Skip to main content
SpringerLink
Log in

Membrane Transporters and Drug Development: Relevance to Pharmacogenomics, Nutrigenomics, Epigenetics, and Systems Biology

  • Protocol
  • First Online:
Membrane Transporters in Drug Discovery and Development

Part of the book series: Methods in Molecular Biology ((MIMB,volume 637))

Abstract

The study of membrane transporters may result in breakthroughs in the discovery of new drugs and the development of safer drugs. Membrane transporters are essential for fundamental cellular functions and normal physiological processes. These molecules influence drug absorption and distribution and play key roles in drug therapeutic effects. A primary goal of current research in drug discovery and development is to fully understand the interactions between transporters and drugs at both the system levels in the human body and the individual level for personalized therapy. Systematic studies of membrane transporters will help in not only better understanding of diseases from the systems biology point of view but also better drug design and development. The exploration of both pharmacogenomics and systems biology in transporters is necessary to connect individuals’ genetic profiles with systematic drug responses in the human body. Understanding of gene–diet interactions and the effects of epigenetic changes on transporter gene expression may help improve clinical drug efficacy. The integration of pharmacogenomics, nutrigenomics, epigenetics, and systems biology may enable us to move from disease treatment to disease prevention and optimal health. The key issues in such integrative understanding include the correlations between structure and function, genotype and phenotype, and systematic interactions among transporters, other proteins, nutrients, drugs, and the environment. The exploration in these key issues may ultimately contribute to personalized medicine with high efficacy but less toxicity.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Clayton, R.A., White, O., Ketchum, K.A., and Venter, J.C. (1997) The first genome from the third domain of life. Nature 29, 459–462.

    Article  Google Scholar 

  2. Lehninger, A.L., (1993) Principles of Biochemistry. Worth Publishing, New York, pp. 1–1013.

    Google Scholar 

  3. Lodish, H., Baltimore, D., Berk, A., Zipursky, S.L., Matsudaira, P., and Darnell, J. (1995) Molecular Cell Biology. Scientific American Books, New York, pp. 1–1417.

    Google Scholar 

  4. Paulsen, I.T., Sliwinski, M.K., and Saier, M.H. Jr. (1998) Microbial genome analyses: global comparisons of transport capabilities based on phylogenies, bioenergetics and substrate specificities. J. Mol. Biol. 277, 573–592.

    Article  CAS  PubMed  Google Scholar 

  5. Paulsen, I.T., Sliwinski,M.K., Nelissen, B., Goffeau, A., and Saier, M.H. Jr. (1998) Unified inventory of established and putative transporters encoded within the complete genome of Saccharomyces cerevisiae. FEBS Lett. 430, 116–125.

    Article  CAS  PubMed  Google Scholar 

  6. Saier, M.H. Jr. (2000) A functional-phylogenetic classification system for transmembrane solute transporters. Microbiol. Mol. Biol. Rev. 64, 354–411.

    Article  CAS  PubMed  Google Scholar 

  7. Higgins, C.F. (1992) ABC transporters: from microorganisms to man. Curr. Opin. Cell Biol. 8, 67–113.

    CAS  Google Scholar 

  8. Martin, M.G., Lostao, M.P., Turk, E., Lam, J., Kreman, M., and Wright, E.M. (1997) Compound missense mutations in the sodium/D-glucose cotransporter result in trafficking defects. Gastroenterology 112, 1206–1212.

    Article  CAS  PubMed  Google Scholar 

  9. Palacin, M., Bertran, J., and Zorzano, A. (2000) Heteromeric amino acid transporters explain inherited aminoacidurias. Curr. Opin. Nephrol. Hypertens. 9, 547–553.

    Article  CAS  PubMed  Google Scholar 

  10. Sheppard, D.N. and Welsh, M.J. (1999) Structure and function of the CFTR chloride channel. Physiol. Rev. 79, S23–S45.

    CAS  PubMed  Google Scholar 

  11. Hu, M., Retz, W., Baader, M., Pesold, B., Adler, G., Henn, F.A., Rosler, M., and Thome, J. (2000) Promoter polymorphism of the 5-HT transporter and Alzheimer’s disease. Neurosci. Lett. 294, 63–65.

    Article  CAS  PubMed  Google Scholar 

  12. Le Couteur, D.G., Leighton, P.W., McCann, S.J., and Pond, S. (1997) Association of a polymorphism in the dopamine-transporter gene with Parkinson’s disease. Mov. Disord. 12, 760–763.

    Article  PubMed  Google Scholar 

  13. Kim, J.W., Kim, D.H., Kim, S.H., and Cha, J.K. (2000) Association of the dopamine transporter gene with Parkinson’s disease in Korean patients. J. Korean Med. Sci. 15, 449–451.

    CAS  PubMed  Google Scholar 

  14. Tan, E.K., Khajavi, M., Thornby, J.I., Nagamitsu, S., Jankovic, J., and Ashizawa, T. (2000) Variability and validity of polymorphism association studies in Parkinson’s disease. Neurology 55, 533–538.

    CAS  PubMed  Google Scholar 

  15. Lee, V.H. (2000) Membrane transporters. Eur. J. Pharm. Sci. 11, S41–S50.

    Article  CAS  PubMed  Google Scholar 

  16. Leusch, A., Volz, A., Muller, G., Wagner, A., Sauer, A., Greischel, A., and Roth, W. (2002) Altered drug disposition of the platelet activating factor antagonist apafant in mdr1a knockout mice. Eur. J. Pharm. Sci. 16, 119–128.

    Article  CAS  PubMed  Google Scholar 

  17. Tamai, I. and Tsuji, A. (2000) Transporter-mediated permeation of drugs across the blood-brain barrier. J. Pharm. Sci. 89, 1371–1388.

    Article  CAS  PubMed  Google Scholar 

  18. Sugiyama, Y., Kusuhara, H., and Suzuki, H. (1999) Kinetic and biochemical analysis of carrier-mediated efflux of drugs through the blood-brain and blood-cerebrospinal fluid barriers: importance in the drug delivery to the brain. J. Control Release. 62, 179–186.

    Article  CAS  PubMed  Google Scholar 

  19. Inui, K.I., Masuda, S., and Saito, H. (2000) Cellular and molecular aspects of drug transport in the kidney. Kidney Int. 58, 944–958.

    Article  CAS  PubMed  Google Scholar 

  20. Sadee, W., Drubbisch, V., and Amidon, G.L. (1995) Biology of membrane transport proteins. Pharm. Res. 12, 1823–1837.

    Article  CAS  PubMed  Google Scholar 

  21. Silverman, J.A. (1999) Multidrug-resistance transporters. Pharm. Biotechnol. 12, 353–386.

    Article  CAS  PubMed  Google Scholar 

  22. Oh, D.M., Han, H.K., and Amidon, G.L. (1999) Drug transport and targeting. Intestinal transport. Pharm. Biotechnol. 12, 59–88.

    Article  CAS  PubMed  Google Scholar 

  23. Kruijtzer, C.M., Beijnen, J.H., Rosing, H., ten Bokkel Huinink, W.W., Schot, M., Jewell, R.C., Paul, E.M., and Schellens, J.H. (2002) Increased oral bioavailability of topotecan in combination with the breast cancer resistance protein and P-glycoprotein inhibitor GF120918. J. Clin. Oncol. 1, 2943–2950.

    Article  Google Scholar 

  24. Iversen, L. (2000) Neurotransmitter transporters: fruitful targets for CNS drug discovery. Mol. Psychiatry. 5, 357–362.

    Article  CAS  PubMed  Google Scholar 

  25. Rund, D., Azar, I., and Shperling, O. (1999) A mutation in the promoter of the multidrug resistance gene (MDR1) in human hematological malignancies may contribute to the pathogenesis of resistant disease. Adv. Exp. Med. Biol. 457, 71–75.

    CAS  PubMed  Google Scholar 

  26. Gerlach, J.H., Kartner, N., Bell, D.R., and Ling, V. (1986) Multidrug resistance. Cancer Surv. 5, 25–46.

    CAS  PubMed  Google Scholar 

  27. Smits, K., Smits, L., et al. (2007) Serotonin transporter polymorphisms and the occurrence of adverse events during treatment with selective serotonin reuptake inhibitors. Int. Clin. Psychopharmacol. 22, 137–143.

    Article  PubMed  Google Scholar 

  28. Raymond, V. and Sattelle, D.B. (2002) Novel animal-health drug targets from ligand-gated chloride channels. Nat. Rev. Drug Discov. 1, 427–436.

    Article  CAS  PubMed  Google Scholar 

  29. Kennedy, G.C. (2000) The impact of genomics on therapeutic drug development. EXS. 89, 1–10.

    CAS  PubMed  Google Scholar 

  30. Evans, W.E. and Relling, M.V. (1999) Pharmacogenomics: translating functional genomics into rational therapeutics. Science 286, 487–491.

    Article  CAS  PubMed  Google Scholar 

  31. Shi, M.M., Bleavins, M.R., and de la Iglesia, F.A. (1999) Technologies for detecting genetic polymorphisms in pharmacogenomics. Mol. Diagn. 4, 343–351.

    Article  CAS  PubMed  Google Scholar 

  32. Sadee, W. (2002) Pharmacogenomics: the implementation phase. AAPS Pharm. Sci. 4, E5.

    Google Scholar 

  33. Emilien, G., Ponchon, M., Caldas, C., Isacson, O., and Maloteaux, J.M. (2000) Impact of genomics on drug discovery and clinical medicine. QJM. 93, 391–423.

    Article  CAS  PubMed  Google Scholar 

  34. Hess, P. and Cooper, D. (1999) Impact of pharmacogenomics on the clinical laboratory. Mol. Diagn. 4, 289–298.

    Article  CAS  PubMed  Google Scholar 

  35. Roses, A.D. (2000) Pharmacogenetics and pharmacogenomics in the discovery and development of medicines. Novartis Found Symp. 229, 63–66.

    Article  CAS  PubMed  Google Scholar 

  36. March, R. (2000) Pharmacogenomics: the genomics of drug response. Yeast 17, 16–21.

    Article  CAS  PubMed  Google Scholar 

  37. Vogel, F. (1959) Moderne probleme der Humangenetik. Ergeb. Inn. Med. Kinderheilkd. 12, 52–125.

    Google Scholar 

  38. Nebert, D.W. (1997) Polymorphisms in drug-metabolizing enzymes: what is their clinical relevance and why do they exist? Am. J. Hum. Genet. 60, 265–271.

    CAS  PubMed  Google Scholar 

  39. Kitano H. (2002) Systems biology: a brief overview. Science 295, 1662–1664.

    Article  CAS  PubMed  Google Scholar 

  40. Winsberg, B.G. and Comings, D.E. (1999) Association of the dopamine transporter gene (DAT1) with poor methylphenidate response. J. Am. Acad. Child Adolesc. Psychiatry 38, 1474–1477.

    Article  CAS  PubMed  Google Scholar 

  41. Assem, M., Schuetz, E.G., Leggas, M., Sun, D., et al. (2004) Interactions between hepatic Mrp4 and Sult2A as revealed by the constitutive androstane receptor and Mrp4 knockout mice. J. Biol. Chem. 279, 22250–22257.

    Article  CAS  PubMed  Google Scholar 

  42. Flieger, O., Engling, A., Bucala, R., Lue, H., Nickel, W., Bernhagen, J. (2003) Regulated secretion of macrophage migration inhibitory factor is mediated by a non-classical pathway involving an ABC transporter. FEBS Lett. 11, 78–86.

    Article  Google Scholar 

  43. Hoffmeyer, S., Burk, O., von Richter, O., Arnold, H.P., Brockmoller, J., Johne, A., Cascorbi, I., Gerloff, T., Roots, I., Eichelbaum, M., Brinkmann, U. (2000) Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc. Natl. Acad. Sci. USA 97, 3473–3478.

    Article  CAS  PubMed  Google Scholar 

  44. Lesch, K.P., Bengel, D., Heils, A., Sabol, S.Z., Greenberg, B.D., Petri, S., Benjamin, J., Muller, C.R., Hamer, D.H., Murphy, D.L. (1996) Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 274, 1527–1531.

    Article  CAS  PubMed  Google Scholar 

  45. Smeraldi, E., Zanardi, R., Benedetti, F., Di Bella, D., Perez, J., Catalano, M. (1998) Polymorphism within the promoter of the serotonin transporter gene and antidepressant efficacy of fluvoxamine. Mol. Psychiatry 3, 508–511.

    Article  CAS  PubMed  Google Scholar 

  46. Kim, D.K., Lim, S.W., Lee, S., Sohn, S.E., Kim, S., Hahn, C.G., Carroll, B.J. (2000) Serotonin transporter gene polymorphism and antidepressant response. Neuroreport. 11, 215–219.

    Article  CAS  PubMed  Google Scholar 

  47. Pollock, B.G., Ferrell, R.E., Mulsant, B.H., Mazumdar, S., Miller, M., Sweet, R.A., Davis, S., Kirshner, M.A., Houck, P.R., Stack, J.A., Reynolds, C.F., Kupfer, D.J. (2000) Allelic variation in the serotonin transporter promoter affects onset of paroxetine treatment response in late-life depression. Neuropsychopharmacology 23, 587–590.

    Article  CAS  PubMed  Google Scholar 

  48. Zanardi, R., Benedetti, F., Di Bella, D., Catalano, M., Smeraldi, E. (2000) Efficacy of paroxetine in depression is influenced by a functional polymorphism within the promoter of the serotonin transporter gene. J. Clin. Psychopharmacol. 20, 105–107.

    Article  CAS  PubMed  Google Scholar 

  49. Camilleri, M., Atanasova, E., Carlson, P.J., Ahmad, U., Kim, H.J., Viramontes, B.E., McKinzie, S., Urrutia, R. (2002) Serotonin-transporter polymorphism pharmacogenetics in diarrhea-predominant irritable bowel syndrome. Gastroenterology 123, 425–432.

    Article  CAS  PubMed  Google Scholar 

  50. Anderson, M.P., Berger, H.A., Rich, D.P., Gregory, R.J., Smith, A.E., Welsh, M.J. (1991) Nucleoside triphosphates are required to open the CFTR chloride channel. Cell 67, 775–784.

    Article  CAS  PubMed  Google Scholar 

  51. Berger, H.A., Anderson, M.P., Gregory, R.J., Thompson, S., Howard, P.W., Maurer, R.A., Mulligan, R., Smith, A.E., Welsh, M.J. (1991) Identification and regulation of the cystic fibrosis transmembrane conductance regulator-generated chloride channel. J. Clin. Invest. 88, 1422–1431.

    Article  CAS  PubMed  Google Scholar 

  52. Lichtermann, D., Hranilovic, D., Trixler, M., Franke, P., Jernej, B., Delmo, C.D., Knapp, M., Schwab, S.G., Maier, W., Wildenauer, D.B. (2000) Support for allelic association of a polymorphic site in the promoter region of the serotonin transporter gene with risk for alcohol dependence. Am. J. Psychiatry 157, 2045–2047.

    Article  CAS  PubMed  Google Scholar 

  53. Hipfner, D.R., Deeley, R.G., Cole, S.P. (1999) Structural, mechanistic and clinical aspects of MRP1. Biochim. Biophys. Acta 1461, 359–376.

    Article  CAS  PubMed  Google Scholar 

  54. Borst, P., Evers, R., Kool, M., Wijnholds, J. (1999) The multidrug resistance protein family. Biochim. Biophys. Acta 1461, 347–357.

    Article  CAS  PubMed  Google Scholar 

  55. Konig, J., Nies, A.T., Cui, Y., Leier, I., Keppler, D. (1999) Conjugate export pumps of the multidrug resistance protein (MRP) family: localization, substrate specificity, and MRP2-mediated drug resistance. Biochim. Biophys. Acta 1461, 377–394.

    Article  CAS  PubMed  Google Scholar 

  56. Bejanin, S., Cervini, R., Mallet, J., Berrard, S. (1994) A unique gene organization for two cholinergic markers, choline acetyltransferase and a putative vesicular transporter of acetylcholine. J. Biol. Chem. 269, 21944–21947.

    CAS  PubMed  Google Scholar 

  57. Erickson, J.D., Varoqui, H., Schafer, M.K., Modi, W., Diebler, M.F., Weihe, E., Rand, J., Eiden, L.E., Bonner, T.I., Usdin, T.B. (1994) Functional identification of a vesicular acetylcholine transporter and its expression from a "cholinergic" gene locus. J. Biol. Chem. 269, 21929–21932.

    CAS  PubMed  Google Scholar 

  58. Protein Data Bank (PDB): http://www.rcsb.org/pdb/ (accessed in May 2009).

  59. Membrane Transporter Database Portal: http://www.pharmtao.com/transporter (accessed in May 2009).

  60. Sissung, T. M., Gardner, E. R., et al. (2008) Pharmacogenetics of membrane transporters: a review of current approaches. Methods Mol. Biol. 448, 41–62.

    Article  CAS  PubMed  Google Scholar 

  61. Lewis, R.A., Shroyer, N.F., Singh, N., Allikmets, R., Hutchinson, A., Li, Y., Lupski, J.R., Leppert, M., Dean, M. (1999) Genotype/Phenotype analysis of a photoreceptor-specific ATP-binding cassette transporter gene, ABCR, in Stargardt disease. Am. J. Hum. Genet. 64, 422–434.

    Article  CAS  PubMed  Google Scholar 

  62. Tokuhiro, S., Yamada, R., Chang, X., Suzuki, A., et al. (2003) An intronic SNP in a RUNX1 binding site of SLC22A4, encoding an organic cation transporter, is associated with rheumatoid arthritis. Nat Genet. 35, 341–348.

    Article  CAS  PubMed  Google Scholar 

  63. Brooks-Wilson, A., Marcil, M., Clee, S. M., Zhang, L.-H., Roomp, K., van Dam, M., Yu, L., Brewer, C., Collins, J. A., Molhuizen, H. O. F., Loubser, O., Ouelette, B. F. F., and 14 others. (1999) Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency. Nat. Genet. 22, 336–345.

    Article  CAS  PubMed  Google Scholar 

  64. Bodzioch, M., Orso, E., Klucken, J., Langmann, T., Bottcher, A., Diederich, W., Drobnik, W., Barlage, S., Buchler, C., Porsch-Ozcurumez, M., Kaminski, W. E., Hahmann, H. W., Oette, K., Rothe, G., Aslanidis, C., Lackner, K. J., Schmitz, G. (1999) The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease. Nat. Genet. 22, 347–351.

    Article  CAS  PubMed  Google Scholar 

  65. Allikmets, R., Shroyer, N. F., Singh, N., Seddon, J. M., Lewis, R. A., Bernstein, P. S., Peiffer, A., Zabriskie, N. A., Hutchinson, A., Dean, M., Lupski, J. R., Leppert, M. (1997) Mutation of the Stargardt disease gene (ABCR) in age-related macular degeneration. Science 277, 1805–1807.

    Article  CAS  PubMed  Google Scholar 

  66. Rivera, A., White, K., Stohr, H., Steiner, K., Hemmrich, N., Grimm, T., Jurklies, B., Lorenz, B., Scholl, H. P. N., Apfelstedt-Sylla, E., Weber, B. H. F. (2000) A comprehensive survey of sequence variation in the ABCA4 (ABCR) gene in Stargardt disease and age-related macular degeneration. Am. J. Hum. Genet. 67, 800–813.

    Article  CAS  PubMed  Google Scholar 

  67. Dixon, P. H., Weerasekera, N., Linton, K. J., Donaldson, O., Chambers, J., Egginton, E., Weaver, J., Nelson-Piercy, C., de Swiet, M., Warnes, G., Elias, E., Higgins, C. F., Johnston, D. G., McCarthy, M. I., Williamson, C. (2000) Heterozygous MDR3 missense mutation associated with intrahepatic cholestasis of pregnancy: evidence for a defect in protein trafficking. Hum. Mol. Genet. 9, 1209–1217.

    Article  CAS  PubMed  Google Scholar 

  68. Cartier, N., Sarde, C.-O., Douar, A.-M., Mosser, J., Mandel, J.-L., Aubourg, P. (1993) Abnormal messenger RNA expression and a missense mutation in patients with X-linked adrenoleukodystrophy. Hum. Mol. Genet. 2, 1949–1951.

    Article  CAS  PubMed  Google Scholar 

  69. Krasemann, E. W., Meier, V., Korenke, G. C., Hunneman, D. H., Hanefeld, F. (1996) Identification of mutations in the ALD-gene of 20 families with adrenoleukodystrophy/adrenomyeloneuropathy. Hum. Genet. 97, 194–197.

    Article  CAS  PubMed  Google Scholar 

  70. Kaler, S. G., Gallo, L. K., Proud, V. K., Percy, A. K., Mark, Y., Segal, N. A., Goldstein, D. S., Holmes, C. S., Gahl, W. A. (1994) Occipital horn syndrome and a mild Menkes phenotype associated with splice site mutations at the MNK locus. Nat. Genet. 8, 195–202.

    Article  CAS  PubMed  Google Scholar 

  71. Figus, A., Angius, A., Loudianos, G., Bertini, C., Dessi, V., Loi, A., Deiana, M., Lovicu, M., Olla, N., Sole, G., De Virgiliis, S., Lilliu, F., and 21 others. (1995) Molecular pathology and haplotype analysis of Wilson disease in Mediterranean populations. Am. J. Hum. Genet. 57, 1318–1324.

    CAS  PubMed  Google Scholar 

  72. Kim, E. K., Yoo, O. J., Song, K. Y., Yoo, H. W., Choi, S. Y., Cho, S. W., Hahn, S. H. (1998) Identification of three novel mutations and a high frequency of the arg778-to-leu mutation in Korean patients with Wilson disease. Hum. Mutat. 11, 275–278.

    Article  CAS  PubMed  Google Scholar 

  73. Jarolim, P., Palek, J., Rubin, H. L., Prchal, J. T., Korsgren, C., Cohen, C. M. (1991) Band 3 Tuscaloosa: pro327-to-arg327 substitution in the cytoplasmic domain of erythrocyte band 3 protein associated with spherocytic hemolytic anemia and partial deficiency of protein 4.2. (Abstract) Blood 78 (suppl.): 252a.

    Google Scholar 

  74. Wang, Y., Korman, S. H., Ye, J., Gargus, J. J., Gutman, A., Taroni, F., Garavaglia, B., Longo, N. (2001) Phenotype and genotype variation in primary carnitine deficiency. Genet. Med. 3, 387–392.

    Article  CAS  PubMed  Google Scholar 

  75. Van Hauwe, P., Everett, L. A., Coucke, P., Scott, D. A., Kraft, M. L., Ris-Stalpers, C., Bolder, C., Otten, B., de Vijlder, J. J. M., Dietrich, N. L., Ramesh, A., Srisailapathy, S. C. R., Parving, A., Cremers, C. W. R. J., Willems, P. J., Smith, R. J. H., Green, E. D., Van Camp, G. (1998) Two frequent missense mutations in Pendred syndrome. Hum. Mol. Genet. 7, 1099–1104.

    Article  PubMed  Google Scholar 

  76. Usami, S., Abe, S., Weston, M. D., Shinkawa, H., Van Camp, G., Kimberling, W. J. (1999) Non-syndromic hearing loss associated with enlarged vestibular aqueduct is caused by PDS mutations. Hum. Genet. 104, 188–192.

    Article  CAS  PubMed  Google Scholar 

  77. Colonna, M., Bresnahan, M., Bahram, S., Strominger, J. L., Spies, T. (1992) Allelic variants of the human putative peptide transporter involved in antigen processing. Proc. Nat. Acad. Sci. USA 89, 3932–3936.

    Article  CAS  PubMed  Google Scholar 

  78. Nebert, D.W. (1999) Pharmacogenetics and pharmacogenomics: why is this relevant to the clinical geneticist? Clin. Genet. 56, 247–258.

    Article  CAS  PubMed  Google Scholar 

  79. Dirckx, C., Donati, M.B., Iacoviello, L. (2000) Pharmacogenetics: a molecular sophistication or a new clinical tool for cardiologists? Ital. Heart J. 1, 662–666.

    CAS  PubMed  Google Scholar 

  80. Mockenhaupt, F.P., Eggelte, T.A., Till, H., Bienzle, U. (2001) Plasmodium falciparum pfcrt and pfmdr1 polymorphisms are associated with the pfdhfr N108 pyrimethamine-resistance mutation in isolates from Ghana. Trop. Med. Int. Health 6, 749–755.

    Article  CAS  PubMed  Google Scholar 

  81. Basco, L.K., Ringwald, P. (2001) Analysis of the key pfcrt point mutation and in vitro and in vivo response to chloroquine in Yaounde, Cameroon. J. Infect. Dis. 183, 1828–1831.

    Article  CAS  PubMed  Google Scholar 

  82. Kim, R.B., Leake, B.F., Choo, E.F., Dresser, G.K., Kubba, S.V., Schwarz, U.I., Taylor, A., Xie, H.G., McKinsey, J., Zhou, S., Lan, L.B., Schuetz, J.D., Schuetz, E.G., Wilkinson, G.R. (2001) Identification of functionally variant MDR1 alleles among European Americans and African Americans. Clin. Pharmacol. Ther. 70, 189–199.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  84. Winsberg, B.G., Comings, D.E. (1999) Association of the dopamine transporter gene (DAT1) with poor methylphenidate response. J. Am. Acad. Child Adolesc. Psychiatry 38, 1474–1477.

    Article  CAS  PubMed  Google Scholar 

  85. Lerman, C., Shields, P.G., Wileyto, E.P., Audrain, J., Hawk, L.H. Jr., Pinto, A., Kucharski, S., Krishnan, S., Niaura, R., Epstein, L.H. (2003) Effects of dopamine transporter and receptor polymorphisms on smoking cessation in a bupropion clinical trial. Health Psychol. 22, 541–548.

    Article  PubMed  Google Scholar 

  86. Ghosh, D., Skinner, M. A., et al. (2007) Pharmacogenomics and nutrigenomics: synergies and differences. Eur. J. Clin. Nutr. 61, 567–574.

    Article  CAS  PubMed  Google Scholar 

  87. de Vogel-van den Bosch, H. M., de Wit, N. J., et al. (2008) A cholesterol-free, high-fat diet suppresses gene expression of cholesterol transporters in murine small intestine. Am. J. Physiol. Gastrointest. Liver Physiol. 294, G1171–1180.

    Google Scholar 

  88. Eny, K. M., Wolever, T. M., et al. (2008) Genetic variant in the glucose transporter type 2 is associated with higher intakes of sugars in two distinct populations. Physiol. Genomics 33, 355–360.

    Article  CAS  PubMed  Google Scholar 

  89. Kim, K. S., Cho, D. Y., et al. (2005) The finding of new genetic polymorphism of UCP-1 A-1766G and its effects on body fat accumulation. Biochim. Biophys. Acta. 1741, 149–155.

    CAS  PubMed  Google Scholar 

  90. Shin, H. D., Kim, K. S., et al. (2005) The effects of UCP-1 polymorphisms on obesity phenotypes among Korean female subjects. Biochem Biophys. Res. Commun. 335, 624–630.

    Article  CAS  PubMed  Google Scholar 

  91. Doege, H., Grimm, D., et al. (2008) Silencing of hepatic fatty acid transporter protein 5 in vivo reverses diet-induced non-alcoholic fatty liver disease and improves hyperglycemia. J. Biol. Chem. 283, 22186–22192.

    Article  CAS  PubMed  Google Scholar 

  92. Uehara, Y., Miura, S., et al. (2007) Unsaturated fatty acids suppress the expression of the ATP-binding cassette transporter G1 (ABCG1) and ABCA1 genes via an LXR/RXR responsive element. Atherosclerosis 191, 11–21.

    Article  CAS  PubMed  Google Scholar 

  93. Ukkola, O., Joanisse, D. R., et al. (2003) Na+-K+-ATPase alpha 2-gene and skeletal muscle characteristics in response to long-term overfeeding. J. Appl. Physiol. 94, 1870–1874.

    CAS  PubMed  Google Scholar 

  94. Mekus, F., Laabs, U., et al. (2003) Genes in the vicinity of CFTR modulate the cystic fibrosis phenotype in highly concordant or discordant F508del homozygous sib pairs. Hum. Genet. 112, 1–11.

    Article  CAS  PubMed  Google Scholar 

  95. Hindlet, P., Bado, A., et al. (2009) Reduced intestinal absorption of dipeptides via PepT1 in mice with diet-induced obesity is associated with leptin receptor down-regulation. J. Biol. Chem. 284, 6801–6808.

    Article  CAS  PubMed  Google Scholar 

  96. Varma, S., Campbell, C. E., et al. (2008) Functional role of conserved transmembrane segment 1 residues in human sodium-dependent vitamin C transporters. Biochemistry 47, 2952–2960.

    Article  CAS  PubMed  Google Scholar 

  97. Luo, S., Kansara, V. S., et al. (2006) Functional characterization of sodium-dependent multivitamin transporter in MDCK-MDR1 cells and its utilization as a target for drug delivery. Mol. Pharm. 3, 329–339.

    Article  CAS  PubMed  Google Scholar 

  98. Hirota, T., Takane, H., et al. (2008) Epigenetic regulation of genes encoding drug-metabolizing enzymes and transporters; DNA methylation and other mechanisms. Curr. Drug Metab. 9, 34–38.

    Article  CAS  PubMed  Google Scholar 

  99. Calcagno, A. M., Fostel, J. M., et al. (2008) Single-step doxorubicin-selected cancer cells overexpress the ABCG2 drug transporter through epigenetic changes. Br. J. Cancer 98, 1515–1524.

    Article  CAS  PubMed  Google Scholar 

  100. Sadee, W. (1998) Genomics and drugs: finding the optimal drug for the right patient. Pharm. Res. 15, 959–963.

    Article  CAS  PubMed  Google Scholar 

  101. Nebert, D.W., Jorge-Nebert, L., Vesell, E.S. (2003) Pharmacogenomics and "individualized drug therapy": high expectations and disappointing achievements. Am. J. Pharmacogenomics 3, 361–370.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. PharmTao, Santa Clara, CA, USA

    Qing Yan

Authors
  1. Qing Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. PharmTao, Santa Clara, USA

    Qing Yan

Rights and permissions

Reprints and permissions

Copyright information

© 2010 Springer Science+Business Media, LLC

About this protocol

Cite this protocol

Yan, Q. (2010). Membrane Transporters and Drug Development: Relevance to Pharmacogenomics, Nutrigenomics, Epigenetics, and Systems Biology. In: Yan, Q. (eds) Membrane Transporters in Drug Discovery and Development. Methods in Molecular Biology, vol 637. Humana Press. https://doi.org/10.1007/978-1-60761-700-6_1

Download citation

  • DOI: https://doi.org/10.1007/978-1-60761-700-6_1

  • Published:

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-60761-699-3

  • Online ISBN: 978-1-60761-700-6

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation