The AAPS Journal

, 20:8 | Cite as

ABCB6, an ABC Transporter Impacting Drug Response and Disease

  • Rebba C. Boswell-Casteel
  • Yu Fukuda
  • John D. Schuetz
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


Recent findings have discovered how insufficiency of ATP-binding cassette (ABC) transporter, ABCB6, can negatively impact human health. These advances were made possible by, first, finding that ABCB6 deficiency was the genetic basis for some severe transfusion reactions and by, second, determining that functionally impaired ABCB6 variants enhanced the severity of porphyria, i.e., diseases associated with defects in heme synthesis. ABCB6 is a broad-spectrum porphyrin transporter that is capable of both exporting and importing heme and its precursors across the plasma membrane and outer mitochondrial membrane, respectively. Biochemical studies have demonstrated that while ABCB6 influences the antioxidant system by reducing the levels of reactive oxygen species, the exact mechanism is currently unknown, though effects on heme synthesis are likely. Furthermore, it is unknown what biochemical or cellular signals determine where ABCB6 localizes in the cell. This review highlights the major recent findings on ABCB6 and focuses on details of its structure, mechanism, transport, contributions to cellular stress, and current clinical implications.


ABCB6 heme liver porphyrin toxicity transporter 



We would like to thank all the members of the Schuetz Lab for the suggestions to improve this manuscript.

Funding Information

This work was supported by NIH grants R01CA194057, P30 CA21745, CA21865, CA194057, CA096832, and by ALSAC.


  1. 1.
    Chiabrando D, Vinchi F, Fiorito V, Mercurio S, Tolosano E. Heme in pathophysiology: a matter of scavenging, metabolism and trafficking across cell membranes. Front Pharmacol. 2014;5:61. Scholar
  2. 2.
    Mense SM, Zhang L. Heme: a versatile signaling molecule controlling the activities of diverse regulators ranging from transcription factors to MAP kinases. Cell Res. 2006;16(8):681–92. Scholar
  3. 3.
    Krammer B, Uberriegler K. In-vitro investigation of ALA-induced protoporphyrin IX. J Photochem Photobiol B. 1996;36(2):121–6. Scholar
  4. 4.
    Krishnamurthy PC, Du G, Fukuda Y, Sun D, Sampath J, Mercer KE, et al. Identification of a mammalian mitochondrial porphyrin transporter. Nature. 2006;443(7111):586–9. Scholar
  5. 5.
    Furuya KN, Bradley G, Sun D, Schuetz EG, Schuetz JD. Identification of a new P-glycoprotein-like ATP-binding cassette transporter gene that is overexpressed during hepatocarcinogenesis. Cancer Res. 1997;57(17):3708–16.PubMedGoogle Scholar
  6. 6.
    Chavan H, Oruganti M, Krishnamurthy P. The ATP-binding cassette transporter ABCB6 is induced by arsenic and protects against arsenic cytotoxicity. Toxicol Sci. 2011;120(2):519–28. Scholar
  7. 7.
    Lynch J, Fukuda Y, Krishnamurthy P, Du G, Schuetz JD. Cell survival under stress is enhanced by a mitochondrial ATP-binding cassette transporter that regulates hemoproteins. Cancer Res. 2009;69(13):5560–7. Scholar
  8. 8.
    Ulrich DL, Lynch J, Wang Y, Fukuda Y, Nachagari D, Du G, et al. ATP-dependent mitochondrial porphyrin importer ABCB6 protects against phenylhydrazine toxicity. J Biol Chem. 2012;287(16):12679–90. Scholar
  9. 9.
    Polireddy K, Chavan H, Abdulkarim BA, Krishnamurthy P. Functional significance of the ATP-binding cassette transporter B6 in hepatocellular carcinoma. Mol Oncol. 2011;5(5):410–25. Scholar
  10. 10.
    Borel F, Han R, Petry H, van Deventer S, Jansen P, Konstantinova P. ATP-binding cassette transporter genes up-regulation in untreated hepatocellular carcinoma is mediated by cellular microRNAs. Hum Gene Ther. 2011;22(10):A112–A.Google Scholar
  11. 11.
    Yasui K, Mihara S, Zhao C, Okamoto H, Saito-Ohara F, Tomida A, et al. Alteration in copy numbers of genes as a mechanism for acquired drug resistance. Cancer Res. 2004;64(4):1403–10. Scholar
  12. 12.
    Park S, Shimizu C, Shimoyama T, Takeda M, Ando M, Kohno T, et al. Gene expression profiling of ATP-binding cassette (ABC) transporters as a predictor of the pathologic response to neoadjuvant chemotherapy in breast cancer patients. Breast Cancer Res Treat. 2006;99(1):9–17. Scholar
  13. 13.
    Heimerl S, Bosserhoff AK, Langmann T, Ecker J, Schmitz G. Mapping ATP-binding cassette transporter gene expression profiles in melanocytes and melanoma cells. Melanoma Res. 2007;17(5):265–73. Scholar
  14. 14.
    Annereau JP, Szakacs G, Tucker CJ, Arciello A, Cardarelli C, Collins J, et al. Analysis of ATP-binding cassette transporter expression in drug-selected cell lines by a microarray dedicated to multidrug resistance. Mol Pharmacol. 2004;66(6):1397–405. Scholar
  15. 15.
    Szakacs G, Annereau JP, Lababidi S, Shankavaram U, Arciello A, Bussey KJ, et al. Predicting drug sensitivity and resistance: profiling ABC transporter genes in cancer cells. Cancer Cell. 2004;6(2):129–37. Scholar
  16. 16.
    Fukuda Y, Cheong PL, Lynch J, Brighton C, Frase S, Kargas V, et al. The severity of hereditary porphyria is modulated by the porphyrin exporter and Lan antigen ABCB6. Nat Commun. 2016;7:12353. Scholar
  17. 17.
    Helias V, Saison C, Ballif BA, Peyrard T, Takahashi J, Takahashi H, et al. ABCB6 is dispensable for erythropoiesis and specifies the new blood group system Langereis. Nat Genet. 2012;44(2):170–3. Scholar
  18. 18.
    Chavan H, Khan MM, Tegos G, Krishnamurthy P. Efficient purification and reconstitution of ATP binding cassette transporter B6 (ABCB6) for functional and structural studies. J Biol Chem. 2013;288(31):22658–69. Scholar
  19. 19.
    Schrodt S, Koch J, Tampe R. Membrane topology of the transporter associated with antigen processing (TAP1) within an assembled functional peptide-loading complex. J Biol Chem. 2006;281(10):6455–62. Scholar
  20. 20.
    Blees A, Reichel K, Trowitzsch S, Fisette O, Bock C, Abele R, et al. Assembly of the MHC I peptide-loading complex determined by a conserved ionic lock-switch. Sci Rep. 2015;5(1):17341. Scholar
  21. 21.
    Oldham ML, Hite RK, Steffen AM, Damko E, Li Z, Walz T, et al. A mechanism of viral immune evasion revealed by cryo-EM analysis of the TAP transporter. Nature. 2016;529(7587):537–40. Scholar
  22. 22.
    Martin GM, Yoshioka C, Rex EA, Fay JF, Xie Q, Whorton MR, et al. Cryo-EM structure of the ATP-sensitive potassium channel illuminates mechanisms of assembly and gating. elife. 2017;6
  23. 23.
    Li N, Wu JX, Ding D, Cheng J, Gao N, Chen L. Structure of a pancreatic ATP-sensitive potassium channel. Cell. 2017;168(1–2):101–10.e10. Scholar
  24. 24.
    Fukuda Y, Aguilar-Bryan L, Vaxillaire M, Dechaume A, Wang Y, Dean M, et al. Conserved intramolecular disulfide bond is critical to trafficking and fate of ATP-binding cassette (ABC) transporters ABCB6 and sulfonylurea receptor 1 (SUR1)/ABCC8. J Biol Chem. 2011;286(10):8481–92. Scholar
  25. 25.
    Kiss K, Kucsma N, Brozik A, Tusnady GE, Bergam P, van Niel G, et al. Role of the N-terminal transmembrane domain in the endo-lysosomal targeting and function of the human ABCB6 protein. Biochem J. 2015;467(1):127–39. Scholar
  26. 26.
    Senior AE, al-Shawi MK, Urbatsch IL. ATP hydrolysis by multidrug-resistance protein from Chinese hamster ovary cells. J Bioenerg Biomembr. 1995;27(1):31–6. Scholar
  27. 27.
    Higgins CF, Linton KJ. The ATP switch model for ABC transporters. Nat Struct Mol Biol. 2004;11(10):918–26. Scholar
  28. 28.
    Zou P, McHaourab HS. Alternating access of the putative substrate-binding chamber in the ABC transporter MsbA. J Mol Biol. 2009;393(3):574–85. Scholar
  29. 29.
    Zou P, Bortolus M, McHaourab HS. Conformational cycle of the ABC transporter MsbA in liposomes: detailed analysis using double electron-electron resonance spectroscopy. J Mol Biol. 2009;393(3):586–97. Scholar
  30. 30.
    Verhalen B, Dastvan R, Thangapandian S, Peskova Y, Koteiche HA, Nakamoto RK, et al. Energy transduction and alternating access of the mammalian ABC transporter P-glycoprotein. Nature. 2017;543(7647):738–41. Scholar
  31. 31.
    Mitsuhashi N, Miki T, Senbongi H, Yokoi N, Yano H, Miyazaki M, et al. MTABC3, a novel mitochondrial ATP-binding cassette protein involved in iron homeostasis. J Biol Chem. 2000;275(23):17536–40. Scholar
  32. 32.
    Paterson JK, Shukla S, Black CM, Tachiwada T, Garfield S, Wincovitch S, et al. Human ABCB6 localizes to both the outer mitochondrial membrane and the plasma membrane. Biochemistry. 2007;46(33):9443–52. Scholar
  33. 33.
    Tsuchida M, Emi Y, Kida Y, Sakaguchi M, Human ABC. Transporter isoform B6 (ABCB6) localizes primarily in the Golgi apparatus. Biochem Biophys Res Commun. 2008;369(2):369–75. Scholar
  34. 34.
    Kiss K, Brozik A, Kucsma N, Toth A, Gera M, Berry L, et al. Shifting the paradigm: the putative mitochondrial protein ABCB6 resides in the lysosomes of cells and in the plasma membrane of erythrocytes. PLoS One. 2012;7(5):e37378. Scholar
  35. 35.
    Schinkel AH, Smit JJ, van Tellingen O, Beijnen JH, Wagenaar E, van Deemter L, et al. Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs. Cell. 1994;77(4):491–502. Scholar
  36. 36.
    Flora SJ. Arsenic-induced oxidative stress and its reversibility. Free Radic Biol Med. 2011;51(2):257–81. Scholar
  37. 37.
    Jalil YA, Ritz V, Jakimenko A, Schmitz-Salue C, Siebert H, Awuah D, et al. Vesicular localization of the rat ATP-binding cassette half-transporter rAbcb6. Am J Physiol Cell Physiol. 2008;294(2):C579–90. Scholar
  38. 38.
    Hosseini MJ, Shaki F, Ghazi-Khansari M, Pourahmad J. Toxicity of copper on isolated liver mitochondria: impairment at complexes I, II, and IV leads to increased ROS production. Cell Biochem Biophys. 2014;70(1):367–81. Scholar
  39. 39.
    Varatharajan S, Abraham A, Karathedath S, Ganesan S, Lakshmi KM, Arthur N, et al. ATP-binding casette transporter expression in acute myeloid leukemia: association with in vitro cytotoxicity and prognostic markers. Pharmacogenomics. 2017;18(3):235–44. Scholar
  40. 40.
    Minami K, Kamijo Y, Nishizawa Y, Tabata S, Horikuchi F, Yamamoto M, et al. Expression of ABCB6 is related to resistance to 5-FU, SN-38 and vincristine. Anticancer Res. 2014;34(9):4767–73.PubMedGoogle Scholar
  41. 41.
    Januchowski R, Zawierucha P, Andrzejewska M, Rucinski M, Zabel M. Microarray-based detection and expression analysis of ABC and SLC transporters in drug-resistant ovarian cancer cell lines. Biomed Pharmacother. 2013;67(3):240–5. Scholar
  42. 42.
    Brea-Calvo G, Siendones E, Sanchez-Alcazar JA, de Cabo R, Navas P. Cell survival from chemotherapy depends on NF-kappaB transcriptional up-regulation of coenzyme Q biosynthesis. PLoS One. 2009;4(4):e5301. Scholar
  43. 43.
    Focaccetti C, Bruno A, Magnani E, Bartolini D, Principi E, Dallaglio K, et al. Effects of 5-fluorouracil on morphology, cell cycle, proliferation, apoptosis, autophagy and ROS production in endothelial cells and cardiomyocytes. PLoS One. 2015;10(2):e0115686. Scholar
  44. 44.
    Groninger E, Meeuwsen-De Boer GJ, De Graaf SS, Kamps WA, De Bont ES. Vincristine induced apoptosis in acute lymphoblastic leukaemia cells: a mitochondrial controlled pathway regulated by reactive oxygen species? Int J Oncol. 2002;21(6):1339–45.PubMedGoogle Scholar
  45. 45.
    Lyoumi S, Abitbol M, Andrieu V, Henin D, Robert E, Schmitt C, et al. Increased plasma transferrin, altered body iron distribution, and microcytic hypochromic anemia in ferrochelatase-deficient mice. Blood. 2007;109(2):811–8. Scholar
  46. 46.
    Murphy AJ, Sarrazy V, Wang N, Bijl N, Abramowicz S, Westerterp M, et al. Deficiency of ATP-binding cassette transporter B6 in megakaryocyte progenitors accelerates atherosclerosis in mice. Arterioscler Thromb Vasc Biol. 2014;34(4):751–8. Scholar
  47. 47.
    Burton MJ, Kapetanaki SM, Chernova T, Jamieson AG, Dorlet P, Santolini J, et al. A heme-binding domain controls regulation of ATP-dependent potassium channels. Proc Natl Acad Sci U S A. 2016;113(14):3785–90. Scholar
  48. 48.
    Zhang C, Li D, Zhang J, Chen X, Huang M, Archacki S, et al. Mutations in ABCB6 cause dyschromatosis universalis hereditaria. J Invest Dermatol. 2013;133(9):2221–8. Scholar
  49. 49.
    Liu H, Li Y, Hung KK, Wang N, Wang C, Chen X, et al. Genome-wide linkage, exome sequencing and functional analyses identify ABCB6 as the pathogenic gene of dyschromatosis universalis hereditaria. PLoS One. 2014;9(2):e87250. Scholar
  50. 50.
    Tsunedomi R, Iizuka N, Yoshimura K, Iida M, Tsutsui M, Hashimoto N, et al. ABCB6 mRNA and DNA methylation levels serve as useful biomarkers for prediction of early intrahepatic recurrence of hepatitis C virus-related hepatocellular carcinoma. Int J Oncol. 2013;42(5):1551–9. Scholar
  51. 51.
    Karatas OF, Guzel E, Duz MB, Ittmann M, Ozen M. The role of ATP-binding cassette transporter genes in the progression of prostate cancer. Prostate. 2016;76(5):434–44. Scholar
  52. 52.
    Kelter G, Steinbach D, Konkimalla VB, Tahara T, Taketani S, Fiebig HH, et al. Role of transferrin receptor and the ABC transporters ABCB6 and ABCB7 for resistance and differentiation of tumor cells towards artesunate. PLoS One. 2007;2(8):e798. Scholar
  53. 53.
    Zhao SG, Chen XF, Wang LG, Yang G, Han DY, Teng L, et al. Increased expression of ABCB6 enhances protoporphyrin IX accumulation and photodynamic effect in human glioma. Ann Surg Oncol. 2013;20(13):4379–88. Scholar
  54. 54.
    Saison C, Helias V, Peyrard T, Merad L, Cartron JP, Arnaud L. The ABCB6 mutation p.Arg192Trp is a recessive mutation causing the Lan- blood type. Vox Sang. 2013;104(2):159–65. Scholar
  55. 55.
    Koszarska M, Kucsma N, Kiss K, Varady G, Gera M, Antalffy G, et al. Screening the expression of ABCB6 in erythrocytes reveals an unexpectedly high frequency of Lan mutations in healthy individuals. PLoS One. 2014;9(10):e111590. Scholar
  56. 56.
    Andolfo I, Alper SL, Delaunay J, Auriemma C, Russo R, Asci R, et al. Missense mutations in the ABCB6 transporter cause dominant familial pseudohyperkalemia. Am J Hematol. 2013;88(1):66–72. Scholar
  57. 57.
    Wang D, Sun J, Solomon SB, Klein HG, Natanson C. Transfusion of older stored blood and risk of death: a meta-analysis. Transfusion. 2012;52(6):1184–95. Scholar
  58. 58.
    Reid ME, Hue-Roye K, Huang A, Velliquette RW, Tani Y, Westhoff CM, et al. Alleles of the LAN blood group system: molecular and serologic investigations. Transfusion. 2014;54(2):398–404. Scholar
  59. 59.
    Wang L, He F, Bu J, Zhen Y, Liu X, Du W, et al. ABCB6 mutations cause ocular coloboma. Am J Hum Genet. 2012;90(1):40–8. Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2017

Authors and Affiliations

  • Rebba C. Boswell-Casteel
    • 1
  • Yu Fukuda
    • 1
  • John D. Schuetz
    • 1
  1. 1.Department of Pharmaceutical SciencesSt. Jude Children’s Research HospitalMemphisUSA

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