functional characterization of human organic anion transporting polypeptide B (OATP-B) in comparison with liver-specific OATP-C. Pharm Res 2001; 18: 1262–1269.
Furihata T, Satoh T, Yamamoto N, Kobayashi K, Chiba K . Hepatocyte nuclear factor 1 alpha is a factor responsible for the interindividual variation of OATP1B1 mRNA levels in adult Japanese livers. Pharm Res 2007; 24: 2327–2332.
Acknowledgements
This work was supported by grants-in-aid from the Ministry of Health, Labor and Welfare of Japan (Health and Labor Sciences Research Grants, Risk Analysis Research on Food and Pharmaceuticals) and was partially supported by a Global COE Program (Global Center for Education and Research in Immune System Regulation and Treatment), MEXT, Japan.
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Furihata, T., Satoh, N., Ohishi, T. et al. Functional analysis of a mutation in the SLCO1B1 gene (c.1628T>G) identified in a Japanese patient with pravastatin-induced myopathy. Pharmacogenomics J 9, 185–193 (2009). https://doi.org/10.1038/tpj.2009.3
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DOI: https://doi.org/10.1038/tpj.2009.3