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Organic anion transporting polypeptides of the OATP/SLC21 family: phylogenetic classification as OATP/SLCO superfamily, new nomenclature and molecular/functional properties

  • The ABC of Solute Carriers
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Abstract

The organic anion transporting polypeptides (rodents: Oatps, human: OATPs) form a superfamily of sodium-independent transport systems that mediate the transmembrane transport of a wide range of amphipathic endogenous and exogenous organic compounds. Since the traditional SLC21 gene classification does not permit an unequivocal and species-independent identification of genes and gene products, all Oatps/OATPs are newly classified within the OATP/SLCO superfamily and subdivided into families (≥40% amino acid sequence identity), subfamilies (≥60% amino acid sequence identity) and individual genes and gene products according to their phylogenetic relationships and chronology of identification. Implementation of this new classification and nomenclature system occurs in agreement with the HUGO Gene Nomenclature Committee (HGNC). Among 52 members of the OATP/SLCO superfamily, 36 members have been identified so far in humans, rat and mouse. The latter are clustered within 6 (out of 12) families (OATP1–OATP6) and 13 subfamilies. Oatps/OATPs represent 12 transmembrane domain proteins and contain the superfamily signature D-X-RW-(I,V)-GAWW-X-G-(F,L)-L. Although species divergence, multispecificity and wide tissue distribution are common characteristics of many Oatps/OATPs, some members of the OATP/SLCO superfamily are highly conserved during evolution, have a high substrate specificity and exhibit unique cellular expression in distinct organs. Hence, while Oatps/OATPs with broad substrate specificity appear to play an important role in the bioavailability, distribution and excretion of numerous exogenous amphipathic organic anionic compounds, Oatps/OATPs with a narrow spectrum of transport substrates may exhibit more specific physiological functions in distinct organs.

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References

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

    Article  CAS  PubMed  Google Scholar 

  2. Meier PJ, Stieger B (2002) Bile salt transporters. Annu Rev Physiol 64:635–661

    Article  CAS  PubMed  Google Scholar 

  3. Tamai I, Nezu J, Uchino H, Sai Y, Oku A, Shimane M, Tsuji A (2000) Molecular identification and characterization of novel members of the human organic anion transporter (OATP) family. Biochem Biophys Res Commun 273:251–260

    Article  CAS  PubMed  Google Scholar 

  4. Nelson DR, Koymans L, Kamataki T, Stegeman JJ, Feyereisen R, Waxman DJ, Waterman MR, Gotoh O, Coon MJ, Estabrook RW, Gunsalus IC, Nebert DW (1996) P450 superfamily: update on new sequences, gene mapping, accession numbers and nomenclature. Pharmacogenetics 6:1–42

    CAS  PubMed  Google Scholar 

  5. Mackenzie PI, Owens IS, Burchell B, Bock KW, Bairoch A, Bélanger A, Fournel-Gigleux S, Green M, Hum DW, Iyanagi T, Lancet D, Louisot P, Magdalou J, Roy Chowdhury J, Ritter JK, Schachter H, Tephly TR, Tipton KF, Nebert DW (1997) The UDP glycosyltransferase gene superfamily: recommended nomenclature update based on evolutionary divergence. Pharmacogenetics 7:255–269

    CAS  PubMed  Google Scholar 

  6. Jacquemin E, Hagenbuch B, Stieger B, Wolkoff AW, Meier PJ (1994) Expression cloning of a rat liver Na+-independent organic anion transporter. Proc Natl Acad Sci USA 91:133–137

    CAS  PubMed  Google Scholar 

  7. Kanai N, Lu R, Satriano JA, Bao Y, Wolkoff AW, Schuster VL (1995) Identification and characterization of a prostaglandin transporter. Science 268:866–869

    CAS  PubMed  Google Scholar 

  8. Kullak-Ublick GA, Hagenbuch B, Stieger B, Schteingart CD, Hofmann AF, Wolkoff AW, Meier PJ (1995) Molecular and functional characterization of an organic anion transporting polypeptide cloned from human liver. Gastroenterology 109:1274–1282

    Google Scholar 

  9. Noé B, Hagenbuch B, Stieger B, Meier PJ (1997) Isolation of a multispecific organic anion and cardiac glycoside transporter from rat brain. Proc Natl Acad Sci USA 94:10346–10350

    CAS  PubMed  Google Scholar 

  10. Walters HC, Craddock AL, Fusegawa H, Willingham MC, Dawson PA (2000) Expression, transport properties, and chromosomal location of organic anion transporter subtype 3. Am J Physiol 279:G1188–G1200

    CAS  Google Scholar 

  11. Shi XY, Bai S, Ford AC, Burk RD, Jacquemin E, Hagenbuch B, Meier PJ, Wolkoff AW (1995) Stable inducible expression of a functional rat liver organic anion transport protein in HeLa cells. J Biol Chem 270:25591–25595

    Article  CAS  PubMed  Google Scholar 

  12. Satlin LM, Amin V, Wolkoff AW (1997) Organic anion transporting polypeptide mediates organic anion/HCO3- exchange. J Biol Chem 272:26340–26345

    Article  CAS  PubMed  Google Scholar 

  13. Li L, Meier PJ, Ballatori N (2000) Oatp2 mediates bidirectional organic solute transport: a role for intracellular glutathione. Mol Pharmacol 58:335–340

    CAS  PubMed  Google Scholar 

  14. Li LQ, Lee TK, Meier PJ, Ballatori N (1998) Identification of glutathione as a driving force and leukotriene C-4 as a substrate for oatp1, the hepatic sinusoidal organic solute transporter. J Biol Chem 273:16184–16191

    Article  CAS  PubMed  Google Scholar 

  15. Glavy JS, Wu SM, Wang PJ, Orr GA, Wolkoff AW (2000) Down-regulation by extracellular ATP of rat hepatocyte organic anion transport is mediated by serine phosophorylation of Oatp1. J Biol Chem 275:1479–1484

    Article  CAS  PubMed  Google Scholar 

  16. Bossuyt X, Muller M, Hagenbuch B, Meier PJ (1996) Polyspecific drug and steroid clearance by an organic anion transporter of mammalian liver. J Pharmacol Exp Ther 276:891–896

    CAS  PubMed  Google Scholar 

  17. Fattinger K, Cattori V, Hagenbuch B, Meier PJ, Stieger B (2000) Rifamycin SV and rifampicin exhibit differential inhibition of the hepatic rat organic anion transporting polypeptides, Oatp1 and Oatp2. Hepatology 32:82–86

    CAS  PubMed  Google Scholar 

  18. Vavricka SR, van Montfoort J, Ha HR, Meier PJ, Fattinger K (2002) Interactions of rifamycin SV and rifampicin with organic anion uptake systems of human liver. Hepatology 36:164–172

    Article  CAS  PubMed  Google Scholar 

  19. Lee TK, Hammond CL, Ballatori N (2001) Intracellular glutathione regulates taurocholate transport in HepG2 cells. Toxicol Appl Pharmacol 174:207–215

    Article  CAS  PubMed  Google Scholar 

  20. Kullak-Ublick GA, Glasa J, Boker C, Oswald M, Grutzner U, Hagenbuch B, Stieger B, Meier PJ, Beuers U, Kramer W, Wess G, Paumgartner G (1997) Chlorambucil-taurocholate is transported by bile acid carriers expressed in human hepatocellular carcinomas. Gastroenterology 113:1295–1305

    Google Scholar 

  21. Gao B, Hagenbuch B, Kullak-Ublick GA, Benke D, Aguzzi A, Meier PJ (2000) Organic anion-transporting polypeptides mediate transport of opioid peptides across blood-brain barrier. J Pharmacol Exp Ther 294:73–79

    CAS  PubMed  Google Scholar 

  22. Kullak-Ublick GA, Ismair MG, Stieger B, Landmann L, Huber R, Pizzagalli F, Fattinger K, Meier PJ, Hagenbuch B (2001) Organic anion-transporting polypeptide B (OATP-B) and its functional comparison with three other OATPs of human liver. Gastroenterology 120:525–533

    Google Scholar 

  23. Lee J, Boyer JL (2000) Molecular alterations in hepatocyte transport mechanisms in acquired cholestatic liver disorders. Semin Liver Dis 20:373–384

    Article  CAS  PubMed  Google Scholar 

  24. Saito H, Masuda S, Inui K (1996) Cloning and functional characterization of a novel rat organic anion transporter mediating basolateral uptake of methotrexate in the kidney. J Biol Chem 271:20719–20725

    Article  CAS  PubMed  Google Scholar 

  25. Abe T, Kakyo M, Sakagami H, Tokui T, Nishio T, Tanemoto M, Nomura H, Hebert SC, Masuno S, Kondo H, Yawo H (1998) Molecular characterization and tissue distribution of a new organic anion transporter subtype (oatp3) that transports thyroid hormones and taurocholate and comparison with oatp2. J Biol Chem 273:22395–22401

    Article  CAS  PubMed  Google Scholar 

  26. Hagenbuch B, Adler ID, Schmid TE (2000) Molecular cloning and functional characterisation of the mouse organic anion transporting polypeptide 1 (Oatp1) and mapping of the gene to chromosome X. Biochem J 345:115–120

    Article  CAS  PubMed  Google Scholar 

  27. van Montfoort J, Schmid TE, Adler ID, Meier PJ, Hagenbuch B (2002) Functional characterization of the mouse organic anion transporting polypeptide 2. Biochim Biophys Acta 1564:183–188

    PubMed  Google Scholar 

  28. Choudhuri S, Ogura K, Klaassen CD (2001) Cloning, expression, and ontogeny of mouse organic anion-transporting polypeptide-5, a kidney specific organic anion transporter. Biochem Biophys Res Commun 280:92–98

    Article  CAS  PubMed  Google Scholar 

  29. Hsiang B, Zhu Y, Wang Z, Wu Y, Sasseville V, Yang W-P, Kirchgessner TG (1999) A novel human hepatic organic anion transporting polypeptide (OATP2). J Biol Chem 274:37161–37168

    Article  CAS  PubMed  Google Scholar 

  30. Abe T, Kakyo M, Tokui T, Nakagomi R, Nishio T, Nakai D, Nomura H, Unno M, Suzuki M, Naitoh T, Matsuno S, Yawo H (1999) Identification of a novel gene family encoding human liver-specific organic anion transporter LST-1. J Biol Chem 274:17159–17163

    Article  CAS  PubMed  Google Scholar 

  31. König J, Cui Y, Nies AT, Keppler D (2000) A novel human organic anion transporting polypeptide localized to the basolateral hepatocyte membrane. Am J Physiol 278:G156–G164

    PubMed  Google Scholar 

  32. Tirona RG, Leake BF, Merino G, Kim RB (2001) Polymorphisms in OATP-C: identification of multiple allelic variants associated with altered transport activity among European- and African-Americans. J Biol Chem 276:35669–35675

    Article  CAS  PubMed  Google Scholar 

  33. Nozawa T, Nakajima M, Tamai I, Noda K, Nezu J, Sai Y, Tsuji A, Yokoi T (2002) Genetic polymorphisms of human organic anion transporters OATP-C (SLC21A6) and OATP-B (SLC21A9): allele frequencies in the Japanese population and functional analysis. J Pharmacol Exp Ther 302:804–813

    Article  CAS  PubMed  Google Scholar 

  34. Michalski C, Cui Y, Nies AT, Nuessler AK, Neuhaus P, Zanger UM, Klein K, Eichelbaum M, Keppler D, Konig J (2002) A naturally occurring mutation in the SLC21A6 gene causing impaired membrane localization of the hepatocyte uptake transporter. J Biol Chem 277:43058–43063

    Article  CAS  PubMed  Google Scholar 

  35. Oswald M, Kullak-Ublick GA, Paumgartner G, Beuers U (2001) Expression of hepatic transporters OATP-C and MRP2 in primary sclerosing cholangitis. Liver 21:247–253

    Article  CAS  PubMed  Google Scholar 

  36. Jung D, Hagenbuch B, Gresh L, Pontoglio M, Meier PJ, Kullak-Ublick GA (2001) Characterization of the human OATP-C (SLC21A6) gene promoter and regulation of liver-specific OATP genes by hepatocyte nuclear factor 1 alpha. J Biol Chem 276:37206–37214

    Article  CAS  PubMed  Google Scholar 

  37. Abe T, Unno M, Onogawa T, Tokui T, Kondo TN, Nakagomi R, Adachi H, Fujiwara K, Okabe M, Suzuki T, Nunoki K, Sato E, Kakyo M, Nishio T, Sugita J, Asano N, Tanemoto M, Seki M, Date F, Ono K, Kondo Y, Shiiba K, Suzuki M, Ohtani H, Shimosegawa T, Iinuma, Nagura H, Ito S, Matsuno S (2001) LST-2, a human liver-specific organic anion transporter, determines methotrexate sensitivity in gastrointestinal cancers. Gastroenterology 120:1689–1699

    CAS  PubMed  Google Scholar 

  38. König J, Cui Y, Nies AT, Keppler D (2000) Localization and genomic organization of a new hepatocellular organic anion transporting polypeptide. J Biol Chem 275:23161–23168

    Article  PubMed  Google Scholar 

  39. Ismair MG, Stieger B, Cattori V, Hagenbuch B, Fried M, Meier PJ, Kullak-Ublick GA (2001) Hepatic uptake of cholecystokinin octapeptide by organic anion-transporting polypeptides OATP4 and OATP8 of rat and human liver. Gastroenterology 121:1185–1190

    CAS  PubMed  Google Scholar 

  40. Jung D, Podvinec M, Meyer UA, Mangelsdorf DJ, Fried M, Meier PJ, Kullak-Ublick GA (2002) Human organic anion transporting polypeptide OATP8 (SLC21A8) promoter is transactivated by the farnesoid X receptor/bile acid receptor. Gastroenterology 122:1954–1966

    CAS  PubMed  Google Scholar 

  41. Cattori V, Hagenbuch B, Hagenbuch N, Stieger B, Ha R, Winterhalter KE, Meier PJ (2000) Identification of organic anion transporting polypeptide 4 (Oatp4) as a major full-length isoform of the liver-specific transporter-1 (rlst-1) in rat liver. FEBS Lett 474:242–245

    Article  CAS  PubMed  Google Scholar 

  42. Ogura K, Choudhuri S, Klaassen CD (2000) Full-length cDNA cloning and genomic organization of the mouse liver-specific organic anion transporter-1 (lst-1). Biochem Biophys Res Commun 272:563–570

    Article  CAS  PubMed  Google Scholar 

  43. Pizzagalli F, Hagenbuch B, Stieger B, Klenk U, Folkers G, Meier PJ (2002) Identification of a novel human organic anion transporting polypeptide (OATP-F) as a high affinity thyroxine transporter. Mol Endocrinol 16:2283–2296

    Article  CAS  PubMed  Google Scholar 

  44. Li JY, Boado RJ, Pardridge WM (2001) Blood-brain barrier genomics. J Cereb Blood Flow Metab 21:61–68

    CAS  PubMed  Google Scholar 

  45. Lu R, Kanai N, Bao Y, Schuster VL (1996) Cloning, in vitro expression, and tissue distribution of a human prostaglandin transporter cDNA (HPGT). J Clin Invest 98:1142–1149

    CAS  PubMed  Google Scholar 

  46. Pucci ML, Bao Y, Chan B, Itoh S, Lu R, Copeland NG, Gilbert DJ, Jenkins NA, Schuster VL (1999) Cloning of mouse prostaglandin transporter PGT cDNA: species-specific substrate affinities. Am J Physiol 299:R734–R741

    Google Scholar 

  47. Nagase T, Ishikawa K, Suyama M, Kikuno R, Hirosawa M, Miyajima N, Tanaka A, Kotani H, Nomura N, Ohara O (1998) Prediction of the coding sequences of unidentified human genes. XII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res 5:355–364

    PubMed  Google Scholar 

  48. St-Pierre MV, Ugele B, Hagenbuch B, Meier PJ, Stallmach T (2002) Characterization of an organic anion transporting polypeptide (OATP-B) in human placenta. J Clin Endocrin Metabol 87:1856–1863

    CAS  Google Scholar 

  49. Nishio T, Adachi H, Nakagomi R, Tokui T, Sato E, Tanemoto M, Fujiwara K, Okabe M, Onogawa T, Suzuki T, Nakai D, Shiiba K, Suzuki M, Ohtani H, Kondo Y, Unno M, Ito S, Iinuma K, Nunoki K, Matsuno S, Abe T (2000) Molecular identification of a rat novel organic anion transporter moat1, which transports prostaglandin D(2), leukotriene C(4), and taurocholate. Biochem Biophys Res Commun 275:831–838

    Article  CAS  PubMed  Google Scholar 

  50. Fujiwara K, Adachi H, Nishio T, Unno M, Tokui T, Okabe M, Onogawa T, Suzuki T, Asano N, Tanemoto M, Seki M, Shiiba K, Suzuki M, Kondo Y, Nunoki K, Shimosegawa T, Iinuma K, Ito S, Matsuno S, Abe T (2001) Identification of thyroid hormone transporters in humans: different molecules are involved in a tissue-specific manner. Endocrinology 142:2005–2012

    CAS  PubMed  Google Scholar 

  51. Sato K, Sugawara J, Sato T, Mizutamari H, Suzuki T, Ito A, Mikkaichi T, Onogawa T, Tanemoto M, Unno M, Abe T, Okamura K (2003) Expression of organic anion transporting polypeptide E (OATP-E) in human placenta. Placenta 24:144–148

    Article  CAS  PubMed  Google Scholar 

  52. Suzuki T, Onogawa T, Asano N, Mizutamari H, Mikkaichi T, Tanemoto M, Abe M, Satoh F, Unno M, Nunoki K, Suzuki M, Hishinuma T, Goto J, Shimosegawa T, Matsuno S, Ito S, Abe T (2003) Identification and characterization of novel rat and human gonad specific organic anion transporters. Mol Endocrinol 3:3

    Google Scholar 

  53. Kawai J, Shinagawa A, Shibata K, Yoshino M, Itoh M, Ishii Y, Arakawa T, Hara A, Fukunishi Y, Konno H, Adachi J, Fukuda S, Aizawa K, Izawa M, Nishi K, Kiyosawa H, Kondo S, Yamanaka I, Saito T, Okazaki Y, Gojobori T, Bono H, Kasukawa T, Saito R, Kadota K, Matsuda H, Ashburner M, Batalov S, Casavant T, Fleischmann W, Gaasterland T, Gissi C, King B, Kochiwa H, Kuehl P, Lewis S, Matsuo Y, Nikaido I, Pesole G, Quackenbush J, Schriml LM, Staubli F, Suzuki R, Tomita M, Wagner L, Washio T, Sakai K, Okido T, Furuno M, Aono H, Baldarelli R, Barsh G, Blake J, Boffelli D, Bojunga N, Carninci P, de Bonaldo MF, Brownstein MJ, Bult C, Fletcher C, Fujita M, Gariboldi M, Gustincich S, Hill D, Hofmann M, Hume DA, Kamiya M, Lee NH, Lyons P, Marchionni L, Mashima J, Mazzarelli J, Mombaerts P, Nordone P, Ring B, Ringwald M, Rodriguez I, Sakamoto N, Sasaki H, Sato K, Schonbach C, Seya T, Shibata Y, Storch KF, Suzuki H, Toyo-oka K, Wang KH, Weitz C, Whittaker C, Wilming L, Wynshaw-Boris A, Yoshida K, Hasegawa Y, Kawaji H, Kohtsuki S, Hayashizaki Y (2001) Functional annotation of a full-length mouse cDNA collection. Nature 409:685–690

    Article  PubMed  Google Scholar 

  54. Page RDM (1996) TREEVIW: an application to display phylogenetic trees on personal computers. Comput Appl Biosci 12:357–358

    CAS  PubMed  Google Scholar 

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Acknowledgements

The authors were supported by the Swiss National Science Foundation (grants 31–59204.99 to B.H. and 31–64140.00 to P.J.M.).

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Hagenbuch, B., Meier, P.J. Organic anion transporting polypeptides of the OATP/SLC21 family: phylogenetic classification as OATP/SLCO superfamily, new nomenclature and molecular/functional properties. Pflugers Arch - Eur J Physiol 447, 653–665 (2004). https://doi.org/10.1007/s00424-003-1168-y

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