The AAPS Journal

, Volume 17, Issue 1, pp 65–82 | Cite as

Role of the Breast Cancer Resistance Protein (BCRP/ABCG2) in Drug Transport—an Update

  • Qingcheng MaoEmail author
  • Jashvant D. Unadkat
Review Article


The human breast cancer resistance protein (BCRP, gene symbol ABCG2) is an ATP-binding cassette (ABC) efflux transporter. It was so named because it was initially cloned from a multidrug-resistant breast cancer cell line where it was found to confer resistance to chemotherapeutic agents such as mitoxantrone and topotecan. Since its discovery in 1998, the substrates of BCRP have been rapidly expanding to include not only therapeutic agents but also physiological substances such as estrone-3-sulfate, 17β-estradiol 17-(β-d-glucuronide) and uric acid. Likewise, at least hundreds of BCRP inhibitors have been identified. Among normal human tissues, BCRP is highly expressed on the apical membranes of the placental syncytiotrophoblasts, the intestinal epithelium, the liver hepatocytes, the endothelial cells of brain microvessels, and the renal proximal tubular cells, contributing to the absorption, distribution, and elimination of drugs and endogenous compounds as well as tissue protection against xenobiotic exposure. As a result, BCRP has now been recognized by the FDA to be one of the key drug transporters involved in clinically relevant drug disposition. We published a highly-accessed review article on BCRP in 2005, and much progress has been made since then. In this review, we provide an update of current knowledge on basic biochemistry and pharmacological functions of BCRP as well as its relevance to drug resistance and drug disposition.


ABCG2 ATP-binding cassette BCRP drug transport transporter 



This work is supported in part by the NIH Grant DA032507. We gratefully thank Dr. Isabelle Ragueneau-Majlessi and Sophie Argon for search of the UW Metabolism and Transport Drug Interaction Database (DIDB) and the UW ePKGene Database for the impact of BCRP and ABCG2 SNPs on drug PK. We greatly acknowledge Dr. Zsolt Bikadi for preparing Fig. 2. Due to a limitation in the number of references imposed by the journal, many excellent studies cannot be cited in this review article. We appreciate the contributions of all of the authors to this important field of research.


  1. 1.
    Mao Q, Unadkat JD. Role of the breast cancer resistance protein (ABCG2) in drug transport. AAPS J. 2005;7:E118–33.PubMedCentralPubMedCrossRefGoogle Scholar
  2. 2.
    Natarajan K, Xie Y, Baer MR, Ross DD. Role of breast cancer resistance protein (BCRP/ABCG2) in cancer drug resistance. Biochem Pharmacol. 2012;83:1084–103.PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Benderra Z, Faussat AM, Sayada L, Perrot JY, Tang R, Chaoui D, et al. MRP3, BCRP, and P-glycoprotein activities are prognostic factors in adult acute myeloid leukemia. Clin Cancer Res. 2005;11:7764–72.PubMedCrossRefGoogle Scholar
  4. 4.
    Dohse M, Scharenberg C, Shukla S, Robey RW, Volkmann T, Deeken JF, et al. Comparison of ATP-binding cassette transporter interactions with the tyrosine kinase inhibitors imatinib, nilotinib, and dasatinib. Drug Metab Dispos. 2010;38:1371–80.PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Jiang X, Zhao Y, Smith C, Gasparetto M, Turhan A, Eaves A, et al. Chronic myeloid leukemia stem cells possess multiple unique features of resistance to BCR-ABL targeted therapies. Leukemia. 2007;21:926–35.PubMedGoogle Scholar
  6. 6.
    de Lima LT, Vivona D, Bueno CT, Hirata RD, Hirata MH, Luchessi AD, et al. Reduced ABCG2 and increased SLC22A1 mRNA expression are associated with imatinib response in chronic myeloid leukemia. Med Oncol. 2014;31:851.PubMedCrossRefGoogle Scholar
  7. 7.
    Diestra JE, Scheffer GL, Catala I, Maliepaard M, Schellens JH, Scheper RJ, et al. Frequent expression of the multi-drug resistance-associated protein BCRP/MXR/ABCP/ABCG2 in human tumours detected by the BXP-21 monoclonal antibody in paraffin-embedded material. J Pathol. 2002;198:213–9.PubMedCrossRefGoogle Scholar
  8. 8.
    Burger H, Foekens JA, Look MP, Meijer-van Gelder ME, Klijn JG, Wiemer EA, et al. RNA expression of breast cancer resistance protein, lung resistance-related protein, multidrug resistance-associated proteins 1 and 2, and multidrug resistance gene 1 in breast cancer: correlation with chemotherapeutic response. Clin Cancer Res. 2003;9:827–36.PubMedGoogle Scholar
  9. 9.
    Yuan JH, Cheng JQ, Jiang LY, Ji WD, Guo LF, Liu JJ, et al. Breast cancer resistance protein expression and 5-fluorouracil resistance. Biomed Environ Sci. 2008;21:290–5.PubMedCrossRefGoogle Scholar
  10. 10.
    Yoh K, Ishii G, Yokose T, Minegishi Y, Tsuta K, Goto K, et al. Breast cancer resistance protein impacts clinical outcome in platinum-based chemotherapy for advanced non-small cell lung cancer. Clin Cancer Res. 2004;10:1691–7.PubMedCrossRefGoogle Scholar
  11. 11.
    Ota S, Ishii G, Goto K, Kubota K, Kim YH, Kojika M, et al. Immunohistochemical expression of BCRP and ERCC1 in biopsy specimen predicts survival in advanced non-small-cell lung cancer treated with cisplatin-based chemotherapy. Lung Cancer. 2009;64:98–104.PubMedCrossRefGoogle Scholar
  12. 12.
    Lee SH, Kim H, Hwang JH, Lee HS, Cho JY, Yoon YS, et al. Breast cancer resistance protein expression is associated with early recurrence and decreased survival in resectable pancreatic cancer patients. Pathol Int. 2012;62:167–75.PubMedCrossRefGoogle Scholar
  13. 13.
    Stacy AE, Jansson PJ, Richardson DR. Molecular pharmacology of ABCG2 and its role in chemoresistance. Mol Pharmacol. 2013;84:655–69.PubMedCrossRefGoogle Scholar
  14. 14.
    Robey RW, Steadman K, Polgar O, Bates SE. ABCG2-mediated transport of photosensitizers: potential impact on photodynamic therapy. Cancer Biol Ther. 2005;4:187–94.PubMedCrossRefGoogle Scholar
  15. 15.
    Robey RW, Honjo Y, van de Laar A, Miyake K, Regis JT, Litman T, et al. A functional assay for detection of the mitoxantrone resistance protein, MXR (ABCG2). Biochim Biophys Acta. 2001;1512:171–82.PubMedCrossRefGoogle Scholar
  16. 16.
    Robey RW, Honjo Y, Morisaki K, Nadjem TA, Runge S, Risbood M, et al. Mutations at amino-acid 482 in the ABCG2 gene affect substrate and antagonist specificity. Br J Cancer. 2003;89:1971–8.PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Litman T, Brangi M, Hudson E, Fetsch P, Abati A, Ross DD, et al. The multidrug-resistant phenotype associated with overexpression of the new ABC half-transporter, MXR (ABCG2). J Cell Sci. 2000;113(Pt 11):2011–21.PubMedGoogle Scholar
  18. 18.
    Hazlehurst LA, Foley NE, Gleason-Guzman MC, Hacker MP, Cress AE, Greenberger LW, et al. Multiple mechanisms confer drug resistance to mitoxantrone in the human 8226 myeloma cell line. Cancer Res. 1999;59:1021–8.PubMedGoogle Scholar
  19. 19.
    Rabindran SK, Ross DD, Doyle LA, Yang W, Greenberger LM. Fumitremorgin C reverses multidrug resistance in cells transfected with the breast cancer resistance protein. Cancer Res. 2000;60:47–50.PubMedGoogle Scholar
  20. 20.
    Nakatomi K, Yoshikawa M, Oka M, Ikegami Y, Hayasaka S, Sano K, et al. Transport of 7-ethyl-10-hydroxycamptothecin (SN-38) by breast cancer resistance protein ABCG2 in human lung cancer cells. Biochem Biophys Res Commun. 2001;288:827–32.PubMedCrossRefGoogle Scholar
  21. 21.
    Rabindran SK, He H, Singh M, Brown E, Collins KI, Annable T, et al. Reversal of a novel multidrug resistance mechanism in human colon carcinoma cells by fumitremorgin C. Cancer Res. 1998;58:5850–8.PubMedGoogle Scholar
  22. 22.
    Maliepaard M, van Gastelen MA, Tohgo A, Hausheer FH, van Waardenburg RC, de Jong LA, et al. Circumvention of breast cancer resistance protein (BCRP)-mediated resistance to camptothecins in vitro using non-substrate drugs or the BCRP inhibitor GF120918. Clin Cancer Res. 2001;7:935–41.PubMedGoogle Scholar
  23. 23.
    Sparreboom A, Gelderblom H, Marsh S, Ahluwalia R, Obach R, Principe P, et al. Diflomotecan pharmacokinetics in relation to ABCG2 421C>A genotype. Clin Pharmacol Ther. 2004;76:38–44.PubMedCrossRefGoogle Scholar
  24. 24.
    Chen ZS, Robey RW, Belinsky MG, Shchaveleva I, Ren XQ, Sugimoto Y, et al. Transport of methotrexate, methotrexate polyglutamates, and 17beta-estradiol 17-(beta-D-glucuronide) by ABCG2: effects of acquired mutations at R482 on methotrexate transport. Cancer Res. 2003;63:4048–54.PubMedGoogle Scholar
  25. 25.
    Volk EL, Farley KM, Wu Y, Li F, Robey RW, Schneider E. Overexpression of wild-type breast cancer resistance protein mediates methotrexate resistance. Cancer Res. 2002;62:5035–40.PubMedGoogle Scholar
  26. 26.
    Volk EL, Schneider E. Wild-type breast cancer resistance protein (BCRP/ABCG2) is a methotrexate polyglutamate transporter. Cancer Res. 2003;63:5538–43.PubMedGoogle Scholar
  27. 27.
    Wang X, Furukawa T, Nitanda T, Okamoto M, Sugimoto Y, Akiyama S, et al. Breast cancer resistance protein (BCRP/ABCG2) induces cellular resistance to HIV-1 nucleoside reverse transcriptase inhibitors. Mol Pharmacol. 2003;63:65–72.PubMedCrossRefGoogle Scholar
  28. 28.
    Wang X, Nitanda T, Shi M, Okamoto M, Furukawa T, Sugimoto Y, et al. Induction of cellular resistance to nucleoside reverse transcriptase inhibitors by the wild-type breast cancer resistance protein. Biochem Pharmacol. 2004;68:1363–70.PubMedCrossRefGoogle Scholar
  29. 29.
    Nakagawa R, Hara Y, Arakawa H, Nishimura S, Komatani H. ABCG2 confers resistance to indolocarbazole compounds by ATP-dependent transport. Biochem Biophys Res Commun. 2002;299:669–75.PubMedCrossRefGoogle Scholar
  30. 30.
    Robey RW, Medina-Perez WY, Nishiyama K, Lahusen T, Miyake K, Litman T, et al. Overexpression of the ATP-binding cassette half-transporter, ABCG2 (Mxr/BCrp/ABCP1), in flavopiridol-resistant human breast cancer cells. Clin Cancer Res. 2001;7:145–52.PubMedGoogle Scholar
  31. 31.
    Erlichman C, Boerner SA, Hallgren CG, Spieker R, Wang XY, James CD, et al. The HER tyrosine kinase inhibitor CI1033 enhances cytotoxicity of 7-ethyl-10-hydroxycamptothecin and topotecan by inhibiting breast cancer resistance protein-mediated drug efflux. Cancer Res. 2001;61:739–48.PubMedGoogle Scholar
  32. 32.
    Burger H, van Tol H, Boersma AW, Brok M, Wiemer EA, Stoter G, et al. Imatinib mesylate (STI571) is a substrate for the breast cancer resistance protein (BCRP)/ABCG2 drug pump. Blood. 2004;104:2940–2.PubMedCrossRefGoogle Scholar
  33. 33.
    Elkind NB, Szentpetery Z, Apati A, Ozvegy-Laczka C, Varady G, Ujhelly O, et al. Multidrug transporter ABCG2 prevents tumor cell death induced by the epidermal growth factor receptor inhibitor Iressa (ZD1839, Gefitinib). Cancer Res. 2005;65:1770–7.PubMedCrossRefGoogle Scholar
  34. 34.
    Brendel C, Scharenberg C, Dohse M, Robey RW, Bates SE, Shukla S, et al. Imatinib mesylate and nilotinib (AMN107) exhibit high-affinity interaction with ABCG2 on primitive hematopoietic stem cells. Leukemia. 2007;21:1267–75.PubMedCrossRefGoogle Scholar
  35. 35.
    Zhou L, Naraharisetti SB, Wang H, Unadkat JD, Hebert MF, Mao Q. The breast cancer resistance protein (Bcrp1/Abcg2) limits fetal distribution of glyburide in the pregnant mouse: an Obstetric-Fetal Pharmacology Research Unit Network and University of Washington Specialized Center of Research Study. Mol Pharmacol. 2008;73:949–59.PubMedCrossRefGoogle Scholar
  36. 36.
    Pavek P, Merino G, Wagenaar E, Bolscher E, Novotna M, Jonker JW, et al. Human breast cancer resistance protein: interactions with steroid drugs, hormones, the dietary carcinogen 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine, and transport of cimetidine. J Pharmacol Exp Ther. 2005;312:144–52.PubMedCrossRefGoogle Scholar
  37. 37.
    van der Heijden J, de Jong MC, Dijkmans BA, Lems WF, Oerlemans R, Kathmann I, et al. Development of sulfasalazine resistance in human T cells induces expression of the multidrug resistance transporter ABCG2 (BCRP) and augmented production of TNFalpha. Ann Rheum Dis. 2004;63:138–43.PubMedCentralPubMedCrossRefGoogle Scholar
  38. 38.
    Merino G, Jonker JW, Wagenaar E, van Herwaarden AE, Schinkel AH. The breast cancer resistance protein (BCRP/ABCG2) affects pharmacokinetics, hepatobiliary excretion, and milk secretion of the antibiotic nitrofurantoin. Mol Pharmacol. 2005;67:1758–64.PubMedCrossRefGoogle Scholar
  39. 39.
    Kitamura S, Maeda K, Wang Y, Sugiyama Y. Involvement of multiple transporters in the hepatobiliary transport of rosuvastatin. Drug Metab Dispos. 2008;36:2014–23.PubMedCrossRefGoogle Scholar
  40. 40.
    Breedveld P, Zelcer N, Pluim D, Sonmezer O, Tibben MM, Beijnen JH, et al. Mechanism of the pharmacokinetic interaction between methotrexate and benzimidazoles: potential role for breast cancer resistance protein in clinical drug-drug interactions. Cancer Res. 2004;64:5804–11.PubMedCrossRefGoogle Scholar
  41. 41.
    Yoshikawa M, Ikegami Y, Hayasaka S, Ishii K, Ito A, Sano K, et al. Novel camptothecin analogues that circumvent ABCG2-associated drug resistance in human tumor cells. Int J Cancer. 2004;110:921–7.PubMedCrossRefGoogle Scholar
  42. 42.
    Hazai E, Hazai I, Ragueneau-Majlessi I, Chung SP, Bikadi Z, Mao Q. Predicting substrates of the human breast cancer resistance protein using a support vector machine method. BMC Bioinforma. 2013;14:130.CrossRefGoogle Scholar
  43. 43.
    Ozvegy-Laczka C, Hegedus T, Varady G, Ujhelly O, Schuetz JD, Varadi A, et al. High-affinity interaction of tyrosine kinase inhibitors with the ABCG2 multidrug transporter. Mol Pharmacol. 2004;65:1485–95.PubMedCrossRefGoogle Scholar
  44. 44.
    Houghton PJ, Germain GS, Harwood FC, Schuetz JD, Stewart CF, Buchdunger E, et al. Imatinib mesylate is a potent inhibitor of the ABCG2 (BCRP) transporter and reverses resistance to topotecan and SN-38 in vitro. Cancer Res. 2004;64:2333–7.PubMedCrossRefGoogle Scholar
  45. 45.
    Shi Z, Peng XX, Kim IW, Shukla S, Si QS, Robey RW, et al. Erlotinib (Tarceva, OSI-774) antagonizes ATP-binding cassette subfamily B member 1 and ATP-binding cassette subfamily G member 2-mediated drug resistance. Cancer Res. 2007;67:11012–20.PubMedCrossRefGoogle Scholar
  46. 46.
    Hegedus C, Ozvegy-Laczka C, Apati A, Magocsi M, Nemet K, Orfi L, et al. Interaction of nilotinib, dasatinib and bosutinib with ABCB1 and ABCG2: implications for altered anti-cancer effects and pharmacological properties. Br J Pharmacol. 2009;158:1153–64.PubMedCentralPubMedCrossRefGoogle Scholar
  47. 47.
    Dai CL, Tiwari AK, Wu CP, Su XD, Wang SR, Liu DG, et al. Lapatinib (Tykerb, GW572016) reverses multidrug resistance in cancer cells by inhibiting the activity of ATP-binding cassette subfamily B member 1 and G member 2. Cancer Res. 2008;68:7905–14.PubMedCentralPubMedCrossRefGoogle Scholar
  48. 48.
    Gupta A, Zhang Y, Unadkat JD, Mao Q. HIV protease inhibitors are inhibitors but not substrates of the human breast cancer resistance protein (BCRP/ABCG2). J Pharmacol Exp Ther. 2004;310:334–41.PubMedCrossRefGoogle Scholar
  49. 49.
    Weiss J, Rose J, Storch CH, Ketabi-Kiyanvash N, Sauer A, Haefeli WE, et al. Modulation of human BCRP (ABCG2) activity by anti-HIV drugs. J Antimicrob Chemother. 2007;59:238–45.PubMedCrossRefGoogle Scholar
  50. 50.
    Chu X, Cai X, Cui D, Tang C, Ghosal A, Chan G, et al. In vitro assessment of drug-drug interaction potential of boceprevir associated with drug metabolizing enzymes and transporters. Drug Metab Dispos. 2013;41:668–81.PubMedCrossRefGoogle Scholar
  51. 51.
    Fujita Y, Noguchi K, Suzuki T, Katayama K, Sugimoto Y. Biochemical interaction of anti-HCV telaprevir with the ABC transporters P-glycoprotein and breast cancer resistance protein. BMC Res Notes. 2013;6:445.PubMedCentralPubMedCrossRefGoogle Scholar
  52. 52.
    Zhang Y, Gupta A, Wang H, Zhou L, Vethanayagam RR, Unadkat JD, et al. BCRP transports dipyridamole and is inhibited by calcium channel blockers. Pharm Res. 2005;22:2023–34.PubMedCrossRefGoogle Scholar
  53. 53.
    Gupta A, Unadkat JD, Mao Q. Interactions of azole antifungal agents with the human breast cancer resistance protein (BCRP). J Pharm Sci. 2007;96:3226–35.PubMedCrossRefGoogle Scholar
  54. 54.
    Yang CH, Chen YC, Kuo ML. Novobiocin sensitizes BCRP/MXR/ABCP overexpressing topotecan-resistant human breast carcinoma cells to topotecan and mitoxantrone. Anticancer Res. 2003;23:2519–23.PubMedGoogle Scholar
  55. 55.
    Shiozawa K, Oka M, Soda H, Yoshikawa M, Ikegami Y, Tsurutani J, et al. Reversal of breast cancer resistance protein (BCRP/ABCG2)-mediated drug resistance by novobiocin, a coumermycin antibiotic. Int J Cancer. 2004;108:146–51.PubMedCrossRefGoogle Scholar
  56. 56.
    Sugimoto Y, Tsukahara S, Imai Y, Ueda K, Tsuruo T. Reversal of breast cancer resistance protein-mediated drug resistance by estrogen antagonists and agonists. Mol Cancer Ther. 2003;2:105–12.PubMedGoogle Scholar
  57. 57.
    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;7:1028–34.PubMedCrossRefGoogle Scholar
  58. 58.
    de Bruin M, Miyake K, Litman T, Robey R, Bates SE. Reversal of resistance by GF120918 in cell lines expressing the ABC half-transporter, MXR. Cancer Lett. 1999;146:117–26.PubMedCrossRefGoogle Scholar
  59. 59.
    Wu CP, Hsiao SH, Sim HM, Luo SY, Tuo WC, Cheng HW, et al. Human ABCB1 (P-glycoprotein) and ABCG2 mediate resistance to BI 2536, a potent and selective inhibitor of Polo-like kinase 1. Biochem Pharmacol. 2013;86:904–13.PubMedCentralPubMedCrossRefGoogle Scholar
  60. 60.
    van Loevezijn A, Allen JD, Schinkel AH, Koomen GJ. Inhibition of BCRP-mediated drug efflux by fumitremorgin-type indolyl diketopiperazines. Bioorg Med Chem Lett. 2001;11:29–32.PubMedCrossRefGoogle Scholar
  61. 61.
    Minderman H, O’Loughlin KL, Pendyala L, Baer MR. VX-710 (biricodar) increases drug retention and enhances chemosensitivity in resistant cells overexpressing P-glycoprotein, multidrug resistance protein, and breast cancer resistance protein. Clin Cancer Res. 2004;10:1826–34.PubMedCrossRefGoogle Scholar
  62. 62.
    Woehlecke H, Osada H, Herrmann A, Lage H. Reversal of breast cancer resistance protein-mediated drug resistance by tryprostatin A. Int J Cancer. 2003;107:721–8.PubMedCrossRefGoogle Scholar
  63. 63.
    Zhang S, Yang X, Morris ME. Flavonoids are inhibitors of breast cancer resistance protein (ABCG2)-mediated transport. Mol Pharmacol. 2004;65:1208–16.PubMedCrossRefGoogle Scholar
  64. 64.
    Kuhnle M, Egger M, Muller C, Mahringer A, Bernhardt G, Fricker G, et al. Potent and selective inhibitors of breast cancer resistance protein (ABCG2) derived from the p-glycoprotein (ABCB1) modulator tariquidar. J Med Chem. 2009;52:1190–7.PubMedCrossRefGoogle Scholar
  65. 65.
    Valdameri G, Genoux-Bastide E, Peres B, Gauthier C, Guitton J, Terreux R, et al. Substituted chromones as highly potent nontoxic inhibitors, specific for the breast cancer resistance protein. J Med Chem. 2012;55:966–70.PubMedCrossRefGoogle Scholar
  66. 66.
    Giri N, Agarwal S, Shaik N, Pan G, Chen Y, Elmquist WF. Substrate-dependent breast cancer resistance protein (Bcrp1/Abcg2)-mediated interactions: consideration of multiple binding sites in in vitro assay design. Drug Metab Dispos. 2009;37:560–70.PubMedCentralPubMedCrossRefGoogle Scholar
  67. 67.
    Pan Y, Chothe PP, Swaan PW. Identification of novel breast cancer resistance protein (BCRP) inhibitors by virtual screening. Mol Pharm. 2013;10:1236–48.PubMedCrossRefGoogle Scholar
  68. 68.
    Bikadi Z, Hazai I, Malik D, Jemnitz K, Veres Z, Hari P, et al. Predicting P-glycoprotein-mediated drug transport based on support vector machine and three-dimensional crystal structure of P-glycoprotein. PLoS One. 2011;6:e25815.PubMedCentralPubMedCrossRefGoogle Scholar
  69. 69.
    Ishikawa T, Hirano H, Saito H, Sano K, Ikegami Y, Yamaotsu N, et al. Quantitative structure-activity relationship (QSAR) analysis to predict drug-drug interactions of ABC transporter ABCG2. Mini-Rev Med Chem. 2012;12:505–14.PubMedCrossRefGoogle Scholar
  70. 70.
    Gandhi YA, Morris ME. Structure-activity relationships and quantitative structure-activity relationships for breast cancer resistance protein (ABCG2). AAPS J. 2009;11:541–52.PubMedCentralPubMedCrossRefGoogle Scholar
  71. 71.
    Nicolle E, Boumendjel A, Macalou S, Genoux E, Ahmed-Belkacem A, Carrupt PA, et al. QSAR analysis and molecular modeling of ABCG2-specific inhibitors. Adv Drug Deliv Rev. 2009;61:34–46.PubMedCrossRefGoogle Scholar
  72. 72.
    Zhang S, Yang X, Coburn RA, Morris ME. Structure activity relationships and quantitative structure activity relationships for the flavonoid-mediated inhibition of breast cancer resistance protein. Biochem Pharmacol. 2005;70:627–39.PubMedCrossRefGoogle Scholar
  73. 73.
    Pick A, Muller H, Wiese M. Structure-activity relationships of new inhibitors of breast cancer resistance protein (ABCG2). Bioorg Med Chem. 2008;16:8224–36.PubMedCrossRefGoogle Scholar
  74. 74.
    Ni Z, Bikadi Z, Rosenberg MF, Mao Q. Structure and function of the human breast cancer resistance protein (BCRP/ABCG2). Curr Drug Metab. 2010;11:603–17.PubMedCentralPubMedCrossRefGoogle Scholar
  75. 75.
    Marks DS, Hopf TA, Sander C. Protein structure prediction from sequence variation. Nat Biotechnol. 2012;30:1072–80.PubMedCentralPubMedCrossRefGoogle Scholar
  76. 76.
    Wang H, Lee EW, Cai X, Ni Z, Zhou L, Mao Q. Membrane topology of the human breast cancer resistance protein (BCRP/ABCG2) determined by epitope insertion and immunofluorescence. Biochemistry. 2008;47:13778–87.PubMedCentralPubMedCrossRefGoogle Scholar
  77. 77.
    Mohrmann K, van Eijndhoven MA, Schinkel AH, Schellens JH. Absence of N-linked glycosylation does not affect plasma membrane localization of breast cancer resistance protein (BCRP/ABCG2). Cancer Chemother Pharmacol. 2005;56:344–50.PubMedCrossRefGoogle Scholar
  78. 78.
    Popov M, Tam LY, Li J, Reithmeier RA. Mapping the ends of transmembrane segments in a polytopic membrane protein. Scanning N-glycosylation mutagenesis of extracytosolic loops in the anion exchanger, band 3. J Biol Chem. 1997;272:18325–32.PubMedCrossRefGoogle Scholar
  79. 79.
    Xu J, Liu Y, Yang Y, Bates S, Zhang JT. Characterization of oligomeric human half-ABC transporter ATP-binding cassette G2. J Biol Chem. 2004;279:19781–9.PubMedCrossRefGoogle Scholar
  80. 80.
    McDevitt CA, Collins RF, Conway M, Modok S, Storm J, Kerr ID, et al. Purification and 3D structural analysis of oligomeric human multidrug transporter ABCG2. Structure. 2006;14:1623–32.PubMedCrossRefGoogle Scholar
  81. 81.
    Rosenberg MF, Bikadi Z, Chan J, Liu X, Ni Z, Cai X, et al. The human breast cancer resistance protein (BCRP/ABCG2) shows conformational changes with mitoxantrone. Structure. 2010;18:482–93.PubMedCentralPubMedCrossRefGoogle Scholar
  82. 82.
    Ni Z, Mark ME, Cai X, Mao Q. Fluorescence resonance energy transfer (FRET) analysis demonstrates dimer/oligomer formation of the human breast cancer resistance protein (BCRP/ABCG2) in intact cells. Int J Biochem Mol Biol. 2010;1:1–15.PubMedCentralPubMedCrossRefGoogle Scholar
  83. 83.
    Haider AJ, Briggs D, Self TJ, Chilvers HL, Holliday ND, Kerr ID. Dimerization of ABCG2 analysed by bimolecular fluorescence complementation. PLoS One. 2011;6:e25818.PubMedCentralPubMedCrossRefGoogle Scholar
  84. 84.
    Kage K, Fujita T, Sugimoto Y. Role of Cys-603 in dimer/oligomer formation of the breast cancer resistance protein BCRP/ABCG2. Cancer Sci. 2005;96:866–72.PubMedCrossRefGoogle Scholar
  85. 85.
    Mitomo H, Kato R, Ito A, Kasamatsu S, Ikegami Y, Kii I, et al. A functional study on polymorphism of the ATP-binding cassette transporter ABCG2: critical role of arginine-482 in methotrexate transport. Biochem J. 2003;373:767–74.PubMedCentralPubMedCrossRefGoogle Scholar
  86. 86.
    Cai X, Bikadi Z, Ni Z, Lee EW, Wang H, Rosenberg MF, et al. Role of basic residues within or near the predicted transmembrane helix 2 of the human breast cancer resistance protein in drug transport. J Pharmacol Exp Ther. 2010;333:670–81.PubMedCentralPubMedCrossRefGoogle Scholar
  87. 87.
    Miwa M, Tsukahara S, Ishikawa E, Asada S, Imai Y, Sugimoto Y. Single amino acid substitutions in the transmembrane domains of breast cancer resistance protein (BCRP) alter cross resistance patterns in transfectants. Int J Cancer. 2003;107:757–63.PubMedCrossRefGoogle Scholar
  88. 88.
    Clark R, Kerr ID, Callaghan R. Multiple drugbinding sites on the R482G isoform of the ABCG2 transporter. Br J Pharmacol. 2006;149:506–15.PubMedCentralPubMedCrossRefGoogle Scholar
  89. 89.
    Ejendal KF, Diop NK, Schweiger LC, Hrycyna CA. The nature of amino acid 482 of human ABCG2 affects substrate transport and ATP hydrolysis but not substrate binding. Protein Sci. 2006;15:1597–607.PubMedCentralPubMedCrossRefGoogle Scholar
  90. 90.
    Li L, Sham YY, Bikadi Z, Elmquist WF. pH-dependent transport of pemetrexed by breast cancer resistance protein. Drug Metab Dispos. 2011;39:1478–85.PubMedCrossRefGoogle Scholar
  91. 91.
    Honjo Y, Hrycyna CA, Yan QW, Medina-Perez WY, Robey RW, van de Laar A, et al. Acquired mutations in the MXR/BCRP/ABCP gene alter substrate specificity in MXR/BCRP/ABCP-overexpressing cells. Cancer Res. 2001;61:6635–9.PubMedGoogle Scholar
  92. 92.
    Ni Z, Bikadi Z, Cai X, Rosenberg MF, Mao Q. Transmembrane helices 1 and 6 of the human breast cancer resistance protein (BCRP/ABCG2): identification of polar residues important for drug transport. Am J Physiol Cell Physiol. 2010;299:C1100–9.PubMedCentralPubMedCrossRefGoogle Scholar
  93. 93.
    Polgar O, Ierano C, Tamaki A, Stanley B, Ward Y, Xia D, et al. Mutational analysis of threonine 402 adjacent to the GXXXG dimerization motif in transmembrane segment 1 of ABCG2. Biochemistry. 2010;49:2235–45.PubMedCentralPubMedCrossRefGoogle Scholar
  94. 94.
    Ni Z, Bikadi Z, Shuster DL, Zhao C, Rosenberg MF, Mao Q. Identification of proline residues in or near the transmembrane helices of the human breast cancer resistance protein (BCRP/ABCG2) that are important for transport activity and substrate specificity. Biochemistry. 2011;50:8057–66.PubMedCentralPubMedCrossRefGoogle Scholar
  95. 95.
    Kage K, Tsukahara S, Sugiyama T, Asada S, Ishikawa E, Tsuruo T, et al. Dominant-negative inhibition of breast cancer resistance protein as drug efflux pump through the inhibition of S-S dependent homodimerization. Int J Cancer. 2002;97:626–30.PubMedCrossRefGoogle Scholar
  96. 96.
    Ozvegy C, Varadi A, Sarkadi B. Characterization of drug transport, ATP hydrolysis, and nucleotide trapping by the human ABCG2 multidrug transporter. Modulation of substrate specificity by a point mutation. J Biol Chem. 2002;277:47980–90.PubMedCrossRefGoogle Scholar
  97. 97.
    Henriksen U, Gether U, Litman T. Effect of walker A mutation (K86M) on oligomerization and surface targeting of the multidrug resistance transporter ABCG2. J Cell Sci. 2005;118:1417–26.PubMedCrossRefGoogle Scholar
  98. 98.
    Hou YX, Li CZ, Palaniyandi K, Magtibay PM, Homolya L, Sarkadi B, et al. Effects of putative catalytic base mutation E211Q on ABCG2-mediated methotrexate transport. Biochemistry. 2009;48:9122–31.PubMedCentralPubMedCrossRefGoogle Scholar
  99. 99.
    Shukla S, Robey RW, Bates SE, Ambudkar SV. The calcium channel blockers, 1,4-dihydropyridines, are substrates of the multidrug resistance-linked ABC drug transporter, ABCG2. Biochemistry. 2006;45:8940–51.PubMedCrossRefGoogle Scholar
  100. 100.
    Imai Y, Nakane M, Kage K, Tsukahara S, Ishikawa E, Tsuruo T, et al. C421A polymorphism in the human breast cancer resistance protein gene is associated with low expression of Q141K protein and low-level drug resistance. Mol Cancer Ther. 2002;1:611–6.PubMedGoogle Scholar
  101. 101.
    Vethanayagam RR, Wang H, Gupta A, Zhang Y, Lewis F, Unadkat JD, et al. Functional analysis of the human variants of breast cancer resistance protein: I206L, N590Y, and D620N. Drug Metab Dispos. 2005;33:697–705.PubMedCrossRefGoogle Scholar
  102. 102.
    Noguchi K, Katayama K, Sugimoto Y. Human ABC transporter ABCG2/BCRP expression in chemoresistance: basic and clinical perspectives for molecular cancer therapeutics. Pharmgenomics Pers Med. 2014;7:53–64.PubMedCentralPubMedGoogle Scholar
  103. 103.
    Maliepaard M, Scheffer GL, Faneyte IF, van Gastelen MA, Pijnenborg AC, Schinkel AH, et al. Subcellular localization and distribution of the breast cancer resistance protein transporter in normal human tissues. Cancer Res. 2001;61:3458–64.PubMedGoogle Scholar
  104. 104.
    Huls M, Brown CD, Windass AS, Sayer R, van den Heuvel JJ, Heemskerk S, et al. The breast cancer resistance protein transporter ABCG2 is expressed in the human kidney proximal tubule apical membrane. Kidney Int. 2008;73:220–5.PubMedCrossRefGoogle Scholar
  105. 105.
    Cooray HC, Blackmore CG, Maskell L, Barrand MA. Localisation of breast cancer resistance protein in microvessel endothelium of human brain. Neuroreport. 2002;13:2059–63.PubMedCrossRefGoogle Scholar
  106. 106.
    Asashima T, Hori S, Ohtsuki S, Tachikawa M, Watanabe M, Mukai C, et al. ATP-binding cassette transporter G2 mediates the efflux of phototoxins on the luminal membrane of retinal capillary endothelial cells. Pharm Res. 2006;23:1235–42.PubMedCrossRefGoogle Scholar
  107. 107.
    Robillard KR, Hoque T, Bendayan R. Expression of ATP-binding cassette membrane transporters in rodent and human Sertoli cells: relevance to the permeability of antiretroviral therapy at the blood-testis barrier. J Pharmacol Exp Ther. 2012;340:96–108.PubMedCrossRefGoogle Scholar
  108. 108.
    Jablonski MR, Jacob DA, Campos C, Miller DS, Maragakis NJ, Pasinelli P, et al. Selective increase of two ABC drug efflux transporters at the blood-spinal cord barrier suggests induced pharmacoresistance in ALS. Neurobiol Dis. 2012;47:194–200.PubMedCentralPubMedCrossRefGoogle Scholar
  109. 109.
    Vlaming ML, Lagas JS, Schinkel AH. Physiological and pharmacological roles of ABCG2 (BCRP): recent findings in Abcg2 knockout mice. Adv Drug Deliv Rev. 2009;61:14–25.PubMedCrossRefGoogle Scholar
  110. 110.
    Agarwal S, Sane R, Ohlfest JR, Elmquist WF. The role of the breast cancer resistance protein (ABCG2) in the distribution of sorafenib to the brain. J Pharmacol Exp Ther. 2011;336:223–33.PubMedCentralPubMedCrossRefGoogle Scholar
  111. 111.
    Polli JW, Olson KL, Chism JP, John-Williams LS, Yeager RL, Woodard SM, et al. An unexpected synergist role of P-glycoprotein and breast cancer resistance protein on the central nervous system penetration of the tyrosine kinase inhibitor lapatinib (N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methylsulfonyl)ethy l]amino}methyl)-2-furyl]-4-quinazolinamine; GW572016). Drug Metab Dispos. 2009;37:439–42.PubMedCrossRefGoogle Scholar
  112. 112.
    Kodaira H, Kusuhara H, Ushiki J, Fuse E, Sugiyama Y. Kinetic analysis of the cooperation of P-glycoprotein (P-gp/Abcb1) and breast cancer resistance protein (Bcrp/Abcg2) in limiting the brain and testis penetration of erlotinib, flavopiridol, and mitoxantrone. J Pharmacol Exp Ther. 2010;333:788–96.PubMedCrossRefGoogle Scholar
  113. 113.
    Zhang Y, Wang H, Unadkat JD, Mao Q. Breast cancer resistance protein 1 limits fetal distribution of nitrofurantoin in the pregnant mouse. Drug Metab Dispos. 2007;35:2154–8.PubMedCrossRefGoogle Scholar
  114. 114.
    Ni Z, Mao Q. ATP-binding cassette efflux transporters in human placenta. Curr Pharm Biotechnol. 2011;12:674–85.PubMedCentralPubMedCrossRefGoogle Scholar
  115. 115.
    Jonker JW, Merino G, Musters S, van Herwaarden AE, Bolscher E, Wagenaar E, et al. The breast cancer resistance protein BCRP (ABCG2) concentrates drugs and carcinogenic xenotoxins into milk. Nat Med. 2005;11:127–9.PubMedCrossRefGoogle Scholar
  116. 116.
    van Herwaarden AE, Wagenaar E, Merino G, Jonker JW, Rosing H, Beijnen JH, et al. Multidrug transporter ABCG2/breast cancer resistance protein secretes riboflavin (vitamin B2) into milk. Mol Cell Biol. 2007;27:1247–53.PubMedCentralPubMedCrossRefGoogle Scholar
  117. 117.
    Kruijtzer CM, Beijnen JH, Rosing H, ten Bokkel Huinink WW, Schot M, Jewell RC, et al. Increased oral bioavailability of topotecan in combination with the breast cancer resistance protein and P-glycoprotein inhibitor GF120918. J Clin Oncol. 2002;20:2943–50.PubMedCrossRefGoogle Scholar
  118. 118.
    Kim KA, Joo HJ, Park JY. Effect of ABCG2 genotypes on the pharmacokinetics of A771726, an active metabolite of prodrug leflunomide, and association of A771726 exposure with serum uric acid level. Eur J Clin Pharmacol. 2011;67:129–34.PubMedCrossRefGoogle Scholar
  119. 119.
    Zamboni WC, Ramanathan RK, McLeod HL, Mani S, Potter DM, Strychor S, et al. Disposition of 9-nitrocamptothecin and its 9-aminocamptothecin metabolite in relation to ABC transporter genotypes. Investig New Drugs. 2006;24:393–401.CrossRefGoogle Scholar
  120. 120.
    Yamasaki Y, Ieiri I, Kusuhara H, Sasaki T, Kimura M, Tabuchi H, et al. Pharmacogenetic characterization of sulfasalazine disposition based on NAT2 and ABCG2 (BCRP) gene polymorphisms in humans. Clin Pharmacol Ther. 2008;84:95–103.PubMedCrossRefGoogle Scholar
  121. 121.
    Urquhart BL, Ware JA, Tirona RG, Ho RH, Leake BF, Schwarz UI, et al. Breast cancer resistance protein (ABCG2) and drug disposition: intestinal expression, polymorphisms and sulfasalazine as an in vivo probe. Pharmacogenet Genomics. 2008;18:439–48.PubMedCentralPubMedCrossRefGoogle Scholar
  122. 122.
    Li J, Cusatis G, Brahmer J, Sparreboom A, Robey RW, Bates SE, et al. Association of variant ABCG2 and the pharmacokinetics of epidermal growth factor receptor tyrosine kinase inhibitors in cancer patients. Cancer Biol Ther. 2007;6:432–8.PubMedCrossRefGoogle Scholar
  123. 123.
    Mizuno T, Fukudo M, Terada T, Kamba T, Nakamura E, Ogawa O, et al. Impact of genetic variation in breast cancer resistance protein (BCRP/ABCG2) on sunitinib pharmacokinetics. Drug Metab Pharmacokinet. 2012;27:631–9.PubMedCrossRefGoogle Scholar
  124. 124.
    Takahashi N, Miura M, Scott SA, Kagaya H, Kameoka Y, Tagawa H, et al. Influence of CYP3A5 and drug transporter polymorphisms on imatinib trough concentration and clinical response among patients with chronic phase chronic myeloid leukemia. J Hum Genet. 2010;55:731–7.PubMedCrossRefGoogle Scholar
  125. 125.
    Zhang W, Yu BN, He YJ, Fan L, Li Q, Liu ZQ, et al. Role of BCRP 421C>A polymorphism on rosuvastatin pharmacokinetics in healthy Chinese males. Clin Chim Acta. 2006;373:99–103.PubMedCrossRefGoogle Scholar
  126. 126.
    Zhou Q, Ruan ZR, Yuan H, Xu DH, Zeng S. ABCB1 gene polymorphisms, ABCB1 haplotypes and ABCG2 c.421c>A are determinants of inter-subject variability in rosuvastatin pharmacokinetics. Die Pharmazie. 2013;68:129–34.PubMedGoogle Scholar
  127. 127.
    Lee HK, Hu M, Lui S, Ho CS, Wong CK, Tomlinson B. Effects of polymorphisms in ABCG2, SLCO1B1, SLC10A1 and CYP2C9/19 on plasma concentrations of rosuvastatin and lipid response in Chinese patients. Pharmacogenomics. 2013;14:1283–94.PubMedCrossRefGoogle Scholar
  128. 128.
    Keskitalo JE, Zolk O, Fromm MF, Kurkinen KJ, Neuvonen PJ, Niemi M. ABCG2 polymorphism markedly affects the pharmacokinetics of atorvastatin and rosuvastatin. Clin Pharmacol Ther. 2009;86:197–203.PubMedCrossRefGoogle Scholar
  129. 129.
    Keskitalo JE, Pasanen MK, Neuvonen PJ, Niemi M. Different effects of the ABCG2 c.421C>A SNP on the pharmacokinetics of fluvastatin, pravastatin and simvastatin. Pharmacogenomics. 2009;10:1617–24.PubMedCrossRefGoogle Scholar
  130. 130.
    Jada SR, Lim R, Wong CI, Shu X, Lee SC, Zhou Q, et al. Role of UGT1A1*6, UGT1A1*28 and ABCG2 c.421C>A polymorphisms in irinotecan-induced neutropenia in Asian cancer patients. Cancer Sci. 2007;98:1461–7.PubMedCrossRefGoogle Scholar
  131. 131.
    de Jong FA, Marsh S, Mathijssen RH, King C, Verweij J, Sparreboom A, et al. ABCG2 pharmacogenetics: ethnic differences in allele frequency and assessment of influence on irinotecan disposition. Clin Cancer Res. 2004;10:5889–94.PubMedCrossRefGoogle Scholar
  132. 132.
    Han JY, Lim HS, Yoo YK, Shin ES, Park YH, Lee SY, et al. Associations of ABCB1, ABCC2, and ABCG2 polymorphisms with irinotecan-pharmacokinetics and clinical outcome in patients with advanced non-small cell lung cancer. Cancer. 2007;110:138–47.PubMedCrossRefGoogle Scholar
  133. 133.
    Sparreboom A, Loos WJ, Burger H, Sissung TM, Verweij J, Figg WD, et al. Effect of ABCG2 genotype on the oral bioavailability of topotecan. Cancer Biol Ther. 2005;4:650–8.PubMedCrossRefGoogle Scholar
  134. 134.
    Rudin CM, Liu W, Desai A, Karrison T, Jiang X, Janisch L, et al. Pharmacogenomic and pharmacokinetic determinants of erlotinib toxicity. J Clin Oncol. 2008;26:1119–27.PubMedCrossRefGoogle Scholar
  135. 135.
    Steeghs N, Gelderblom H, Wessels J, Eskens FA, de Bont N, Nortier JW, et al. Pharmacogenetics of telatinib, a VEGFR-2 and VEGFR-3 tyrosine kinase inhibitor, used in patients with solid tumors. Investig New Drugs. 2011;29:137–43.CrossRefGoogle Scholar
  136. 136.
    Chew SC, Singh O, Chen X, Ramasamy RD, Kulkarni T, Lee EJ, et al. The effects of CYP3A4, CYP3A5, ABCB1, ABCC2, ABCG2 and SLCO1B3 single nucleotide polymorphisms on the pharmacokinetics and pharmacodynamics of docetaxel in nasopharyngeal carcinoma patients. Cancer Chemother Pharmacol. 2011;67:1471–8.PubMedCrossRefGoogle Scholar
  137. 137.
    Yamakawa Y, Hamada A, Nakashima R, Yuki M, Hirayama C, Kawaguchi T, et al. Association of genetic polymorphisms in the influx transporter SLCO1B3 and the efflux transporter ABCB1 with imatinib pharmacokinetics in patients with chronic myeloid leukemia. Ther Drug Monit. 2011;33:244–50.PubMedGoogle Scholar
  138. 138.
    Seong SJ, Lim M, Sohn SK, Moon JH, Oh SJ, Kim BS, et al. Influence of enzyme and transporter polymorphisms on trough imatinib concentration and clinical response in chronic myeloid leukemia patients. Ann Oncol. 2013;24:756–60.PubMedCrossRefGoogle Scholar
  139. 139.
    Steeghs N, Mathijssen RH, Wessels JA, de Graan AJ, van der Straaten T, Mariani M, et al. Influence of pharmacogenetic variability on the pharmacokinetics and toxicity of the aurora kinase inhibitor danusertib. Investig New Drugs. 2011;29:953–62.CrossRefGoogle Scholar
  140. 140.
    Zhou Q, Ruan ZR, Yuan H, Zeng S. CYP2C9*3(1075A>C), MDR1 G2677T/A and MDR1 C3435T are determinants of inter-subject variability in fluvastatin pharmacokinetics in healthy Chinese volunteers. Arzneimittelforschung. 2012;62:519–24.PubMedCrossRefGoogle Scholar
  141. 141.
    Zhou Q, Ruan ZR, Jiang B, Yuan H, Zeng S. Simvastatin pharmacokinetics in healthy Chinese subjects and its relations with CYP2C9, CYP3A5, ABCB1, ABCG2 and SLCO1B1 polymorphisms. Die Pharmazie. 2013;68:124–8.PubMedGoogle Scholar
  142. 142.
    Ieiri I, Suwannakul S, Maeda K, Uchimaru H, Hashimoto K, Kimura M, et al. SLCO1B1 (OATP1B1, an uptake transporter) and ABCG2 (BCRP, an efflux transporter) variant alleles and pharmacokinetics of pitavastatin in healthy volunteers. Clin Pharmacol Ther. 2007;82:541–7.PubMedCrossRefGoogle Scholar
  143. 143.
    Zhou Q, Chen QX, Ruan ZR, Yuan H, Xu HM, Zeng S. CYP2C9*3(1075A>C), ABCB1 and SLCO1B1 genetic polymorphisms and gender are determinants of inter-subject variability in pitavastatin pharmacokinetics. Die Pharmazie. 2013;68:187–94.PubMedGoogle Scholar
  144. 144.
    Oh ES, Kim CO, Cho SK, Park MS, Chung JY. Impact of ABCC2, ABCG2 and SLCO1B1 polymorphisms on the pharmacokinetics of pitavastatin in humans. Drug Metab Pharmacokinet. 2013;28:196–202.PubMedCrossRefGoogle Scholar
  145. 145.
    Adkison KK, Vaidya SS, Lee DY, Koo SH, Li L, Mehta AA, et al. The ABCG2 C421A polymorphism does not affect oral nitrofurantoin pharmacokinetics in healthy Chinese male subjects. Br J Clin Pharmacol. 2008;66:233–9.PubMedCentralPubMedCrossRefGoogle Scholar
  146. 146.
    Adkison KK, Vaidya SS, Lee DY, Koo SH, Li L, Mehta AA, et al. Oral sulfasalazine as a clinical BCRP probe substrate: pharmacokinetic effects of genetic variation (C421A) and pantoprazole coadministration. J Pharm Sci. 2010;99:1046–62.PubMedGoogle Scholar
  147. 147.
    Yamada A, Maeda K, Ishiguro N, Tsuda Y, Igarashi T, Ebner T, et al. The impact of pharmacogenetics of metabolic enzymes and transporters on the pharmacokinetics of telmisartan in healthy volunteers. Pharmacogenet Genomics. 2011;21:523–30.PubMedCrossRefGoogle Scholar
  148. 148.
    Chen WQ, Shu Y, Li Q, Xu LY, Roederer MW, Fan L, et al. Polymorphism of ORM1 is associated with the pharmacokinetics of telmisartan. PLoS One. 2013;8:e70341.PubMedCentralPubMedCrossRefGoogle Scholar
  149. 149.
    Kim CO, Cho SK, Oh ES, Park MS, Chung JY. Influence of ABCC2, SLCO1B1, and ABCG2 polymorphisms on the pharmacokinetics of olmesartan. J Cardiovasc Pharmacol. 2012;60:49–54.PubMedCrossRefGoogle Scholar
  150. 150.
    Ogasawara K, Chitnis SD, Gohh RY, Christians U, Akhlaghi F. Multidrug resistance-associated protein 2 (MRP2/ABCC2) haplotypes significantly affect the pharmacokinetics of tacrolimus in kidney transplant recipients. Clin Pharmacokinet. 2013;52:751–62.PubMedCentralPubMedCrossRefGoogle Scholar
  151. 151.
    Kim HS, Sunwoo YE, Ryu JY, Kang HJ, Jung HE, Song IS, et al. The effect of ABCG2 V12M, Q141K and Q126X, known functional variants in vitro, on the disposition of lamivudine. Br J Clin Pharmacol. 2007;64:645–54.PubMedCentralPubMedCrossRefGoogle Scholar
  152. 152.
    Giacomini KM, Huang SM, Tweedie DJ, Benet LZ, Brouwer KL, Chu X, et al. Membrane transporters in drug development. Nat Rev Drug Discov. 2010;9:215–36.PubMedCrossRefGoogle Scholar
  153. 153.
    Pham PA, la Porte CJ, Lee LS, van Heeswijk R, Sabo JP, Elgadi MM, et al. Differential effects of tipranavir plus ritonavir on atorvastatin or rosuvastatin pharmacokinetics in healthy volunteers. Antimicrob Agents Chemother. 2009;53:4385–92.PubMedCentralPubMedCrossRefGoogle Scholar
  154. 154.
    Busti AJ, Bain AM, Hall 2nd RG, Bedimo RG, Leff RD, Meek C, et al. Effects of atazanavir/ritonavir or fosamprenavir/ritonavir on the pharmacokinetics of rosuvastatin. J Cardiovasc Pharmacol. 2008;51:605–10.PubMedCrossRefGoogle Scholar
  155. 155.
    Kiser JJ, Gerber JG, Predhomme JA, Wolfe P, Flynn DM, Hoody DW. Drug/drug interaction between lopinavir/ritonavir and rosuvastatin in healthy volunteers. J Acquir Immune Defic Syndr. 2008;47:570–8.PubMedCrossRefGoogle Scholar
  156. 156.
    Simonson SG, Raza A, Martin PD, Mitchell PD, Jarcho JA, Brown CD, et al. Rosuvastatin pharmacokinetics in heart transplant recipients administered an antirejection regimen including cyclosporine. Clin Pharmacol Ther. 2004;76:167–77.PubMedCrossRefGoogle Scholar
  157. 157.
    Allred AJ, Bowen CJ, Park JW, Peng B, Williams DD, Wire MB, et al. Eltrombopag increases plasma rosuvastatin exposure in healthy volunteers. Br J Clin Pharmacol. 2011;72:321–9.PubMedCentralPubMedCrossRefGoogle Scholar
  158. 158.
    Takeuchi K, Sugiura T, Matsubara K, Sato R, Shimizu T, Masuo Y, et al. Interaction of novel platelet-increasing agent eltrombopag with rosuvastatin via breast cancer resistance protein in humans. Drug Metab Dispos. 2014;42:726–34.PubMedCrossRefGoogle Scholar
  159. 159.
    Polli JW, Hussey E, Bush M, Generaux G, Smith G, Collins D, et al. Evaluation of drug interactions of GSK1292263 (a GPR119 agonist) with statins: from in vitro data to clinical study design. Xenobiotica. 2013;43:498–508.PubMedCrossRefGoogle Scholar
  160. 160.
    Kusuhara H, Furuie H, Inano A, Sunagawa A, Yamada S, Wu C, et al. Pharmacokinetic interaction study of sulphasalazine in healthy subjects and the impact of curcumin as an in vivo inhibitor of BCRP. Br J Pharmacol. 2012;166:1793–803.PubMedCentralPubMedCrossRefGoogle Scholar
  161. 161.
    Suzuki K, Doki K, Homma M, Tamaki H, Hori S, Ohtani H, et al. Co-administration of proton pump inhibitors delays elimination of plasma methotrexate in high-dose methotrexate therapy. Br J Clin Pharmacol. 2009;67:44–9.PubMedCentralPubMedCrossRefGoogle Scholar
  162. 162.
    Ranchon F, Vantard N, Gouraud A, Schwiertz V, Franchon E, Pham BN, et al. Suspicion of drug-drug interaction between high-dose methotrexate and proton pump inhibitors: a case report—should the practice be changed? Chemotherapy. 2011;57:225–9.PubMedCrossRefGoogle Scholar
  163. 163.
    Watanabe T, Kusuhara H, Maeda K, Shitara Y, Sugiyama Y. Physiologically based pharmacokinetic modeling to predict transporter-mediated clearance and distribution of pravastatin in humans. J Pharmacol Exp Ther. 2009;328:652–62.PubMedCrossRefGoogle Scholar
  164. 164.
    Huang L, Wang Y, Grimm S. ATP-dependent transport of rosuvastatin in membrane vesicles expressing breast cancer resistance protein. Drug Metab Dispos. 2006;34:738–42.PubMedCrossRefGoogle Scholar
  165. 165.
    Prasad B, Lai Y, Lin Y, Unadkat JD. Interindividual variability in the hepatic expression of the human breast cancer resistance protein (BCRP/ABCG2): effect of age, sex, and genotype. J Pharm Sci. 2013;102:787–93.PubMedCrossRefGoogle Scholar
  166. 166.
    Jonker JW, Buitelaar M, Wagenaar E, Van Der Valk MA, Scheffer GL, Scheper RJ, et al. The breast cancer resistance protein protects against a major chlorophyll-derived dietary phototoxin and protoporphyria. Proc Natl Acad Sci USA. 2002;99:15649–54.PubMedCentralPubMedCrossRefGoogle Scholar
  167. 167.
    Zhou S, Zong Y, Ney PA, Nair G, Stewart CF, Sorrentino BP. Increased expression of the Abcg2 transporter during erythroid maturation plays a role in decreasing cellular protoporphyrin IX levels. Blood. 2005;105:2571–6.PubMedCrossRefGoogle Scholar
  168. 168.
    Naylor CS, Jaworska E, Branson K, Embleton MJ, Chopra R. Side population/ABCG2-positive cells represent a heterogeneous group of haemopoietic cells: implications for the use of adult stem cells in transplantation and plasticity protocols. Bone Marrow Transplant. 2005;35:353–60.PubMedCrossRefGoogle Scholar
  169. 169.
    Lechner A, Leech CA, Abraham EJ, Nolan AL, Habener JF. Nestin-positive progenitor cells derived from adult human pancreatic islets of Langerhans contain side population (SP) cells defined by expression of the ABCG2 (BCRP1) ATP-binding cassette transporter. Biochem Biophys Res Commun. 2002;293:670–4.PubMedCrossRefGoogle Scholar
  170. 170.
    Shimano K, Satake M, Okaya A, Kitanaka J, Kitanaka N, Takemura M, et al. Hepatic oval cells have the side population phenotype defined by expression of ATP-binding cassette transporter ABCG2/BCRP1. Am J Pathol. 2003;163:3–9.PubMedCentralPubMedCrossRefGoogle Scholar
  171. 171.
    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;279:24218–25.PubMedCrossRefGoogle Scholar
  172. 172.
    Evseenko DA, Murthi P, Paxton JW, Reid G, Emerald BS, Mohankumar KM, et al. The ABC transporter BCRP/ABCG2 is a placental survival factor, and its expression is reduced in idiopathic human fetal growth restriction. FASEB J. 2007;21:3592–605.PubMedCrossRefGoogle Scholar
  173. 173.
    Biri A, Bozkurt N, Turp A, Kavutcu M, Himmetoglu O, Durak I. Role of oxidative stress in intrauterine growth restriction. Gynecol Obstet Invest. 2007;64:187–92.PubMedCrossRefGoogle Scholar
  174. 174.
    Woodward OM, Kottgen A, Coresh J, Boerwinkle E, Guggino WB, Kottgen M. Identification of a urate transporter, ABCG2, with a common functional polymorphism causing gout. Proc Natl Acad Sci USA. 2009;106:10338–42.PubMedCentralPubMedCrossRefGoogle Scholar
  175. 175.
    Xiong H, Callaghan D, Jones A, Bai J, Rasquinha I, Smith C, et al. ABCG2 is upregulated in Alzheimer’s brain with cerebral amyloid angiopathy and may act as a gatekeeper at the blood–brain barrier for Abeta(1–40) peptides. J Neurosci. 2009;29:5463–75.PubMedCentralPubMedCrossRefGoogle Scholar
  176. 176.
    Saison C, Helias V, Ballif BA, Peyrard T, Puy H, Miyazaki T, et al. Null alleles of ABCG2 encoding the breast cancer resistance protein define the new blood group system Junior. Nat Genet. 2012;44:174–7.PubMedCentralPubMedCrossRefGoogle Scholar
  177. 177.
    Bailey-Dell KJ, Hassel B, Doyle LA, Ross DD. Promoter characterization and genomic organization of the human breast cancer resistance protein (ATP-binding cassette transporter G2) gene. Biochim Biophys Acta. 2001;1520:234–41.PubMedCrossRefGoogle Scholar
  178. 178.
    Ee PL, Kamalakaran S, Tonetti D, He X, Ross DD, Beck WT. Identification of a novel estrogen response element in the breast cancer resistance protein (ABCG2) gene. Cancer Res. 2004;64:1247–51.PubMedCrossRefGoogle Scholar
  179. 179.
    Wang H, Lee EW, Zhou L, Leung PC, Ross DD, Unadkat JD, et al. Progesterone receptor (PR) isoforms PRA and PRB differentially regulate expression of the breast cancer resistance protein in human placental choriocarcinoma BeWo cells. Mol Pharmacol. 2008;73:845–54.PubMedCrossRefGoogle Scholar
  180. 180.
    To KK, Robey R, Zhan Z, Bangiolo L, Bates SE. Upregulation of ABCG2 by romidepsin via the aryl hydrocarbon receptor pathway. Mol Cancer Res. 2011;9:516–27.PubMedCrossRefGoogle Scholar
  181. 181.
    Szatmari I, Vamosi G, Brazda P, Balint BL, Benko S, Szeles L, et al. Peroxisome proliferator-activated receptor gamma-regulated ABCG2 expression confers cytoprotection to human dendritic cells. J Biol Chem. 2006;281:23812–23.PubMedCrossRefGoogle Scholar
  182. 182.
    Honorat M, Mesnier A, Di Pietro A, Lin V, Cohen P, Dumontet C, et al. Dexamethasone down-regulates ABCG2 expression levels in breast cancer cells. Biochem Biophys Res Commun. 2008;375:308–14.PubMedCrossRefGoogle Scholar
  183. 183.
    Yasuda S, Itagaki S, Hirano T, Iseki K. Expression level of ABCG2 in the placenta decreases from the mid stage to the end of gestation. Biosci Biotechnol Biochem. 2005;69:1871–6.PubMedCrossRefGoogle Scholar
  184. 184.
    Li W, Jia M, Qin X, Hu J, Zhang X, Zhou G. Harmful effect of ERbeta on BCRP-mediated drug resistance and cell proliferation in ERalpha/PR-negative breast cancer. FEBS J. 2013;280:6128–40.PubMedCrossRefGoogle Scholar
  185. 185.
    Imai Y, Ishikawa E, Asada S, Sugimoto Y. Estrogen-mediated post transcriptional down-regulation of breast cancer resistance protein/ABCG2. Cancer Res. 2005;65:596–604.PubMedCrossRefGoogle Scholar
  186. 186.
    Wang H, Zhou L, Gupta A, Vethanayagam RR, Zhang Y, Unadkat JD, et al. Regulation of BCRP/ABCG2 expression by progesterone and 17beta-estradiol in human placental BeWo cells. Am J Physiol Endocrinol Metab. 2006;290:E798–807.PubMedCrossRefGoogle Scholar
  187. 187.
    Hartz AM, Mahringer A, Miller DS, Bauer B. 17-beta-Estradiol: a powerful modulator of blood–brain barrier BCRP activity. J Cereb Blood Flow Metab. 2010;30:1742–55.PubMedCentralPubMedCrossRefGoogle Scholar
  188. 188.
    Wu X, Zhang X, Sun L, Zhang H, Li L, Wang X, et al. Progesterone negatively regulates BCRP in progesterone receptor-positive human breast cancer cells. Cell Physiol Biochem. 2013;32:344–54.PubMedCrossRefGoogle Scholar
  189. 189.
    Pradhan M, Bembinster LA, Baumgarten SC, Frasor J. Proinflammatory cytokines enhance estrogen-dependent expression of the multidrug transporter gene ABCG2 through estrogen receptor and NF{kappa}B cooperativity at adjacent response elements. J Biol Chem. 2010;285:31100–6.PubMedCentralPubMedCrossRefGoogle Scholar
  190. 190.
    Turner JG, Gump JL, Zhang C, Cook JM, Marchion D, Hazlehurst L, et al. ABCG2 expression, function, and promoter methylation in human multiple myeloma. Blood. 2006;108:3881–9.PubMedCentralPubMedCrossRefGoogle Scholar
  191. 191.
    To KK, Zhan Z, Bates SE. Aberrant promoter methylation of the ABCG2 gene in renal carcinoma. Mol Cell Biol. 2006;26:8572–85.PubMedCentralPubMedCrossRefGoogle Scholar
  192. 192.
    To KK, Zhan Z, Litman T, Bates SE. Regulation of ABCG2 expression at the 3′ untranslated region of its mRNA through modulation of transcript stability and protein translation by a putative microRNA in the S1 colon cancer cell line. Mol Cell Biol. 2008;28:5147–61.PubMedCentralPubMedCrossRefGoogle Scholar
  193. 193.
    To KK, Robey RW, Knutsen T, Zhan Z, Ried T, Bates SE. Escape from hsa-miR-519c enables drug-resistant cells to maintain high expression of ABCG2. Mol Cancer Ther. 2009;8:2959–68.PubMedCentralPubMedCrossRefGoogle Scholar
  194. 194.
    Wang F, Xue X, Wei J, An Y, Yao J, Cai H, et al. hsa-miR-520h downregulates ABCG2 in pancreatic cancer cells to inhibit migration, invasion, and side populations. Br J Cancer. 2010;103:567–74.PubMedCentralPubMedCrossRefGoogle Scholar
  195. 195.
    Pan YZ, Morris ME, Yu AM. MicroRNA-328 negatively regulates the expression of breast cancer resistance protein (BCRP/ABCG2) in human cancer cells. Mol Pharmacol. 2009;75:1374–9.PubMedCentralPubMedCrossRefGoogle Scholar
  196. 196.
    Xie Y, Xu K, Linn DE, Yang X, Guo Z, Shimelis H, et al. The 44-kDa Pim-1 kinase phosphorylates BCRP/ABCG2 and thereby promotes its multimerization and drug-resistant activity in human prostate cancer cells. J Biol Chem. 2008;283:3349–56.PubMedCrossRefGoogle Scholar
  197. 197.
    Peng H, Qi J, Dong Z, Zhang JT. Dynamic vs static ABCG2 inhibitors to sensitize drug resistant cancer cells. PLoS One. 2010;5:e15276.PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2014

Authors and Affiliations

  1. 1.Department of Pharmaceutics, School of PharmacyUniversity of WashingtonSeattleUSA

Personalised recommendations