The AAPS Journal

, Volume 19, Issue 6, pp 1643–1655 | Cite as

Alternative Splicing: Expanding Diversity in Major ABC and SLC Drug Transporters

  • Ji Eun Park
  • Gongmi Ryoo
  • Wooin LeeEmail author
Review Article Theme: Roles of Transporters in Disease and Drug Therapy
Part of the following topical collections:
  1. Theme: Roles of Transporters in Disease and Drug Therapy


Alternative splicing is an important mechanism of genetic regulation enhancing diversity and complexity of the transcriptome and proteome from the finite number of genes. Many reported cases demonstrate that alternative splicing events can lead to changes in the expression/function of proteins during disease development and progression. For pharmacogenes that can influence drug disposition and response, the role of alternative splicing has begun to receive increasing attention as an under-explored source of variable drug response. Here, we provide an overview of alternative spliced variants reported for the major drug transporters of SLC and ABC families with their possible implications in disease and drug therapy. As more comprehensive analyses on the abundance and functional outcomes of variably spliced isoforms of major drug transporters become available, it will be possible to utilize the obtained knowledge as novel therapeutic targets for tailored treatment strategies.


alternative splicing ABC transporters drug transporters SLC transporters 

Supplementary material

12248_2017_150_Fig3_ESM.gif (139 kb)

(GIF 139 kb)

12248_2017_150_MOESM1_ESM.tiff (6.9 mb)
High-resolution image (TIFF 7083 kb)
12248_2017_150_Fig4_ESM.jpg (1.1 mb)

(JPG 1.13 mb)


  1. 1.
    Berget SM, Moore C, Sharp PA. Spliced segments at the 5′ terminus of adenovirus 2 late mRNA. Proc Natl Acad Sci U S A. 1977;74(8):3171–5.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Chow LT, Gelinas RE, Broker TR, Roberts RJ. An amazing sequence arrangement at the 5′ ends of adenovirus 2 messenger RNA. Cell. 1977;12(1):1–8.PubMedCrossRefGoogle Scholar
  3. 3.
    Gilbert W. Why genes in pieces? Nature. 1978;271(5645):501.PubMedCrossRefGoogle Scholar
  4. 4.
    Gutierrez-Arcelus M, Ongen H, Lappalainen T, Montgomery SB, Buil A, Yurovsky A, et al. Tissue-specific effects of genetic and epigenetic variation on gene regulation and splicing. PLoS Genet. 2015;11(1):e1004958.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Pan Q, Shai O, Lee LJ, Frey BJ, Blencowe BJ. Deep surveying of alternative splicing complexity in the human transcriptome by high-throughput sequencing. Nat Genet. 2008;40(12):1413–5.PubMedCrossRefGoogle Scholar
  6. 6.
    Wang ET, Sandberg R, Luo S, Khrebtukova I, Zhang L, Mayr C, et al. Alternative isoform regulation in human tissue transcriptomes. Nature. 2008;456(7221):470–6.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Keren H, Lev-Maor G, Ast G. Alternative splicing and evolution: diversification, exon definition and function. Nat Rev Genet. 2010;11(5):345–55.PubMedCrossRefGoogle Scholar
  8. 8.
    Gao Q, Sun W, Ballegeer M, Libert C, Chen W. Predominant contribution of cis-regulatory divergence in the evolution of mouse alternative splicing. Mol Syst Biol. 2015;11(7):816.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Chen L, Tovar-Corona JM, Urrutia AO. Alternative splicing: a potential source of functional innovation in the eukaryotic genome. Int J Evol Biol. 2012;2012:596274.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Tress ML, Abascal F, Valencia A. Alternative splicing may not be the key to proteome complexity. Trends Biochem Sci. 2017;42(2):98–110.PubMedCrossRefGoogle Scholar
  11. 11.
    Mockenhaupt S, Makeyev EV. Non-coding functions of alternative pre-mRNA splicing in development. Sem Cell Dev Biol. 2015;47–48:32–9.CrossRefGoogle Scholar
  12. 12.
    Scotti MM, Swanson MS. RNA mis-splicing in disease. Nat Rev Genet. 2016;17(1):19–32.PubMedCrossRefGoogle Scholar
  13. 13.
    Tazi J, Bakkour N, Stamm S. Alternative splicing and disease. Biochim Biophys Acta. 2009;1792(1):14–26.PubMedCrossRefGoogle Scholar
  14. 14.
    Chhibber A, French CE, Yee SW, Gamazon ER, Theusch E, Qin X, et al. Transcriptomic variation of pharmacogenes in multiple human tissues and lymphoblastoid cell lines. Pharmacogenomics J. 2017;17(2):137–45.PubMedCrossRefGoogle Scholar
  15. 15.
    International Transporter C, Giacomini KM, Huang SM, Tweedie DJ, Benet LZ, Brouwer KL, et al. Membrane transporters in drug development. Nat Rev Drug Discov. 2010;9(3):215–36.CrossRefGoogle Scholar
  16. 16.
    Turman CM, Hatley JM, Ryder DJ, Ravindranath V, Strobel HW. Alternative splicing within the human cytochrome P450 superfamily with an emphasis on the brain: the convolution continues. Expert Opin Drug Metab Toxicol. 2006;2(3):399–418.PubMedCrossRefGoogle Scholar
  17. 17.
    Annalora AJ, Marcus CB, Iversen PL. Alternative splicing in the cytochrome P450 superfamily expands protein diversity to augment gene function and redirect human drug metabolism. Drug Metab Dispos. 2017;45(4):375–89.PubMedCrossRefGoogle Scholar
  18. 18.
    Guillemette C, Levesque E, Harvey M, Bellemare J, Menard V. UGT genomic diversity: beyond gene duplication. Drug Metab Rev. 2010;42(1):24–44.PubMedCrossRefGoogle Scholar
  19. 19.
    Black DL. Mechanisms of alternative pre-messenger RNA splicing. Annu Rev Biochem. 2003;72:291–336.PubMedCrossRefGoogle Scholar
  20. 20.
    Gallego-Paez LM, Bordone MC, Leote AC, Saraiva-Agostinho N, Ascensao-Ferreira M, Barbosa-Morais NL. Alternative splicing: the pledge, the turn, and the prestige: the key role of alternative splicing in human biological systems. Hum Genet. 2017;136(9):1015–1042.Google Scholar
  21. 21.
    Alekseyenko AV, Kim N, Lee CJ. Global analysis of exon creation versus loss and the role of alternative splicing in 17 vertebrate genomes. RNA. 2007;13(5):661–70.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Artamonova II, Gelfand MS. Comparative genomics and evolution of alternative splicing: the pessimists’ science. Chem Rev. 2007;107(8):3407–30.PubMedCrossRefGoogle Scholar
  23. 23.
    Yeo G, Holste D, Kreiman G, Burge CB. Variation in alternative splicing across human tissues. Genome Biol. 2004;5(10):R74.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Hoskins AA, Moore MJ. The spliceosome: a flexible, reversible macromolecular machine. Trends Biochem Sci. 2012;37(5):179–88.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Jurica MS, Moore MJ. Pre-mRNA splicing: awash in a sea of proteins. Mol Cell. 2003;12(1):5–14.PubMedCrossRefGoogle Scholar
  26. 26.
    Zaphiropoulos PG. Genetic variations and alternative splicing: the glioma associated oncogene 1, GLI1. Front Genet. 2012;3:119.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Lewis BP, Green RE, Brenner SE. Evidence for the widespread coupling of alternative splicing and nonsense-mediated mRNA decay in humans. Proc Natl Acad Sci U S A. 2003;100(1):189–92.PubMedCrossRefGoogle Scholar
  28. 28.
    Srinivasan S, Bingham JL, Johnson D. The ABCs of human alternative splicing: a review of ATP-binding cassette transporter splicing. Curr Opin Drug Discov Dev. 2009;12(1):149–58.Google Scholar
  29. 29.
    Byrne JA, Strautnieks SS, Ihrke G, Pagani F, Knisely AS, Linton KJ, et al. Missense mutations and single nucleotide polymorphisms in ABCB11 impair bile salt export pump processing and function or disrupt pre-messenger RNA splicing. Hepatology. 2009;49(2):553–67.PubMedCrossRefGoogle Scholar
  30. 30.
    Davit-Spraul A, Oliveira C, Gonzales E, Gaignard P, Therond P, Jacquemin E. Liver transcript analysis reveals aberrant splicing due to silent and intronic variations in the ABCB11 gene. Mol Genet Metab. 2014;113(3):225–9.PubMedCrossRefGoogle Scholar
  31. 31.
    Van der Bliek AM, Baas F, Ten Houte de Lange T, Kooiman PM, Van der Velde-Koerts T, Borst P. The human mdr3 gene encodes a novel P-glycoprotein homologue and gives rise to alternatively spliced mRNAs in liver. EMBO J. 1987;6(11):3325–31.PubMedPubMedCentralGoogle Scholar
  32. 32.
    Khabou B, Siala-Sahnoun O, Gargouri L, Mkaouar-Rebai E, Keskes L, Hachicha M, et al. In silico investigation of the impact of synonymous variants in ABCB4 gene on mRNA stability/structure, splicing accuracy and codon usage: potential contribution to PFIC3 disease. Comput Biol Chem. 2016;65:103–9.PubMedCrossRefGoogle Scholar
  33. 33.
    Schneider G, Paus TC, Kullak-Ublick GA, Meier PJ, Wienker TF, Lang T, et al. Linkage between a new splicing site mutation in the MDR3 alias ABCB4 gene and intrahepatic cholestasis of pregnancy. Hepatology. 2007;45(1):150–8.PubMedCrossRefGoogle Scholar
  34. 34.
    Tavian D, Degiorgio D, Roncaglia N, Vergani P, Cameroni I, Colombo R, et al. A new splicing site mutation of the ABCB4 gene in intrahepatic cholestasis of pregnancy with raised serum gamma-GT. Dig Liver Dis. 2009;41(9):671–5.PubMedCrossRefGoogle Scholar
  35. 35.
    Lamba JK, Adachi M, Sun D, Tammur J, Schuetz EG, Allikmets R, et al. Nonsense mediated decay downregulates conserved alternatively spliced ABCC4 transcripts bearing nonsense codons. Hum Mol Genet. 2003;12(2):99–109.PubMedCrossRefGoogle Scholar
  36. 36.
    Ansari M, Sauty G, Labuda M, Gagne V, Laverdiere C, Moghrabi A, et al. Polymorphisms in multidrug resistance-associated protein gene 4 is associated with outcome in childhood acute lymphoblastic leukemia. Blood. 2009;114(7):1383–6.PubMedCrossRefGoogle Scholar
  37. 37.
    Gradhand U, Lang T, Schaeffeler E, Glaeser H, Tegude H, Klein K, et al. Variability in human hepatic MRP4 expression: influence of cholestasis and genotype. Pharmacogenomics J. 2008;8(1):42–52.PubMedCrossRefGoogle Scholar
  38. 38.
    Janke D, Mehralivand S, Strand D, Godtel-Armbrust U, Habermeier A, Gradhand U, et al. 6-mercaptopurine and 9-(2-phosphonyl-methoxyethyl) adenine (PMEA) transport altered by two missense mutations in the drug transporter gene ABCC4. Hum Mutat. 2008;29(5):659–69.PubMedCrossRefGoogle Scholar
  39. 39.
    Toh S, Wada M, Uchiumi T, Inokuchi A, Makino Y, Horie Y, et al. Genomic structure of the canalicular multispecific organic anion-transporter gene (MRP2/cMOAT) and mutations in the ATP-binding-cassette region in Dubin-Johnson syndrome. Am J Hum Genet. 1999;64(3):739–46.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Kajihara S, Hisatomi A, Mizuta T, Hara T, Ozaki I, Wada I, et al. A splice mutation in the human canalicular multispecific organic anion transporter gene causes Dubin-Johnson syndrome. Biochem Biophys Res Commun. 1998;253(2):454–7.PubMedCrossRefGoogle Scholar
  41. 41.
    Tate G, Li M, Suzuki T, Mitsuya T. A new mutation of the ATP-binding cassette, sub-family C, member 2 (ABCC2) gene in a Japanese patient with Dubin-Johnson syndrome. Genes Genet Syst. 2002;77(2):117–21.PubMedCrossRefGoogle Scholar
  42. 42.
    Kanda D, Takagi H, Kawahara Y, Yata Y, Takakusagi T, Hatanaka T, et al. Novel large-scale deletion (whole exon 7) in the ABCC2 gene in a patient with the Dubin-Johnson syndrome. Drug Metab Pharmacokinet. 2009;24(5):464–8.PubMedCrossRefGoogle Scholar
  43. 43.
    Mor-Cohen R, Zivelin A, Rosenberg N, Goldberg I, Seligsohn U. A novel ancestral splicing mutation in the multidrug resistance protein 2 gene causes Dubin-Johnson syndrome in Ashkenazi Jewish patients. Hepatol Res. 2005;31(2):104–11.PubMedCrossRefGoogle Scholar
  44. 44.
    Nakanishi T, Bailey-Dell KJ, Hassel BA, Shiozawa K, Sullivan DM, Turner J, et al. Novel 5′ untranslated region variants of BCRP mRNA are differentially expressed in drug-selected cancer cells and in normal human tissues: implications for drug resistance, tissue-specific expression, and alternative promoter usage. Cancer Res. 2006;66(10):5007–11.PubMedCrossRefGoogle Scholar
  45. 45.
    Poonkuzhali B, Lamba J, Strom S, Sparreboom A, Thummel K, Watkins P, et al. Association of breast cancer resistance protein/ABCG2 phenotypes and novel promoter and intron 1 single nucleotide polymorphisms. Drug Metab Dispos. 2008;36(4):780–95.PubMedCrossRefGoogle Scholar
  46. 46.
    Strautnieks SS, Byrne JA, Pawlikowska L, Cebecauerova D, Rayner A, Dutton L, et al. Severe bile salt export pump deficiency: 82 different ABCB11 mutations in 109 families. Gastroenterology. 2008;134(4):1203–14.PubMedCrossRefGoogle Scholar
  47. 47.
    van Mil SW, van der Woerd WL, van der Brugge G, Sturm E, Jansen PL, Bull LN, et al. Benign recurrent intrahepatic cholestasis type 2 is caused by mutations in ABCB11. Gastroenterology. 2004;127(2):379–84.PubMedCrossRefGoogle Scholar
  48. 48.
    Arrese M, Macias RI, Briz O, Perez MJ, Marin JJ. Molecular pathogenesis of intrahepatic cholestasis of pregnancy. Expert Rev Mol Med. 2008;10:e9.PubMedCrossRefGoogle Scholar
  49. 49.
    Oude Elferink RP, Paulusma CC. Function and pathophysiological importance of ABCB4 (MDR3 P-glycoprotein). Pflugers Arch. 2007;453(5):601–10.PubMedCrossRefGoogle Scholar
  50. 50.
    Hu Y, Tanzer LR, Cao J, Geringer CD, Moore RE. Use of long RT-PCR to characterize splice variant mRNAs. BioTechniques. 1998;25(2):224–9.PubMedGoogle Scholar
  51. 51.
    Russel FG, Koenderink JB, Masereeuw R. Multidrug resistance protein 4 (MRP4/ABCC4): a versatile efflux transporter for drugs and signalling molecules. Trends Pharmacol Sci. 2008;29(4):200–7.PubMedCrossRefGoogle Scholar
  52. 52.
    Wen J, Luo J, Huang W, Tang J, Zhou H, Zhang W. The pharmacological and physiological role of multidrug-resistant protein 4. J Pharmacol Exp Ther. 2015;354(3):358–75.PubMedCrossRefGoogle Scholar
  53. 53.
    Chen C, Klaassen CD. Rat multidrug resistance protein 4 (Mrp4, Abcc4): molecular cloning, organ distribution, postnatal renal expression, and chemical inducibility. Biochem Biophys Res Commun. 2004;317(1):46–53.PubMedCrossRefGoogle Scholar
  54. 54.
    Mesrian TH, Rahgozar S, Mojtabavi NM. ABCC4 functional SNP in the 3′ splice acceptor site of exon 8 (G912T) is associated with unfavorable clinical outcome in children with acute lymphoblastic leukemia. Cancer Chemother Pharmacol. 2017;80(1):109–17.CrossRefGoogle Scholar
  55. 55.
    Kartenbeck J, Leuschner U, Mayer R, Keppler D. Absence of the canalicular isoform of the MRP gene-encoded conjugate export pump from the hepatocytes in Dubin-Johnson syndrome. Hepatology. 1996;23(5):1061–6.PubMedGoogle Scholar
  56. 56.
    Scheffer GL, Kool M, de Haas M, de Vree JM, Pijnenborg AC, Bosman DK, et al. Tissue distribution and induction of human multidrug resistant protein 3. Lab Investig. 2002;82(2):193–201.PubMedCrossRefGoogle Scholar
  57. 57.
    Kool M, van der Linden M, de Haas M, Scheffer GL, de Vree JM, Smith AJ, et al. MRP3, an organic anion transporter able to transport anti-cancer drugs. Proc Natl Acad Sci U S A. 1999;96(12):6914–9.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    van de Wetering K, Feddema W, Helms JB, Brouwers JF, Borst P. Targeted metabolomics identifies glucuronides of dietary phytoestrogens as a major class of MRP3 substrates in vivo. Gastroenterology. 2009;137(5):1725–35.PubMedCrossRefGoogle Scholar
  59. 59.
    Fromm MF, Leake B, Roden DM, Wilkinson GR, Kim RB. Human MRP3 transporter: identification of the 5′-flanking region, genomic organization and alternative splice variants. Biochim Biophys Acta. 1999;1415(2):369–74.PubMedCrossRefGoogle Scholar
  60. 60.
    Stacy AE, Jansson PJ, Richardson DR. Molecular pharmacology of ABCG2 and its role in chemoresistance. Mol Pharmacol. 2013;84(5):655–69.PubMedCrossRefGoogle Scholar
  61. 61.
    Zhou S, Schuetz JD, Bunting KD, Colapietro AM, Sampath J, Morris JJ, et al. The ABC transporter Bcrp1/ABCG2 is expressed in a wide variety of stem cells and is a molecular determinant of the side-population phenotype. Nat Med. 2001;7(9):1028–34.PubMedCrossRefGoogle Scholar
  62. 62.
    Sandor S, Jordanidisz T, Schamberger A, Varady G, Erdei Z, Apati A, et al. Functional characterization of the ABCG2 5′ non-coding exon variants: stem cell specificity, translation efficiency and the influence of drug selection. Biochim Biophys Acta. 2016;1859(7):943–51.PubMedCrossRefGoogle Scholar
  63. 63.
    Krishnamurthy P, Ross DD, Nakanishi T, Bailey-Dell K, Zhou S, Mercer KE, et al. The stem cell marker Bcrp/ABCG2 enhances hypoxic cell survival through interactions with Heme. J Biol Chem. 2004;279(23):24218–25.PubMedCrossRefGoogle Scholar
  64. 64.
    Zong Y, Zhou S, Fatima S, Sorrentino BP. Expression of mouse Abcg2 mRNA during hematopoiesis is regulated by alternative use of multiple leader exons and promoters. J Biol Chem. 2006;281(40):29625–32.PubMedCrossRefGoogle Scholar
  65. 65.
    Hayer M, Bonisch H, Bruss M. Molecular cloning, functional characterization and genomic organization of four alternatively spliced isoforms of the human organic cation transporter 1 (hOCT1/SLC22A1). Ann Hum Genet. 1999;63(Pt 6):473–82.PubMedCrossRefGoogle Scholar
  66. 66.
    Grinfeld J, Gerrard G, Alikian M, Alonso-Dominguez J, Ale S, Valganon M, et al. A common novel splice variant of SLC22A1 (OCT1) is associated with impaired responses to imatinib in patients with chronic myeloid leukaemia. Br J Haematol. 2013;163(5):631–9.PubMedCrossRefGoogle Scholar
  67. 67.
    Herraez E, Lozano E, Macias RI, Vaquero J, Bujanda L, Banales JM, et al. Expression of SLC22A1 variants may affect the response of hepatocellular carcinoma and cholangiocarcinoma to sorafenib. Hepatology. 2013;58(3):1065–73.PubMedCrossRefGoogle Scholar
  68. 68.
    Urakami Y, Akazawa M, Saito H, Okuda M, Inui K. cDNA cloning, functional characterization, and tissue distribution of an alternatively spliced variant of organic cation transporter hOCT2 predominantly expressed in the human kidney. J Am Soc Nephrol. 2002;13(7):1703–10.PubMedCrossRefGoogle Scholar
  69. 69.
    Hotchkiss AG, Berrigan L, Pelis RM. Organic anion transporter 2 transcript variant 1 shows broad ligand selectivity when expressed in multiple cell lines. Front Pharmacol. 2015;6:216.PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Enomoto A, Takeda M, Shimoda M, Narikawa S, Kobayashi Y, Kobayashi Y, et al. Interaction of human organic anion transporters 2 and 4 with organic anion transport inhibitors. J Pharmacol Exp Ther. 2002;301(3):797–802.PubMedCrossRefGoogle Scholar
  71. 71.
    Cropp CD, Komori T, Shima JE, Urban TJ, Yee SW, More SS, et al. Organic anion transporter 2 (SLC22A7) is a facilitative transporter of cGMP. Mol Pharmacol. 2008;73(4):1151–8.PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Lee W, Belkhiri A, Lockhart AC, Merchant N, Glaeser H, Harris EI, et al. Overexpression of OATP1B3 confers apoptotic resistance in colon cancer. Cancer Res. 2008;68(24):10315–23.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Thakkar N, Kim K, Jang ER, Han S, Kim K, Kim D, et al. A cancer-specific variant of the SLCO1B3 gene encodes a novel human organic anion transporting polypeptide 1B3 (OATP1B3) localized mainly in the cytoplasm of colon and pancreatic cancer cells. Mol Pharm. 2013;10(1):406–16.PubMedCrossRefGoogle Scholar
  74. 74.
    Imai S, Kikuchi R, Tsuruya Y, Naoi S, Nishida S, Kusuhara H, et al. Epigenetic regulation of organic anion transporting polypeptide 1B3 in cancer cell lines. Pharm Res. 2013;30(11):2880–90.PubMedCrossRefGoogle Scholar
  75. 75.
    Nagai M, Furihata T, Matsumoto S, Ishii S, Motohashi S, Yoshino I, et al. Identification of a new organic anion transporting polypeptide 1B3 mRNA isoform primarily expressed in human cancerous tissues and cells. Biochem Biophys Res Commun. 2012;418(4):818–23.PubMedCrossRefGoogle Scholar
  76. 76.
    Teft WA, Welch S, Lenehan J, Parfitt J, Choi YH, Winquist E, et al. OATP1B1 and tumour OATP1B3 modulate exposure, toxicity, and survival after irinotecan-based chemotherapy. Br J Cancer. 2015;112(5):857–65.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Ramachandran A, Betts G, Bhana S, Helme G, Blick C, Moller-Levet C, et al. An in vivo hypoxia metagene identifies the novel hypoxia inducible factor target gene SLCO1B3. Eur J Cancer. 2013;49(7):1741–51.PubMedCrossRefGoogle Scholar
  78. 78.
    Maeda T, Hirayama M, Higashi R, Sato M, Tamai I. Characterization of human OATP2B1 (SLCO2B1) gene promoter regulation. Pharm Res. 2006;23(3):513–20.PubMedCrossRefGoogle Scholar
  79. 79.
    Pomari E, Nardi A, Fiore C, Celeghin A, Colombo L, Dalla VL. Transcriptional control of human organic anion transporting polypeptide 2B1 gene. J Steroid Biochem Mol Biol. 2009;115(3–5):146–52.PubMedCrossRefGoogle Scholar
  80. 80.
    Knauer MJ, Girdwood AJ, Kim RB, Tirona RG. Transport function and transcriptional regulation of a liver-enriched human organic anion transporting polypeptide 2B1 transcriptional start site variant. Mol Pharmacol. 2013;83(6):1218–28.PubMedCrossRefGoogle Scholar
  81. 81.
    Saito H, Motohashi H, Mukai M, Inui K. Cloning and characterization of a pH-sensing regulatory factor that modulates transport activity of the human H+/peptide cotransporter, PEPT1. Biochem Biophys Res Commun. 1997;237(3):577–82.PubMedCrossRefGoogle Scholar
  82. 82.
    Urtti A, Johns SJ, Sadee W. Genomic structure of proton-coupled oligopeptide transporter hPEPT1 and pH-sensing regulatory splice variant. AAPS PharmSci. 2001;3(1):E6.PubMedGoogle Scholar
  83. 83.
    Anderle P, Nielsen CU, Pinsonneault J, Krog PL, Brodin B, Sadee W. Genetic variants of the human dipeptide transporter PEPT1. J Pharmacol Exp Ther. 2006;316(2):636–46.PubMedCrossRefGoogle Scholar
  84. 84.
    Masuda S, Terada T, Yonezawa A, Tanihara Y, Kishimoto K, Katsura T, et al. Identification and functional characterization of a new human kidney-specific H+/organic cation antiporter, kidney-specific multidrug and toxin extrusion 2. J Am Soc Nephrol. 2006;17(8):2127–35.PubMedCrossRefGoogle Scholar
  85. 85.
    Hyrsova L, Smutny T, Trejtnar F, Pavek P. Expression of organic cation transporter 1 (OCT1): unique patterns of indirect regulation by nuclear receptors and hepatospecific gene regulation. Drug Metab Rev. 2016;48(2):139–58.PubMedCrossRefGoogle Scholar
  86. 86.
    Goswami S, Gong L, Giacomini K, Altman RB, Klein TE. PharmGKB summary: very important pharmacogene information for SLC22A1. Pharmacogenet Genomics. 2014;24(6):324–8.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Watkins DB, Hughes TP, White DL. OCT1 and imatinib transport in CML: is it clinically relevant? Leukemia. 2015;29(10):1960–9.PubMedCrossRefGoogle Scholar
  88. 88.
    Zhou Y, Ye W, Wang Y, Jiang Z, Meng X, Xiao Q, et al. Genetic variants of OCT1 influence glycemic response to metformin in Han Chinese patients with type-2 diabetes mellitus in Shanghai. Int J Clin Exp Pathol. 2015;8(8):9533–42.PubMedPubMedCentralGoogle Scholar
  89. 89.
    Shikata E, Yamamoto R, Takane H, Shigemasa C, Ikeda T, Otsubo K, et al. Human organic cation transporter (OCT1 and OCT2) gene polymorphisms and therapeutic effects of metformin. J Hum Genet. 2007;52(2):117–22.PubMedCrossRefGoogle Scholar
  90. 90.
    Grimm D, Lieb J, Weyer V, Vollmar J, Darstein F, Lautem A, et al. Organic cation transporter 1 (OCT1) mRNA expression in hepatocellular carcinoma as a biomarker for sorafenib treatment. BMC Cancer. 2016;16:94.PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Motohashi H, Inui K. Organic cation transporter OCTs (SLC22) and MATEs (SLC47) in the human kidney. AAPS J. 2013;15(2):581–8.PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Urban TJ, Sebro R, Hurowitz EH, Leabman MK, Badagnani I, Lagpacan LL, et al. Functional genomics of membrane transporters in human populations. Genome Res. 2006;16(2):223–30.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Shen H, Lai Y, Rodrigues AD. Organic anion transporter 2: an enigmatic human solute carrier. Drug Metab Dispos. 2017;45(2):228–36.PubMedCrossRefGoogle Scholar
  94. 94.
    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(24):17159–63.PubMedCrossRefGoogle Scholar
  95. 95.
    Thakkar N, Lockhart AC, Lee W. Role of organic anion-transporting polypeptides (OATPs) in cancer therapy. AAPS J. 2015;17(3):535–45.PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Furihata T, Sun Y, Chiba K. Cancer-type organic anion transporting polypeptide 1B3: current knowledge of the gene structure, expression profile, functional implications and future perspectives. Curr Drug Metab. 2015;16(6):474–85.PubMedCrossRefGoogle Scholar
  97. 97.
    Lockhart AC, Harris E, Lafleur BJ, Merchant NB, Washington MK, Resnick MB, et al. Organic anion transporting polypeptide 1B3 (OATP1B3) is overexpressed in colorectal tumors and is a predictor of clinical outcome. Clin Exp Gastroenterol. 2008;1:1–7.PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Muto M, Onogawa T, Suzuki T, Ishida T, Rikiyama T, Katayose Y, et al. Human liver-specific organic anion transporter-2 is a potent prognostic factor for human breast carcinoma. Cancer Sci. 2007;98(10):1570–6.PubMedCrossRefGoogle Scholar
  99. 99.
    Meyer zu Schwabedissen HE, Ware JA, Tirona RG, Kim RB. Identification, expression, and functional characterization of full-length and splice variants of murine organic anion transporting polypeptide 1b2. Mol Pharm. 2009;6(6):1790–7.PubMedCrossRefGoogle Scholar
  100. 100.
    Hays A, Apte U, Hagenbuch B. Organic anion transporting polypeptides expressed in pancreatic cancer may serve as potential diagnostic markers and therapeutic targets for early stage adenocarcinomas. Pharm Res. 2013;30(9):2260–9.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Sun Y, Furihata T, Ishii S, Nagai M, Harada M, Shimozato O, et al. Unique expression features of cancer-type organic anion transporting polypeptide 1B3 mRNA expression in human colon and lung cancers. Clin Transl Med. 2014;3:37.PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Sun Y, Harada M, Shimozato O, Souda H, Takiguchi N, Nabeya Y, et al. Cancer-type OATP1B3 mRNA has the potential to become a detection and prognostic biomarker for human colorectal cancer. Biomark Med. 2017;11(8):629–639.Google Scholar
  103. 103.
    Han S, Kim K, Thakkar N, Kim D, Lee W. Role of hypoxia inducible factor-1alpha in the regulation of the cancer-specific variant of organic anion transporting polypeptide 1B3 (OATP1B3), in colon and pancreatic cancer. Biochem Pharmacol. 2013;86(6):816–23.PubMedCrossRefGoogle Scholar
  104. 104.
    Ichihara S, Kikuchi R, Kusuhara H, Imai S, Maeda K, Sugiyama Y. DNA methylation profiles of organic anion transporting polypeptide 1B3 in cancer cell lines. Pharm Res. 2010;27(3):510–6.PubMedCrossRefGoogle Scholar
  105. 105.
    Niemi M, Pasanen MK, Neuvonen PJ. Organic anion transporting polypeptide 1B1: a genetically polymorphic transporter of major importance for hepatic drug uptake. Pharmacol Rev. 2011;63(1):157–81.PubMedCrossRefGoogle Scholar
  106. 106.
    Link E, Parish S, Armitage J, Bowman L, Heath S, Matsuda F, et al. SLCO1B1 variants and statin-induced myopathy—a genomewide study. N Engl J Med. 2008;359(8):789–99.PubMedCrossRefGoogle Scholar
  107. 107.
    Kim SR, Saito Y, Sai K, Kurose K, Maekawa K, Kaniwa N, et al. Genetic variations and frequencies of major haplotypes in SLCO1B1 encoding the transporter OATP1B1 in Japanese subjects: SLCO1B1*17 is more prevalent than *15. Drug Metab Pharmacokinet. 2007;22(6):456–61.PubMedCrossRefGoogle Scholar
  108. 108.
    Kullak-Ublick GA, Ismair MG, Stieger B, Landmann L, Huber R, Pizzagalli F, et al. Organic anion-transporting polypeptide B (OATP-B) and its functional comparison with three other OATPs of human liver. Gastroenterology. 2001;120(2):525–33.PubMedCrossRefGoogle Scholar
  109. 109.
    Nozawa T, Imai K, Nezu J, Tsuji A, Tamai I. Functional characterization of pH-sensitive organic anion transporting polypeptide OATP-B in human. J Pharmacol Exp Ther. 2004;308(2):438–45.PubMedCrossRefGoogle Scholar
  110. 110.
    Fei YJ, Kanai Y, Nussberger S, Ganapathy V, Leibach FH, Romero MF, et al. Expression cloning of a mammalian proton-coupled oligopeptide transporter. Nature. 1994;368(6471):563–6.PubMedCrossRefGoogle Scholar
  111. 111.
    Gaildrat P, Moller M, Mukda S, Humphries A, Carter DA, Ganapathy V, et al. A novel pineal-specific product of the oligopeptide transporter PepT1 gene: circadian expression mediated by cAMP activation of an intronic promoter. J Biol Chem. 2005;280(17):16851–60.PubMedCrossRefGoogle Scholar
  112. 112.
    Graul RC, Sadee W. Sequence alignments of the H(+)-dependent oligopeptide transporter family PTR: inferences on structure and function of the intestinal PET1 transporter. Pharm Res. 1997;14(4):388–400.PubMedCrossRefGoogle Scholar
  113. 113.
    Pinsonneault J, Nielsen CU, Sadee W. Genetic variants of the human H+/dipeptide transporter PEPT2: analysis of haplotype functions. J Pharmacol Exp Ther. 2004;311(3):1088–96.PubMedCrossRefGoogle Scholar
  114. 114.
    Zhang EY, Emerick RM, Pak YA, Wrighton SA, Hillgren KM. Comparison of human and monkey peptide transporters: PEPT1 and PEPT2. Mol Pharm. 2004;1(3):201–10.PubMedCrossRefGoogle Scholar
  115. 115.
    Otsuka M, Matsumoto T, Morimoto R, Arioka S, Omote H, Moriyama Y. A human transporter protein that mediates the final excretion step for toxic organic cations. Proc Natl Acad Sci U S A. 2005;102(50):17923–8.PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Yonezawa A, Inui K. Importance of the multidrug and toxin extrusion MATE/SLC47A family to pharmacokinetics, pharmacodynamics/toxicodynamics and pharmacogenomics. Br J Pharmacol. 2011;164(7):1817–25.PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Tanihara Y, Masuda S, Sato T, Katsura T, Ogawa O, Inui K. Substrate specificity of MATE1 and MATE2-K, human multidrug and toxin extrusions/H(+)-organic cation antiporters. Biochem Pharmacol. 2007;74(2):359–71.PubMedCrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2017

Authors and Affiliations

  1. 1.College of Pharmacy and Research Institute of Pharmaceutical SciencesSeoul National UniversitySeoulSouth Korea

Personalised recommendations