Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Functional analysis of a mutation in the SLCO1B1 gene (c.1628T>G) identified in a Japanese patient with pravastatin-induced myopathy

The Pharmacogenomics Journal volume 9, pages 185–193 (2009)Cite this article

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

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

  1. 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.

    Article  CAS  PubMed  Google Scholar 

  2. 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.

    Article  CAS  PubMed  Google Scholar 

  3. 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.

    Article  CAS  PubMed  Google Scholar 

  4. 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.

    Article  CAS  PubMed  Google Scholar 

  5. 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.

    Article  CAS  PubMed  Google Scholar 

  6. 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.

    Article  CAS  PubMed  Google Scholar 

  7. 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.

    Article  CAS  PubMed  Google Scholar 

  8. 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.

    Article  CAS  PubMed  Google Scholar 

  9. 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.

    Article  CAS  PubMed  Google Scholar 

  10. Pasanen MK, Neuvonen M, Neuvonen PJ, Niemi M . SLCO1B1 polymorphism markedly affects the pharmacokinetics of simvastatin acid. Pharmacogenet Genomics 2006; 16: 873–879.

    Article  CAS  PubMed  Google Scholar 

  11. 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.

    Article  PubMed  Google Scholar 

  12. 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.

    Article  CAS  PubMed  Google Scholar 

  13. 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.

    Article  CAS  PubMed  Google Scholar 

  14. 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.

    Article  CAS  PubMed  Google Scholar 

  15. 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.

    Article  CAS  PubMed  Google Scholar 

  16. 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.

    Article  CAS  PubMed  Google Scholar 

  17. Hagenbuch B, Meier PJ . The superfamily of organic anion transporting polypeptides. Biochim Biophys Acta 2003; 1609: 1–18.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  19. 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.

    Article  CAS  PubMed  Google Scholar 

  20. 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.

    Article  CAS  PubMed  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

  1. Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan

    Tomomi Furihata, Naoki Satoh, Tomoharu Ohishi, Miyuki Ugajin, Yoshio Kameyama, Kaori Morimoto, Sayaka Matsumoto, Keiko Yamashita, Kaoru Kobayashi & Kan Chiba

  2. Pharmaceutical Research Laboratories, R&D Group, Nippon Kayaku Co. Ltd., Tokyo, Japan

    Yoshio Kameyama

Authors
  1. Tomomi Furihata
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Naoki Satoh
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tomoharu Ohishi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Miyuki Ugajin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yoshio Kameyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kaori Morimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Sayaka Matsumoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Keiko Yamashita
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Kaoru Kobayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Kan Chiba
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tomomi Furihata.

Additional information

Duality of Interest

None declared.

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/tpj.2009.3

Keywords

This article is cited by

Search

Advanced search

Quick links