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An update on ABCB1 pharmacogenetics: insights from a 3D model into the location and evolutionary conservation of residues corresponding to SNPs associated with drug pharmacokinetics

The Pharmacogenomics Journal volume 11, pages 315–325 (2011)Cite this article

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Abstract

The human ABCB1 protein, (P-glycoprotein or MDR1) is a membrane-bound glycoprotein that harnesses the energy of ATP hydrolysis to drive the unidirectional transport of substrates from the cytoplasm to the extracellular space. As a large range of therapeutic agents are known substrates of ABCB1 protein, its role in the onset of multidrug resistance has been the focus of much research. This role has been of particular interest in the field of pharmacogenomics where genetic variation within the ABCB1 gene, particularly in the form of single nucleotide polymorphisms (SNPs), is believed to contribute to inter-individual variation in ABCB1 function and drug response. In this review we provide an update on the influence of coding region SNPs within the ABCB1 gene on drug pharmacokinetics. By utilizing the crystal structure of the mouse ABCB1 homolog (Abcb1a), which is 87% homologous to the human sequence, we accompany this discussion with a graphical representation of residue location for amino acids corresponding to human ABCB1 coding region SNPs. Also, an assessment of residue conservation, which is calculated following multiple sequence alignment of 11 confirmed sequences of ABCB1 homologs, is presented and discussed. Superimposing a ‘heat map’ of residue homology to the Abcb1a crystal structure has permitted additional insights into both the conservation of individual residues and the conservation of their immediate surroundings. Such graphical representation of residue location and conservation supplements this update of ABCB1 pharmacogenetics to help clarify the often confounding reports on the influence of ABCB1 polymorphisms on drug pharmacokinetics and response.

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References

  1. Tusnady GE, Sarkadi B, Simon I, Varadi A . Membrane topology of human ABC proteins. FEBS Lett 2006; 580: 1017–1022.

    Article  CAS  PubMed  Google Scholar 

  2. Tate SK, Sisodiya SM . Multidrug resistance in epilepsy: a pharmacogenomic update. Expert Opin Pharmacother 2007; 8: 1441–1449.

    Article  CAS  PubMed  Google Scholar 

  3. Leschziner GD, Andrew T, Pirmohamed M, Johnson MR . ABCB1 genotype and PGP expression, function and therapeutic drug response: a critical review and recommendations for future research. Pharmacogenomics J 2007; 7: 154–179.

    Article  CAS  PubMed  Google Scholar 

  4. Pal D, Mitra AK . MDR- and CYP3A4-mediated drug-drug interactions. J Neuroimmune Pharmacol 2006; 1: 323–339.

    Article  PubMed  Google Scholar 

  5. Vourvahis M, Kashuba AD . Mechanisms of pharmacokinetic and pharmacodynamic drug interactions associated with ritonavir-enhanced tipranavir. Pharmacotherapy 2007; 27: 888–909.

    Article  CAS  PubMed  Google Scholar 

  6. Harmsen S, Meijerman I, Beijnen JH, Schellens JH . The role of nuclear receptors in pharmacokinetic drug-drug interactions in oncology. Cancer Treat Rev 2007; 33: 369–380.

    Article  CAS  PubMed  Google Scholar 

  7. Chapuy B, Koch R, Radunski U, Corsham S, Cheong N, Inagaki N et al. Intracellular ABC transporter A3 confers multidrug resistance in leukemia cells by lysosomal drug sequestration. Leukemia 2008; 22: 1576–1586.

    Article  CAS  PubMed  Google Scholar 

  8. Rajagopal A, Simon SM . Subcellular localization and activity of multidrug resistance proteins. Mol Biol Cell 2003; 14: 3389–3399.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Cascorbi I . Role of pharmacogenetics of ATP-binding cassette transporters in the pharmacokinetics of drugs. Pharmacol Ther 2006; 112: 457–473.

    Article  CAS  PubMed  Google Scholar 

  10. Dean M, Rzhetsky A, Allikmets R . The human ATP-binding cassette (ABC) transporter superfamily. Genome Res 2001; 11: 1156–1166.

    Article  CAS  PubMed  Google Scholar 

  11. Juliano RL, Ling V . A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochim Biophys Acta 1976; 455: 152–162.

    Article  CAS  PubMed  Google Scholar 

  12. Aller SG, Yu J, Ward A, Weng Y, Chittaboina S, Zhuo R et al. Structure of P-glycoprotein reveals a molecular basis for poly-specific drug binding. Science 2009; 323: 1718–1722.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Higgins CF, Linton KJ . The ATP switch model for ABC transporters. Nat Struct Mol Biol 2004; 11: 918–926.

    Article  CAS  PubMed  Google Scholar 

  14. Sauna ZE, Smith MM, Muller M, Kerr KM, Ambudkar SV . The mechanism of action of multidrug-resistance-linked P-glycoprotein. J Bioenerg Biomembr 2001; 33: 481–491.

    Article  CAS  PubMed  Google Scholar 

  15. Ambudkar SV, Kim IW, Xia D, Sauna ZE . The A-loop, a novel conserved aromatic acid subdomain upstream of the Walker A motif in ABC transporters, is critical for ATP binding. FEBS Lett 2006; 580: 1049–1055.

    Article  CAS  PubMed  Google Scholar 

  16. Gottesman MM, Pastan I, Ambudkar SV . P-glycoprotein and multidrug resistance. Curr Opin Genet Dev 1996; 6: 610–617.

    Article  CAS  PubMed  Google Scholar 

  17. Kim IW, Peng XH, Sauna ZE, FitzGerald PC, Xia D, Muller M et al. The conserved tyrosine residues 401 and 1044 in ATP sites of human P-glycoprotein are critical for ATP binding and hydrolysis: evidence for a conserved subdomain, the A-loop in the ATP-binding cassette. Biochemistry 2006; 45: 7605–7616.

    Article  CAS  PubMed  Google Scholar 

  18. Sharom FJ . ABC multidrug transporters: structure, function and role in chemoresistance. Pharmacogenomics 2008; 9: 105–127.

    Article  CAS  PubMed  Google Scholar 

  19. Sauna ZE, Ambudkar SV . About a switch: how P-glycoprotein (ABCB1) harnesses the energy of ATP binding and hydrolysis to do mechanical work. Mol Cancer Ther 2007; 6: 13–23.

    Article  CAS  PubMed  Google Scholar 

  20. Sheps JA . Biochemistry. Through a mirror, differently. Science 2009; 323: 1679–1680.

    Article  CAS  PubMed  Google Scholar 

  21. Wang Z, Wang J, Tantoso E, Wang B, Tai AY, Ooi LL et al. Signatures of recent positive selection at the ATP-binding cassette drug transporter superfamily gene loci. Hum Mol Genet 2007; 16: 1367–1380.

    Article  CAS  PubMed  Google Scholar 

  22. Wang Z, Wang J, Chong SS, Lee CGL . Mining potential functionally significant polymorphisms at the ATP-binding- cassette transporter genes. Curr Pharmacogenomics Personalized Med 2009; 7: 40–58.

    Article  Google Scholar 

  23. Zhou SF . Structure, function and regulation of P-glycoprotein and its clinical relevance in drug disposition. Xenobiotica 2008; 38: 802–832.

    Article  CAS  PubMed  Google Scholar 

  24. Larkin MA, Blackshields G, Brown NP, Chenna R, McGettigan PA, McWilliam H et al. Clustal W and Clustal X version 2.0. Bioinformatics 2007; 23: 2947–2948.

    Article  CAS  PubMed  Google Scholar 

  25. Thompson JD, Gibson TJ, Higgins DG . Multiple sequence alignment using ClustalW and ClustalX. Curr Protoc Bioinformatics 2002; Chapter 2, Unit 2.3.

  26. Leschziner G, Zabaneh D, Pirmohamed M, Owen A, Rogers J, Coffey AJ et al. Exon sequencing and high resolution haplotype analysis of ABC transporter genes implicated in drug resistance. Pharmacogenet Genomics 2006; 16: 439–450.

    Article  CAS  PubMed  Google Scholar 

  27. Kim RB, Leake BF, Choo EF, Dresser GK, Kubba SV, Schwarz UI et al. Identification of functionally variant MDR1 alleles among European Americans and African Americans. Clin Pharmacol Ther 2001; 70: 189–199.

    Article  CAS  PubMed  Google Scholar 

  28. Tang K, Wong LP, Lee EJ, Chong SS, Lee CG . Genomic evidence for recent positive selection at the human MDR1 gene locus. Hum Mol Genet 2004; 13: 783–797.

    Article  CAS  PubMed  Google Scholar 

  29. Tang K, Ngoi SM, Gwee PC, Chua JM, Lee EJ, Chong SS et al. Distinct haplotype profiles and strong linkage disequilibrium at the MDR1 multidrug transporter gene locus in three ethnic Asian populations. Pharmacogenetics 2002; 12: 437–450.

    Article  CAS  PubMed  Google Scholar 

  30. Sai K, Kaniwa N, Itoda M, Saito Y, Hasegawa R, Komamura K et al. Haplotype analysis of ABCB1/MDR1 blocks in a Japanese population reveals genotype-dependent renal clearance of irinotecan. Pharmacogenetics 2003; 13: 741–757.

    Article  CAS  PubMed  Google Scholar 

  31. Kroetz DL, Pauli-Magnus C, Hodges LM, Huang CC, Kawamoto M, Johns SJ et al. Sequence diversity and haplotype structure in the human ABCB1 (MDR1, multidrug resistance transporter) gene. Pharmacogenetics 2003; 13: 481–494.

    Article  CAS  PubMed  Google Scholar 

  32. Leslie EM, Deeley RG, Cole SP . Multidrug resistance proteins: role of P-glycoprotein, MRP1, MRP2, and BCRP (ABCG2) in tissue defense. Toxicol Appl Pharmacol 2005; 204: 216–237.

    Article  CAS  PubMed  Google Scholar 

  33. Tombline G, Bartholomew L, Gimi K, Tyndall GA, Senior AE . Synergy between conserved ABC signature Ser residues in P-glycoprotein catalysis. J Biol Chem 2004; 279: 5363–5373.

    Article  CAS  PubMed  Google Scholar 

  34. Fung KL, Gottesman MM . A synonymous polymorphism in a common MDR1 (ABCB1) haplotype shapes protein function. Biochim Biophys Acta 2009; 1794: 860–871.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Tsai CJ, Sauna ZE, Kimchi-Sarfaty C, Ambudkar SV, Gottesman MM, Nussinov R . Synonymous mutations and ribosome stalling can lead to altered folding pathways and distinct minima. J Mol Biol 2008; 383: 281–291.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Kimchi-Sarfaty C, Oh JM, Kim IW, Sauna ZE, Calcagno AM, Ambudkar SV et al. A ‘silent’ polymorphism in the MDR1 gene changes substrate specificity. Science 2007; 315: 525–528.

    Article  CAS  PubMed  Google Scholar 

  37. Kyte J, Doolittle RF . A simple method for displaying the hydropathic character of a protein. J Mol Biol 1982; 157: 105–132.

    Article  CAS  PubMed  Google Scholar 

  38. Marzolini C, Paus E, Buclin T, Kim RB . Polymorphisms in human MDR1 (P-glycoprotein): recent advances and clinical relevance. Clin Pharmacol Ther 2004; 75: 13–33.

    Article  CAS  PubMed  Google Scholar 

  39. Choi KH, Chen CJ, Kriegler M, Roninson IB . An altered pattern of cross-resistance in multidrug-resistant human cells results from spontaneous mutations in the mdr1 (P-glycoprotein) gene. Cell 1988; 53: 519–529.

    Article  CAS  PubMed  Google Scholar 

  40. Omote H, Figler RA, Polar MK, Al-Shawi MK . Improved energy coupling of human P-glycoprotein by the glycine 185 to valine mutation. Biochemistry 2004; 43: 3917–3928.

    Article  CAS  PubMed  Google Scholar 

  41. Omote H, Al-Shawi MK . Interaction of transported drugs with the lipid bilayer and P-glycoprotein through a solvation exchange mechanism. Biophys J 2006; 90: 4046–4059.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Kimchi-Sarfaty C, Gribar JJ, Gottesman MM . Functional characterization of coding polymorphisms in the human MDR1 gene using a vaccinia virus expression system. Mol Pharmacol 2002; 62: 1–6.

    Article  CAS  PubMed  Google Scholar 

  43. Sakurai A, Onishi Y, Hirano H, Seigneuret M, Obanayama K, Kim G et al. Quantitative structure--activity relationship analysis and molecular dynamics simulation to functionally validate nonsynonymous polymorphisms of human ABC transporter ABCB1 (P-glycoprotein/MDR1). Biochemistry 2007; 46: 7678–7693.

    Article  CAS  PubMed  Google Scholar 

  44. Woodahl EL, Yang Z, Bui T, Shen DD, Ho RJ . MDR1 G1199A polymorphism alters permeability of HIV protease inhibitors across P-glycoprotein-expressing epithelial cells. AIDS 2005; 19: 1617–1625.

    Article  CAS  PubMed  Google Scholar 

  45. Woodahl EL, Crouthamel MH, Bui T, Shen DD, Ho RJ . MDR1 (ABCB1) G1199A (Ser400Asn) polymorphism alters transepithelial permeability and sensitivity to anticancer agents. Cancer Chemother Pharmacol 2009; 64: 183–188.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Woodahl EL, Yang Z, Bui T, Shen DD, Ho RJ . Multidrug resistance gene G1199A polymorphism alters efflux transport activity of P-glycoprotein. J Pharmacol Exp Ther 2004; 310: 1199–1207.

    Article  CAS  PubMed  Google Scholar 

  47. Crouthamel MH, Wu D, Yang Z, Ho RJ . A novel MDR1 G1199T variant alters drug resistance and efflux transport activity of P-glycoprotein in recombinant Hek cells. J Pharm Sci 2006; 95: 2767–2777.

    Article  CAS  PubMed  Google Scholar 

  48. Green H, Soderkvist P, Rosenberg P, Horvath G, Peterson C . ABCB1 G1199A polymorphism and ovarian cancer response to paclitaxel. J Pharm Sci 2008; 97: 2045–2048.

    Article  CAS  PubMed  Google Scholar 

  49. Jeong H, Herskowitz I, Kroetz DL, Rine J . Function-altering SNPs in the human multidrug transporter gene ABCB1 identified using a Saccharomyces-based assay. PLoS Genet 2007; 3: e39.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Gow JM, Hodges LM, Chinn LW, Kroetz DL . Substrate-dependent effects of human ABCB1 coding polymorphisms. J Pharmacol Exp Ther 2008; 325: 435–442.

    Article  CAS  PubMed  Google Scholar 

  51. Crettol S, Venetz JP, Fontana M, Aubert JD, Pascual M, Eap CB . CYP3A7, CYP3A5, CYP3A4, and ABCB1 genetic polymorphisms, cyclosporine concentration, and dose requirement in transplant recipients. Ther Drug Monit 2008; 30: 689–699.

    Article  CAS  PubMed  Google Scholar 

  52. Crettol S, Deglon JJ, Besson J, Croquette-Krokar M, Hammig R, Gothuey I et al. ABCB1 and cytochrome P450 genotypes and phenotypes: influence on methadone plasma levels and response to treatment. Clin Pharmacol Ther 2006; 80: 668–681.

    Article  CAS  PubMed  Google Scholar 

  53. Liu L, Fan L, Peng X, Hu D, Zhou H . MDR1 C2005T polymorphism changes substrate specificity. Cancer Chemother Pharmacol 2010; 66: 617–623.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by grants from the Academic Research Fund-Ministry of Education Tier 2 (MOET206B3105) to C.G. L. Lee through the National University of Singapore; the National Medical Research Council (NMRC) (NMRC/0993/2005), Singapore to C.G.L. Lee through the National Cancer Centre, Singapore; as well as blockfunding to C.G.L. Lee through the National Cancer Centre.

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  1. S J Wolf and M Bachtiar: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    S J Wolf, M Bachtiar, J Wang & C G L Lee

  2. Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    T S Sim

  3. Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    S S Chong

  4. Division of Medical Sciences, National Cancer Centre, Singapore, Singapore

    C G L Lee

  5. Duke-NUS Graduate Medical School, Singapore, Singapore

    C G L Lee

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Correspondence to C G L Lee.

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Wolf, S., Bachtiar, M., Wang, J. et al. An update on ABCB1 pharmacogenetics: insights from a 3D model into the location and evolutionary conservation of residues corresponding to SNPs associated with drug pharmacokinetics. Pharmacogenomics J 11, 315–325 (2011). https://doi.org/10.1038/tpj.2011.16

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