Drug transporter pharmacogenetics in nucleoside-based therapies

Pharmacogenomics

Volumn 11, Issue 6, 2010, Pages 809-841

  Errasti Murugarren, Ekaitz ^a,b   Pastor Anglada, Maral ^a,b  

^a UNIVERSITY OF BARCELONA   (Spain)

^b INSTITUTO DE SALUD CARLOS III   (Spain)

Author keywords

ABC; Chemotherapy; Nucleobase; Nucleoside; Pharmacogenetics; Plasma membrane transporter; Polymorphic variant; SLC

Indexed keywords

6 MERCAPTOPURINE DERIVATIVE; ADEFOVIR; AZATHIOPRINE; BREAST CANCER RESISTANCE PROTEIN; CYCLOPHOSPHAMIDE; DEOXYURIDINE; FLOXURIDINE; FLUOROURACIL; GEMCITABINE; LAMIVUDINE; METHOTREXATE; MULTIDRUG RESISTANCE PROTEIN 1; MULTIDRUG RESISTANCE PROTEIN 2; MULTIDRUG RESISTANCE PROTEIN 3; MULTIDRUG RESISTANCE PROTEIN 4; NUCLEOSIDE DERIVATIVE; NUCLEOTIDE TRANSPORTER; ORGANIC CATION TRANSPORTER; ORGANIC CATION TRANSPORTER 2; PEPTIDE TRANSPORTER 1; PROTEIN ABCB; PROTEIN SLC22; PROTEIN SLC28A1; PROTEIN SLC29A1; PROTEIN SLC29A2; PROTEIN SLC29A3; PROTEIN SLC29A4; UNCLASSIFIED DRUG; UNINDEXED DRUG; ZALCITABINE; ZIDOVUDINE; CARRIER PROTEIN; NUCLEOSIDE;

BLOOD BRAIN BARRIER; CANCER COMBINATION CHEMOTHERAPY; CELL MEMBRANE; CELLULAR DISTRIBUTION; DNA POLYMORPHISM; DRUG STRUCTURE; DRUG TRANSPORT; GENE ACTIVITY; GENE EXPRESSION; GENE FUNCTION; GENE MUTATION; GENE TRANSLOCATION; GENETIC VARIABILITY; HUMAN; MULTIGENE FAMILY; PHARMACOGENOMICS; PROMOTER REGION; REVIEW; SINGLE NUCLEOTIDE POLYMORPHISM; TISSUE DISTRIBUTION; BIOAVAILABILITY; CHEMICAL STRUCTURE; DRUG EFFECTS; ENZYME SPECIFICITY; GENETICS; METABOLISM; PHARMACOGENETICS;

BIOLOGICAL AVAILABILITY; CARRIER PROTEINS; CELL MEMBRANE; HUMANS; MOLECULAR STRUCTURE; NUCLEOSIDES; PHARMACOGENETICS; SUBSTRATE SPECIFICITY;

EID: 77952895164     PISSN: 14622416     EISSN: 17448042     Source Type: Journal    
DOI: 10.2217/pgs.10.70     Document Type: Review

References (274)

1. Anderle P, Huang Y, Sadee W: Intestinal membrane transport of drugs and nutrients: genomics of membrane transporters using expression microarrays. Eur. J. Pharm. Sci. 21(1), 17-24 (2004).
2. Pastor-Anglada M, Cano-Soldado P, Molina-Arcas M et al.: Cell entry and export of nucleoside analogues. Virus Res. 107(2), 151-164 (2005).
3. Pastor-Anglada M, Cano-Soldado P, Errasti-Murugarren E, Casado FJ: SLC28 genes and concentrative nucleoside transporter (CNT) proteins. Xenobiotica 38(7-8), 972-994 (2008).
4. Young JD, Yao SY, Sun L, Cass CE, Baldwin SA: Human equilibrative nucleoside transporter (ENT) family of nucleoside and nucleobase transporter proteins. Xenobiotica 38(7-8), 995-1021 (2008).
5. Mackey JR, Yao SY, Smith KM et al.: Gemcitabine transport in xenopus oocytes expressing recombinant plasma membrane mammalian nucleoside transporters. J. Natl Cancer Inst. 91(21), 1876-1881 (1999).
6. Mata JF, Garcia-Manteiga JM, Lostao MP et al.: Role of the human concentrative nucleoside transporter (hCNT1) in the cytotoxic action of 5[prime]-deoxy-5-fuorouridine, an active intermediate metabolite of capecitabine, a novel oral anticancer drug. Mol. Pharmacol. 59(6), 1542-1548 (2001).
7. Cano-Soldado P, Lorrayoz IM, Molina-Arcas M et al.: Interaction of nucleoside inhibitors of HIV-1 reverse transcriptase with the concentrative nucleoside transporter-1 (SLC28A1). Antivir. Ther. 9(6), 993-1002 (2004).
8. Lang TT, Selner M, Young JD, Cass CE: Acquisition of human concentrative nucleoside transporter 2 (HCNT2) activity by gene transfer confers sensitivity to fuoropyrimidine nucleosides in drug-resistant leukemia cells. Mol. Pharmacol. 60(5), 1143-1152 (2001).
9. Errasti-Murugarren E, Pastor-Anglada M, Casado FJ: Role of CNT3 in the transepithelial fux of nucleosides and nucleoside-derived drugs. J. Physiol. 582(Pt 3), 1249-1260 (2007).
10. Ritzel M W, Ng AM, Yao SY et al.: Molecular identifcation and characterization of novel human and mouse concentrative Na+- nucleoside cotransporter proteins (hCNT3 and mCNT3) broadly selective for purine and pyrimidine nucleosides (system CIB). J. Biol. Chem. 276(4), 2914-2927 (2001).
11. Naito T, Tokashiki S, Mino Y et al.: Impact of concentrative nucleoside transporter 1 gene polymorphism on oral bioavailability of mizoribine in stable kidney transplant recipients. Basic Clin. Pharmacol. Toxicol. 106(4), 310-316 (2009).
12. Osses N, Pearson JD, Yudilevich DL, Jarvis SM: Hypoxanthine enters human vascular endothelial cells (ECV 304) via the nitrobenzylthioinosine-insensitive equilibrative nucleoside transporter. Biochem. J. 317 (Pt 3), 843-848 (1996).
13. Crawford CR, Patel DH, Naeve C, Belt JA: Cloning of the human equilibrative, nitrobenzylmercaptopurine riboside (NBMPR)-insensitive nucleoside transporter EI by functional expression in a transport-defcient cell line. J. Biol. Chem. 273(9), 5288-5293 (1998).
14. Mani RS, Hammond JR, Marjan JM et al.: Demonstration of equilibrative nucleoside transporters (hENT1 and hENT2) in nuclear envelopes of cultured human choriocarcinoma (BeWo) cells by functional reconstitution in proteoliposomes. J. Biol. Chem. 273(46), 30818-30825 (1998).
15. Lai Y, Tse CM, Unadkat JD: Mitochondrial expression of the human equilibrative nucleoside transporter 1 (hENT1) results in enhanced mitochondrial toxicity of antiviral drugs. J. Biol. Chem. 279(6), 4490-4497 (2004).
16. Baldwin SA, Yao SY, Hyde RJ et al.: Functional characterization of novel human and mouse equilibrative nucleoside transporters (hENT3 and mENT3) located in intracellular membranes. J. Biol. Chem. 280(16), 15880-15887 (2005).
17. Govindarajan R, Leung GP, Zhou M, Tse CM, Wang J, Unadkat JD: Facilitated mitochondrial import of antiviral and anticancer nucleoside drugs by human equilibrative nucleoside transporter-3. Am. J. Physiol. Gastrointest. Liver Physiol. 296(4), G910-G922 (2009).
18. Scruggs ER, Dirks Naylor AJ: Mechanisms of zidovudine-induced mitochondrial toxicity and myopathy. Pharmacology 82(2), 83-88 (2008).
19. Zhou M, Xia L, Engel K, Wang J: Molecular determinants of substrate selectivity of a novel organic cation transporter (PMAT) in the SLC29 family. J. Biol. Chem. 282(5), 3188-3195 (2007).
20. Li H, Smolen GA, Beers LF et al.: Adenosine transporter ENT4 is a direct target of EWS/WT1 translocation product and is highly expressed in desmoplastic small round cell tumor. PLoS One 3(6), E2353 (2008).
21. Ciarimboli G: Organic cation transporters. Xenobiotica 38(7-8), 936-971 (2008).
22. Srimaroeng C, Perry JL, Pritchard JB: Physiology, structure, and regulation of the cloned organic anion transporters. Xenobiotica 38(7-8), 889-935 (2008).
23. Hu H, Endres CJ, Chang C et al.: Electrophysiological characterization and modeling of the structure activity relationship of the human concentrative nucleoside transporter 3 (hCNT3). Mol. Pharmacol. 69(5), 1542-1553 (2006).
24. Fotoohi AK, Lindqvist M, Peterson C, Albertioni F: Involvement of the concentrative nucleoside transporter 3 and equilibrative nucleoside transporter 2 in the resistance of T-lymphoblastic cell lines to thiopurines. Biochem. Biophys. Res. Commun. 343(1), 208-215 (2006).
25. Minuesa G, Volk C, Molina-Arcas M et al.: Transport of lamivudine [(-)-b-l-2́,3́-dideoxy-3́-thiacytidine] and high-affnity interaction of nucleoside reverse transcriptase inhibitors with human organic cation transporters 1, 2, and 3. J. Pharmacol. Exp. Ther. 329(1), 252-261 (2009).
26. Takeda M, Khamdang S, Narikawa S et al.: Human organic anion transporters and human organic cation transporters mediate renal antiviral transport. J. Pharmacol. Exp. Ther. 300(3), 918-924 (2002). (Pubitemid 34164996)
27. Tzvetkov MV, Vormfelde SV, Balen D et al.: The effects of genetic polymorphisms in the organic cation transporters OCT1, OCT2, and OCT3 on the renal clearance of metformin. Clin. Pharmacol. Ther. 86(3), 299-306 (2009).
28. Song IS, Shin HJ, Shim EJ et al.: Genetic variants of the organic cation transporter 2 infuence the disposition of metformin. Clin. Pharmacol. Ther. 84(5), 559-562 (2008).
29. Vanwert AL, Gionfriddo MR, Sweet DH: Organic anion transporters: discovery, pharmacology, regulation and roles in pathophysiology. Biopharm. Drug Dispos. 31(1), 1-71 (2010).
30. Kobayashi Y, Ohshiro N, Tsuchiya A, Kohyama N, Ohbayashi M, Yamamoto T: Renal transport of organic compounds mediated by mouse organic anion transporter 3 (mOAT3): further substrate specifcity of mOAT3. Drug Metab. Dispos. 32(5), 479-483 (2004).
31. Kobayashi Y, Ohshiro N, Sakai R, Ohbayashi M, Kohyama N, Yamamoto T: Transport mechanism and substrate specifcity of human organic anion transporter 2 (hOAT2 [SLC22A7]). J. Pharm. Pharmacol. 57(5), 573-578 (2005).
32. Rubio-Aliaga I, Daniel H: Peptide transporters and their roles in physiological processes and drug disposition. Xenobiotica 38(7-8), 1022-1042 (2008).
33. Ganapathy ME, Huang W, Wang H, Ganapathy V, Leibach FH: Valacyclovir: a substrate for the intestinal and renal peptide transporters PepT1 and PepT2. Biochem. Biophys. Res. Commun. 246(2), 470-475 (1998).
34. Thomsen AE, Christensen MS, Bagger MA, Steffansen B: Acyclovir prodrug for the intestinal di/tri-peptide transporter PepT1: comparison of in vivo bioavailability in rats and transport in Caco-2 cells. Eur. J. Pharm. Sci. 23(4-5), 319-325 (2004).
35. Landowski CP, Song X, Lorenzi PL, Hilfnger JM, Amidon GL: Floxuridine amino acid ester prodrugs: enhancing Caco-2 permeability and resistance to glycosidic bond metabolism. Pharm. Res. 22(9), 1510-1518 (2005).
36. Zhou SF: Structure, function and regulation of P-glycoprotein and its clinical relevance in drug disposition. Xenobiotica 38(7-8), 802-832 (2008).
37. Zhou SF, Wang LL, Di YM et al.: Substrates and inhibitors of human multidrug resistance associated proteins and the implications in drug development. Curr. Med. Chem. 15(20), 1981-2039 (2008).
38. Loo T W, Clarke DM: Mutational ana lysis of ABC proteins. Arch. Biochem. Biophys. 476(1), 51-64 (2008).
39. Weiss J, Theile D, Ketabi-Kiyanvash N, Lindenmaier H, Haefeli WE: Inhibition of MRP1/ABCC1, MRP2/ABCC2, and MRP3/ABCC3 by nucleoside, nucleotide, and non-nucleoside reverse transcriptase inhibitors. Drug Metab. Dispos. 35(3), 340-344 (2007).
40. Walsh N, Larkin A, Kennedy S et al.: Expression of multidrug resistance markers ABCB1 (MDR-1/P-gp) and ABCC1 (MRP-1) in renal cell carcinoma. BMC Urol. 9, 6 (2009).
41. Nagashige M, Ushigome F, Koyabu N et al.: Basal membrane localization of MRP1 in human placental trophoblast. Placenta 24(10), 951-958 (2003).
42. Servais A, Lechat P, Zahr N et al.: [Tubular transporters OAT1 and MRP2 and clearance of adefovir]. Nephrol. Ther. 1(5), 296-300 (2005).
43. Cundy KC: Clinical pharmacokinetics of the antiviral nucleotide analogues cidofovir and adefovir. Clin. Pharmacokinet. 36(2), 127-143 (1999).
44. Rius M, Nies AT, Hummel-Eisenbeiss J, Jedlitschky G, Keppler D: Cotransport of reduced glutathione with bile salts by MRP4 (ABCC4) localized to the basolateral hepatocyte membrane. Hepatology 38(2), 374-384 (2003).
45. Lee K, Klein-Szanto AJ, Kruh GD: Analysis of the MRP4 drug resistance profle in transfected NIH3T3 cells. J. Natl Cancer Inst. 92(23), 1934-1940 (2000).
46. Van Aubel RA, Smeets PH, Peters JG, Bindels RJ, Russel FG: The MRP4/ABCC4 gene encodes a novel apical organic anion transporter in human kidney proximal tubules: putative effux pump for urinary cAMP and cGMP. J. Am. Soc. Nephrol. 13(3), 595-603 (2002).
47. Meyer Zu Schwabedissen HE, Grube M, Heydrich B et al.: Expression, localization, and function of MRP5 (ABCC5), a transporter for cyclic nucleotides, in human placenta and cultured human trophoblasts: effects of gestational age and cellular differentiation. Am. J. Pathol. 166(1), 39-48 (2005).
48. Hopper-Borge E, Xu X, Shen T, Shi Z, Chen ZS, Kruh GD: Human multidrug resistance protein 7 (ABCC10) is a resistance factor for nucleoside analogues and epothilone B. Cancer Res. 69(1), 178-184 (2009).
49. Robey RW, To KK, Polgar O et al.: ABCG2: a perspective. Adv. Drug Deliv. Rev. 61(1), 3-13 (2009).
50. Gradhand U, Kim RB: Pharmacogenomics of MRP transporters (ABCC1-5) and BCRP (ABCG2). Drug Metab. Rev. 40(2), 317-354 (2008).
51. Heinemann V, Hertel LW, Grindey GB, Plunkett W: Comparison of the cellular pharmacokinetics and toxicity of 2́,2́-difuorodeoxycytidine and 1-b-D-arabinofuranosylcytosine. Cancer Res. 48(14), 4024-4031 (1988).
52. Abbruzzese JL, Grunewald R, Weeks EA et al.: A Phase I clinical, plasma, and cellular pharmacology study of gemcitabine. J. Clin. Oncol. 9(3), 491-498 (1991).
53. Molina-Arcas M, Marce S, Villamor N et al.: Equilibrative nucleoside transporter-2 (hENT2) protein expression correlates with ex vivo sensitivity to fudarabine in chronic lymphocytic leukemia (CLL) cells. Leukemia 19(1), 64-68 (2005).
54. Dresser MJ, Leabman MK, Giacomini KM: Transporters involved in the elimination of drugs in the kidney: organic anion transporters and organic cation transporters. J. Pharm. Sci. 90(4), 397-421 (2001).
55. Zair ZM, Eloranta JJ, Stieger B, Kullak-Ublick GA: Pharmacogenetics of OATP (SLC21/SLCO), OAT and OCT (SLC22) and PepT (SLC15) transporters in the intestine, liver and kidney. Pharmacogenomics 9(5), 597-624 (2008).
56. Wada M: Single nucleotide polymorphisms in ABCC2 and ABCB1 genes and their clinical impact in physiology and drug response. Cancer Lett. 234(1), 40-50 (2006).
57. Molho-Pessach V, Lerer I, Abeliovich D et al.: The H syndrome is caused by mutations in the nucleoside transporter hENT3. Am. J. Hum. Genet. 83(4), 529-534 (2008).
58. Lazar A, Walitza S, Jetter A et al.: Novel mutations of the extraneuronal monoamine transporter gene in children and adolescents with obsessive-compulsive disorder. Int. J. Neuropsychopharmacol. 11(1), 35-48 (2008).
59. Gray JH, Mangravite LM, Owen RP et al.: Functional and genetic diversity in the concentrative nucleoside transporter, CNT1, in human populations. Mol. Pharmacol. 65(3), 512-519 (2004).
60. Soo RA, Wang LZ, Ng SS et al.: Distribution of gemcitabine pathway genotypes in ethnic Asians and their association with outcome in non-small cell lung cancer patients. Lung Cancer 63(1), 121-127 (2009).
61. Owen RP, Gray JH, Taylor TR et al.: Genetic ana lysis and functional characterization of polymorphisms in the human concentrative nucleoside transporter, CNT2. Pharmacogenet. Genomics 15(2), 83-90 (2005).
62. Li L, Tan CM, Koo SH, Chong KT, Lee EJ: Identifcation and functional ana lysis of variants in the human concentrative nucleoside transporter 2, hCNT2 (SLC28A2) in Chinese, Malays and Indians. Pharmacogenet. Genomics 17(9), 783-786 (2007).
63. Li L, Koo SH, Hong IH, Lee EJ: Identifcation of functional promoter haplotypes of human concentrative nucleoside transporter 2, hCNT2 (SLC28A2). Drug Metab. Pharmacokinet. 24(2), 161-166 (2009).
64. Yee SW, Shima JE, Hesselson S et al.: Identifcation and characterization of proximal promoter polymorphisms in the human concentrative nucleoside transporter 2 (SLC28A2). J. Pharmacol. Exp. Ther. 328(3), 699-707 (2009).
65. Badagnani I, Chan W, Castro RA et al.: Functional ana lysis of genetic variants in the human concentrative nucleoside transporter 3 (CNT3; SLC28A3). Pharmacogenomics J. 5(3), 157-165 (2005).
66. Damaraju S, Zhang J, Visser F et al.: Identifcation and functional characterization of variants in human concentrative nucleoside transporter 3, hCNT3 (SLC28A3), arising from single nucleotide polymorphisms in coding regions of the hCNT3 gene. Pharmacogenet. Genomics 15(3), 173-182 (2005).
67. Errasti-Murugarren E, Cano-Soldado P, Pastor-Anglada M, Casado FJ: Functional characterization of a nucleoside-derived drug transporter variant (hCNT3c602r) showing altered sodium-binding capacity. Mol. Pharmacol. 73(2), 379-386 (2008).
68. Myers SN, Goyal RK, Roy JD, Fairfull LD, Wilson JW, Ferrell RE: Functional single nucleotide polymorphism haplotypes in the human equilibrative nucleoside transporter 1. Pharmacogenet. Genomics 16(5), 315-320 (2006).
69. Owen R P, Lagpacan LL, Taylor TR et al.: Functional characterization and haplotype ana lysis of polymorphisms in the human equilibrative nucleoside transporter, ENT2. Drug Metab. Dispos. 34(1), 12-15 (2006).
70. Cliffe ST, Kramer JM, Hussain K et al.: SLC29A3 gene is mutated in pigmented hypertrichosis with insulin-dependent diabetes mellitus syndrome and interacts with the insulin signaling pathway. Hum. Mol. Genet. 18(12), 2257-2265 (2009).
71. Shu Y, Leabman MK, Feng B et al.: Evolutionary conservation predicts function of variants of the human organic cation transporter, OCT1. Proc. Natl Acad. Sci. USA 100(10), 5902-5907 (2003).
72. Shu Y, Sheardown SA, Brown C et al.: Effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action. J. Clin. Invest 117(5), 1422-1431 (2007).
73. Kerb R, Brinkmann U, Chatskaia N et al.: Identifcation of genetic variations of the human organic cation transporter hOCT1 and their functional consequences. Pharmacogenetics 12(8), 591-595 (2002).
74. Song IS, Shin HJ, Shin JG: Genetic variants of organic cation transporter 2 (OCT2) signifcantly reduce metformin uptake in oocytes. Xenobiotica 38(9), 1252-1262 (2008).
75. Leabman MK, Huang CC, Kawamoto M et al.: Polymorphisms in a human kidney xenobiotic transporter, OCT2, exhibit altered function. Pharmacogenetics 12(5), 395-405 (2002).
76. Ogasawara K, Terada T, Motohashi H et al.: Analysis of regulatory polymorphisms in organic ion transporter genes (SLC22A) in the kidney. J. Hum. Genet. 53(7), 607-614 (2008).
77. Nies AT, Koepsell H, Winter S et al.: Expression of organic cation transporters OCT1 (SLC22A1) and OCT3 (SLC22A3) is affected by genetic factors and cholestasis in human liver. Hepatology 50(4), 1227-1240 (2009).
78. Bleasby K, Hall LA, Perry JL, Mohrenweiser H W, Pritchard JB: Functional consequences of single nucleotide polymorphisms in the human organic anion transporter hOAT1 (SLC22A6). J. Pharmacol. Exp. Ther. 314(2), 923-931 (2005).
79. Fujita T, Brown C, Carlson EJ et al.: Functional ana lysis of polymorphisms in the organic anion transporter, SLC22A6 (OAT1). Pharmacogenet. Genomics 15(4), 201-209 (2005).
80. Erdman AR, Mangravite LM, Urban TJ et al.: The human organic anion transporter 3 (OAT3; SLC22A8): genetic variation and functional genomics. Am. J. Physiol. Renal Physiol. 290(4), F905-F912 (2006).
81. Anderle P, Nielsen CU, Pinsonneault J, Krog PL, Brodin B, Sadee W: Genetic variants of the human dipeptide transporter PepT1. J. Pharmacol. Exp. Ther. 316(2), 636-646 (2006).
82. Zucchelli M, Torkvist L, Bresso F et al.: PepT1 oligopeptide transporter (SLC15A1) gene polymorphism in infammatory bowel disease. Infamm. Bowel Dis. 15(10), 1562-1569 (2009).
83. Zhang EY, Fu DJ, Pak YA et al.: Genetic polymorphisms in human proton-dependent dipeptide transporter PepT1: implications for the functional role of pro586. J. Pharmacol. Exp. Ther. 310(2), 437-445 (2004).
84. Gervasini G, Carrillo JA, Garcia M, San Jose C, Cabanillas A, Benitez J: Adenosine triphosphate-binding cassette B1 (ABCB1) (multidrug resistance 1) G2677T/A gene polymorphism is associated with high risk of lung cancer. Cancer 107(12), 2850-2857 (2006).
85. Swerts K, De Moerloose B, Dhooge C, Laureys G, Benoit Y, Philippe J: Prognostic signifcance of multidrug resistance-related proteins in childhood acute lymphoblastic leukaemia. Eur. J. Cancer 42(3), 295-309 (2006).
86. Mendoza JL, Urcelay E, Lana R et al.: MDR1 polymorphisms and response to azathioprine therapy in patients with Crohn's disease. Infamm. Bowel Dis. 13(5), 585-590 (2007).
87. Kim RB, Leake BF, Choo EF et al.: Identifcation of functionally variant MDR1 alleles among European Americans and African Americans. Clin. Pharmacol. Ther. 70(2), 189-199 (2001).
88. 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. 62(1), 1-6 (2002).
89. Salama NN, Yang Z, Bui T, Ho RJ: MDR1 haplotypes signifcantly minimize intracellular uptake and transcellular P-gp substrate transport in recombinant LLC-PK1 cells. J. Pharm. Sci. 95(10), 2293-2308 (2006).
90. Hoffmeyer S, Burk O, Von Richter O et al.: 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(7), 3473-3478 (2000).
91. Nakamura T, Sakaeda T, Horinouchi M et al.: Effect of the mutation (C3435T) at exon 26 of the MDR1 gene on expression level of MDR1 messenger ribonucleic acid in duodenal enterocytes of healthy japanese subjects. Clin. Pharmacol. Ther. 71(4), 297-303 (2002).
92. Goto M, Masuda S, Saito H et al.: C3435T polymorphism in the MDR1 gene affects the enterocyte expression level of CYP3A4 rather than Pgp in recipients of living-donor liver transplantation. Pharmacogenetics 12(6), 451-457 (2002).
93. Turgut S, Yaren A, Kursunluoglu R, Turgut G: MDR1 C3435T polymorphism in patients with breast cancer. Arch. Med. Res. 38(5), 539-544 (2007).
94. George J, Dharanipragada K, Krishnamachari S, Chandrasekaran A, Sam SS, Sunder E: A single-nucleotide polymorphism in the MDR1 gene as a predictor of response to neoadjuvant chemotherapy in breast cancer. Clin. Breast Cancer 9(3), 161-165 (2009).
95. Siegsmund M, Brinkmann U, Schaffeler E et al.: Association of the P-glycoprotein transporter MDR1(C3435T) polymorphism with the susceptibility to renal epithelial tumors. J. Am. Soc. Nephrol. 13(7), 1847-1854 (2002).
96. Jamroziak K, Mlynarski W, Balcerczak E et al.: Functional C3435T polymorphism of MDR1 gene: an impact on genetic susceptibility and clinical outcome of childhood acute lymphoblastic leukemia. Eur. J. Haematol. 72(5), 314-321 (2004).
97. Farnood A, Naderi N, Moghaddam SJ et al.: The frequency of C3435T MDR1 gene polymorphism in iranian patients with ulcerative colitis. Int. J. Colorectal Dis. 22(9), 999-1003 (2007).
98. 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. 64(1), 183-188 (2009).
99. Tanabe M, Ieiri I, Nagata N et al.: Expression of P-glycoprotein in human placenta: relation to genetic polymorphism of the multidrug resistance (MDR)-1 gene. J. Pharmacol. Exp. Ther. 297(3), 1137-1143 (2001).
100. Conrad S, Kauffmann HM, Ito K et al.: A naturally occurring mutation in MRP1 results in a selective decrease in organic anion transport and in increased doxorubicin resistance. Pharmacogenetics 12(4), 321-330 (2002).
101. Letourneau IJ, Deeley RG, Cole SP: Functional characterization of non?synonymous single nucleotide polymorphisms in the gene encoding human multidrug resistance protein 1 (MRP1/ABCC1). Pharmacogenet. Genomics 15(9), 647-657 (2005).
102. Wang Z, Wang B, Tang K, Lee EJ, Chong SS, Lee CG: A functional polymorphism within the MRP1 gene locus identifed through its genomic signature of positive selection. Hum. Mol. Genet. 14(14), 2075-2087 (2005).
103. Hulot JS, Villard E, Maguy A et al.: A mutation in the drug transporter gene ABCC2 associated with impaired methotrexate elimination. Pharmacogenet. Genomics 15(5), 277-285 (2005).
104. Izzedine H, Hulot JS, Villard E et al.: Association between ABCC2 gene haplotypes and tenofovir-induced proximal tubulopathy. J. Infect Dis. 194(11), 1481-1491 (2006).
105. Meyer Zu Schwabedissen HE, Jedlitschky G, Gratz M et al.: Variable expression of MRP2 (ABCC2) in human placenta: infuence of gestational age and cellular differentiation. Drug Metab. Dispos. 33(7), 896-904 (2005).
106. Giessmann T, Modess C, Hecker U et al.: CYP2D6 genotype and induction of intestinal drug transporters by rifampin predict presystemic clearance of carvedilol in healthy subjects. Clin. Pharmacol. Ther. 75(3), 213-222 (2004).
107. Lang T, Hitzl M, Burk O et al.: Genetic polymorphisms in the multidrug resistance-associated protein 3 (ABCC3, MRP3) gene and relationship to its mRNA and protein expression in human liver. Pharmacogenetics 14(3), 155-164 (2004).
108. Kobayashi K, Ito K, Takada T, Sugiyama Y, Suzuki H: Functional ana lysis of nonsynonymous single nucleotide polymorphism type ATP-binding cassette transmembrane transporter subfamily C member 3. Pharmacogenet. Genomics 18(9), 823-833 (2008).
109. Fukushima-Uesaka H, Saito Y, Maekawa K et al.: Genetic variations of the ABC transporter gene ABCC3 in a Japanese population. Drug Metab. Pharmacokinet. 22(2), 129-135 (2007).
110. Müller P, Asher N, Heled M, Cohen SB, Risch A, Rund D: Polymorphisms in transporter and Phase II metabolism genes as potential modifers of the predisposition to and treatment outcome of de novo acute myeloid leukemia in Israeli ethnic groups. Leuk. Res. 32(6), 919-929 (2008).
111. Abla N, Chinn LW, Nakamura T et al.: The human multidrug resistance protein 4 (MRP4, ABCC4): functional ana lysis of a highly polymorphic gene. J. Pharmacol. Exp. Ther. 325(3), 859-868 (2008).
112. Janke D, Mehralivand S, Strand D et al.: 6-mercaptopurine and 9-(2-phosphonyl-methoxyethyl) adenine (PMEA) transport altered by two missense mutations in the drug transporter gene ABCC4. Hum. Mutat 29(5), 659-669 (2008).
113. Krishnamurthy P, Schwab M, Takenaka K et al.: Transporter-mediated protection against thiopurine-induced hematopoietic toxicity. Cancer Res. 68(13), 4983-4989 (2008).
114. Kiser JJ, Aquilante CL, Anderson PL, King TM, Carten ML, Fletcher CV: Clinical and genetic determinants of intracellular tenofovir diphosphate concentrations in HIV-infected patients. J. Acquir. Immune Defc. Syndr. 47(3), 298-303 (2008).
115. Anderson PL, Lamba J, Aquilante CL, Schuetz E, Fletcher CV: Pharmacogenetic characteristics of indinavir, zidovudine, and lamivudine therapy in HIV-infected adults: a pilot study. J. Acquir. Immune Defc. Syndr. 42(4), 441-449 (2006).
116. Gradhand U, Lang T, Schaeffeler E et al.: Variability in human hepatic MRP4 expression: infuence of cholestasis and genotype. Pharmacogenomics J. 8(1), 42-52 (2008).
117. Toyoda Y, Sakurai A, Mitani Y et al.: Earwax, osmidrosis, and breast cancer: why does one SNP (538G>A) in the human ABC transporter ABCC11 gene determine earwax type-FASEB J. 23(6), 2001-2013 (2009).
118. Tamura A, Onishi Y, An R et al.: In vitro evaluation of photosensitivity risk related to genetic polymorphisms of human ABC transporter ABCG2 and inhibition by drugs. Drug Metab. Pharmacokinet. 22(6), 428-440 (2007).
119. Mizuarai S, Aozasa N, Kotani H: Single nucleotide polymorphisms result in impaired membrane localization and reduced ATPase activity in multidrug transporter ABCG2. Int. J. Cancer 109(2), 238-246 (2004).
120. Yanase K, Tsukahara S, Mitsuhashi J, Sugimoto Y: Functional SNPs of the breast cancer resistance protein-therapeutic effects and inhibitor development. Cancer Lett. 234(1), 73-80 (2006).
121. Furukawa T, Wakabayashi K, Tamura A et al.: Major SNP (Q141K) variant of human ABC transporter ABCG2 undergoes lysosomal and proteasomal degradations. Pharm. Res. 26(2), 469-479 (2009).
122. Tamura A, Watanabe M, Saito H et al.: Functional validation of the genetic polymorphisms of human ATP-binding cassette (ABC) transporter ABCG2: identifcation of alleles that are defective in porphyrin transport. Mol. Pharmacol. 70(1), 287-296 (2006).
123. Tamura A, Wakabayashi K, Onishi Y et al.: Re-evaluation and functional classifcation of non-synonymous single nucleotide polymorphisms of the human ATP-binding cassette transporter ABCG2. Cancer Sci. 98(2), 231-239 (2007).
124. Sparreboom A, Gelderblom H, Marsh S et al.: Difomotecan pharmacokinetics in relation to ABCG2 421C>A genotype. Clin. Pharmacol. Ther. 76(1), 38-44 (2004).
125. Sparreboom A, Loos WJ, Burger H et al.: Effect of ABCG2 genotype on the oral bioavailability of topotecan. Cancer Biol. Ther. 4(6), 650-658 (2005).
126. Mey V, Giovannetti E, De Braud F et al.: In vitro synergistic cytotoxicity of gemcitabine and pemetrexed and pharmacogenetic evaluation of response to gemcitabine in bladder cancer patients. Br. J. Cancer 95(3), 289-297 (2006).
127. Marechal R, Mackey JR, Lai R et al.: Human equilibrative nucleoside transporter 1 and human concentrative nucleoside transporter 3 predict survival after adjuvant gemcitabine therapy in resected pancreatic adenocarcinoma. Clin. Cancer Res. 15(8), 2913-2919 (2009).
128. Marce S, Molina-Arcas M, Villamor N et al.: Expression of human equilibrative nucleoside transporter 1 (hENT1) and its correlation with gemcitabine uptake and cytotoxicity in mantle cell lymphoma. Haematologica 91(7), 895-902 (2006).
129. Galmarini CM: Correlation of hENT1 expression and function with gemcitabine cytotoxicity in mantle cell lymphoma lines and clinical samples. Haematologica 91(7), 866B (2006).
130. Giovannetti E, Del Tacca M, Mey V et al.: Transcription ana lysis of human equilibrative nucleoside transporter-1 predicts survival in pancreas cancer patients treated with gemcitabine. Cancer Res. 66(7), 3928-3935 (2006).
131. Farrell JJ, Elsaleh H, Garcia M et al.: Human equilibrative nucleoside transporter 1 levels predict response to gemcitabine in patients with pancreatic cancer. Gastroenterology 136(1), 187-195 (2009).
132. Spratlin J, Sangha R, Glubrecht D et al.: The absence of human equilibrative nucleoside transporter 1 is associated with reduced survival in patients with gemcitabine-treated pancreas adenocarcinoma. Clin. Cancer Res. 10(20), 6956-6961 (2004).
133. Santini D, Perrone G, Vincenzi B et al.: Human equilibrative nucleoside transporter 1 (hENT1) protein is associated with short survival in resected ampullary cancer. Ann Oncol. 19(4), 724-728 (2008).
134. Stam RW, Den Boer ML, Meijerink JP et al.: Differential mRNA expression of ARA-C-metabolizing enzymes explains ARA-C sensitivity in MLL gene-rearranged infant acute lymphoblastic leukemia. Blood 101(4), 1270-1276 (2003).
135. Tsujie M, Nakamori S, Nakahira S et al.: Human equilibrative nucleoside transporter 1, as a predictor of 5-fuorouracil resistance in human pancreatic cancer. Anticancer Res. 27(4B), 2241-2249 (2007).
136. Gloeckner-Hofmann K, Guillen-Gomez E, Schmidtgen C et al.: Expression of the high-affnity fuoropyrimidine-preferring nucleoside transporter hCNT1 correlates with decreased disease-free survival in breast cancer. Oncology 70(3), 238-244 (2006).
137. Rabascio C, Laszlo D, Andreola G et al.: Expression of the human concentrative nucleotide transporter 1 (hCNT1) gene correlates with clinical response in patients affected by Waldenström's macroglobulinemia (WM) and small lymphocytic lymphoma (SLL) undergoing a combination treatment with 2-chloro-2́-deoxyadenosine (2-CDA) and rituximab. Leuk. Res. 34(4), 454-457 (2009).
138. Farre X, Guillen-Gomez E, Sanchez L et al.: Expression of the nucleoside-derived drug transporters hCNT1, hENT1 and hENT2 in gynecologic tumors. Int. J. Cancer 112(6), 959-966 (2004).
139. Oguri T, Achiwa H, Muramatsu H et al.: The absence of human equilibrative nucleoside transporter 1 expression predicts nonresponse to gemcitabine-containing chemotherapy in non-small cell lung cancer. Cancer Lett. 256(1), 112-119 (2007).
140. Hubeek I, Stam RW, Peters GJ et al.: The human equilibrative nucleoside transporter 1 mediates in vitro cytarabine sensitivity in childhood acute myeloid leukaemia. Br. J. Cancer 93(12), 1388-1394 (2005).
141. Wojtal KA, Eloranta JJ, Hruz P et al.: Changes in mRNA expression levels of solute carrier transporters in infammatory bowel disease patients. Drug Metab. Dispos. 37(9), 1871-1877 (2009).
142. Bakhiya N, Arlt VM, Bahn A, Burckhardt G, Phillips DH, Glatt H: Molecular evidence for an involvement of organic anion transporters (OATs) in aristolochic acid nephropathy. Toxicology 264(1-2), 74-79 (2009).
143. Andreadis C, Gimotty PA, Wahl P et al.: Members of the glutathione and ABC-transporter families are associated with clinical outcome in patients with diffuse large B-cell lymphoma. Blood 109(8), 3409-3416 (2007).
144. Shi H, Lu D, Shu Y, Shi W, Lu S, Wang K: Expression of multidrug-resistance-related proteins P-glycoprotein, glutathione-S- transferases, topoisomerase-II and lung resistance protein in primary gastric cardiac adenocarcinoma. Cancer Invest 26(4), 344-351 (2008).
145. Kourti M, Vavatsi N, Gombakis N et al.: Expression of multidrug resistance 1 (MDR1), multidrug resistance-related protein 1 (MRP1), lung resistance protein (LRP), and breast cancer resistance protein (BCRP) genes and clinical outcome in childhood acute lymphoblastic leukemia. Int. J. Hematol. 86(2), 166-173 (2007).
146. Huh HJ, Park CJ, Jang S et al.: Prognostic signifcance of multidrug resistance gene 1 (MDR1), multidrug resistance-related protein (MRP) and lung resistance protein (LRP) mRNA expression in acute leukemia. J. Korean Med. Sci. 21(2), 253-258 (2006).
147. Noma B, Sasaki T, Fujimoto Y et al.: Expression of multidrug resistance-associated protein 2 is involved in chemotherapy resistance in human pancreatic cancer. Int. J. Oncol. 33(6), 1187-1194 (2008).
148. Hinoshita E, Uchiumi T, Taguchi K et al.: Increased expression of an ATP-binding cassette superfamily transporter, multidrug resistance protein 2, in human colorectal carcinomas. Clin. Cancer Res. 6(6), 2401-2407 (2000).
149. Nies AT, Konig J, Pfannschmidt M, Klar E, Hofmann WJ, Keppler D: Expression of the multidrug resistance proteins MRP2 and MRP3 in human hepatocellular carcinoma. Int. J. Cancer 94(4), 492-499 (2001).
150. Rost D, Konig J, Weiss G, Klar E, Stremmel W, Keppler D: Expression and localization of the multidrug resistance proteins MRP2 and MRP3 in human gallbladder epithelia. Gastroenterology 121(5), 1203-1208 (2001).
151. Konig J, Hartel M, Nies AT et al.: Expression and localization of human multidrug resistance protein (ABCC) family members in pancreatic carcinoma. Int. J. Cancer 115(3), 359-367 (2005).
152. Rau S, Autschbach F, Riedel HD et al.: Expression of the multidrug resistance proteins MRP2 and MRP3 in human cholangiocellular carcinomas. Eur. J. Clin. Invest 38(2), 134-142 (2008).
153. Norris MD, Smith J, Tanabe K et al.: Expression of multidrug transporter MRP4/ABCC4 is a marker of poor prognosis in neuroblastoma and confers resistance to irinotecan in vitro. Mol. Cancer Ther. 4(4), 547-553 (2005).
154. Hagmann W, Jesnowski R, Faissner R, Guo C, Lohr JM: ATP-binding cassette c transporters in human pancreatic carcinoma cell lines. Upregulation in 5-fuorouracil-resistant cells. Pancreatology 9(1-2), 136-144 (2009).
155. Steinbach D, Gillet J P, Sauerbrey A et al.: ABCA3 as a possible cause of drug resistance in childhood acute myeloid leukemia. Clin. Cancer Res. 12(14 Pt 1), 4357-4363 (2006).
156. Kim YH, Ishii G, Goto K et al.: Expression of breast cancer resistance protein is associated with a poor clinical outcome in patients with small-cell lung cancer. Lung Cancer 65(1), 105-111 (2009).
157. Englund G, Jacobson A, Rorsman F, Artursson P, Kindmark A, Ronnblom A: Effux transporters in ulcerative colitis: decreased expression of BCRP (ABCG2) and Pgp (ABCB1). Infamm. Bowel Dis. 13(3), 291-297 (2007).
158. Gutmann H, Hruz P, Zimmermann C et al.: Breast cancer resistance protein and P-glycoprotein expression in patients with newly diagnosed and therapy-refractory ulcerative colitis compared with healthy controls. Digestion 78(2-3), 154-162 (2008).
159. Solbach TF, Paulus B, Weyand M, Eschenhagen T, Zolk O, Fromm MF: ATP-binding cassette transporters in human heart failure. Naunyn Schmiedebergs Arch. Pharmacol. 377(3), 231-243 (2008).
160. Aller SG, Yu J, Ward A et al.: Structure of P-glycoprotein reveals a molecular basis for poly-specifc drug binding. Science 323(5922), 1718-1722 (2009).
161. Saiko P, Horvath Z, Jaeger W, Schott H, Fritzer-Szekeres M, Szekeres T: Heterodinucleoside phosphates of 5-fuorodeoxyuridine and arabinofuranosylcytosine-new drugs in cancer chemotherapy-In vivo 19(1), 205-214 (2005).
162. Wan L, Cao D, Zeng J, Yan R, Pizzorno G: Modulation of uridine phosphorylase gene expression by tumor necrosis factor-a enhances the antiproliferative activity of the capecitabine intermediate 5́-deoxy-5- fuorouridine in breast cancer cells. Mol. Pharmacol. 69(4), 1389-1395 (2006).
163. Tsuzuki M, Handa K, Yamamoto K et al.: Chronic myeloid leukemia following chemotherapy with 5́-deoxy-5-fuorouridine for gastric cancer. Intern. Med. 47(19), 1739-1741 (2008).
164. Suehisa H, Toyooka S: Adjuvant chemotherapy for completely resected non-small-cell lung cancer. Acta Med. Okayama 63(5), 223-230 (2009).
165. Hillcoat BL, Mcculloch PB, Figueredo AT, Ehsan MH, Rosenfeld JM: Clinical response and plasma levels of 5-fuorouracil in patients with colonic cancer treated by drug infusion. Br. J. Cancer 38(6), 719-724 (1978).
166. Wang WS, Tzeng CH, Chiou TJ et al.: High-dose cytarabine and mitoxantrone as salvage therapy for refractory non-Hodgkin's lymphoma. Jpn. J. Clin. Oncol. 27(3), 154-157 (1997).
167. Wong A, Soo RA, Yong W P, Innocenti F: Clinical pharmacology and pharmacogenetics of gemcitabine. Drug Metab. Rev. 41(2), 77-88 (2009).
168. Ferrandina G, Mey V, Nannizzi S et al.: Expression of nucleoside transporters, deoxycitidine kinase, ribonucleotide reductase regulatory subunits, and gemcitabine catabolic enzymes in primary ovarian cancer. Cancer Chemother. Pharmacol. 65(4), 679-686 (2010).
169. Sharma A, Mohanti B, Raina V et al.: A Phase II study of gemcitabine and oxaliplatin (Oxigem) in unresectable gall bladder cancer. Cancer Chemother. Pharmacol. 65(3), 497-502 (2010).
170. Garcia-Manero G: Demethylating agents in myeloid malignancies. Curr. Opin. Oncol. 20(6), 705-710 (2008).
171. Hollenbach PW, Nguyen AN, Brady H et al.: A comparison of azacitidine and decitabine activities in acute myeloid leukemia cell lines. PLoS One 5(2), E9001 (2010).
172. Muller A, Florek M: 5-azacytidine/azacitidine. Recent Results Cancer Res. 184, 159-170 (2010).
173. Flotho C, Claus R, Batz C et al.: The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on cancer gene expression in acute myeloid leukemia cells. Leukemia 23(6), 1019-1028 (2009).
174. Robak T, Korycka A, Lech-Maranda E, Robak P: Current status of older and new purine nucleoside analogues in the treatment of lymphoproliferative diseases. Molecules 14(3), 1183-1226 (2009).
175. Bellezza I, Tucci A, Minelli A: 2-chloroadenosine and human prostate cancer cells. Anticancer Agents Med. Chem. 8(7), 783-789 (2008).
176. Hentosh P, Peffey DM: The cladribine conundrum: deciphering the drug's mechanism of action. Expert Opin. Drug Metab. Toxicol. 6(1), 75-81 (2010).
177. Mori N, Yokooji T, Kamio Y, Murakami T: Characterization of intestinal absorption of mizoribine mediated by concentrative nucleoside transporters in rats. Eur. J. Pharmacol. 586(1-3), 52-58 (2008).
178. Naka K, Ikeda M, Abe K, Dansako H, Kato N: Mizoribine inhibits hepatitis C virus RNA replication: effect of combination with interferon-a. Biochem. Biophys. Res. Commun. 330(3), 871-879 (2005).
179. Sahasranaman S, Howard D, Roy S: Clinical pharmacology and pharmacogenetics of thiopurines. Eur. J. Clin. Pharmacol. 64(8), 753-767 (2008).
180. Prefontaine E, Macdonald JK, Sutherland LR: Azathioprine or 6-mercaptopurine for induction of remission in Crohn's disease. Cochrane Database Syst. Rev. (4), CD000545 (2009).
181. Prefontaine E, Sutherland LR, Macdonald JK, Cepoiu M: Azathioprine or 6-mercaptopurine for maintenance of remission in Crohn's disease. Cochrane Database Syst. Rev. (1), CD000067 (2009).
182. Shey M, Kongnyuy EJ, Shang J, Wiysonge CS: A combination drug of abacavir-lamivudine-zidovudine (Trizivir) for treating HIV infection and aids. Cochrane Database Syst. Rev. (3), CD005481 (2009).
183. Tozzi V: Pharmacogenetics of antiretrovirals. Antiviral Res. 85(1), 190-200 (2010).
184. Chien RN, Liaw YF: Nucleos(t)ide analogues for hepatitis B virus: strategies for long-term success. Best Pract. Res. Clin. Gastroenterol. 22(6), 1081-1092 (2008).
185. Achenbach CJ, Scarsi KK, Murphy RL: Abacavir/lamivudine fxed-dose combination antiretroviral therapy for the treatment of HIV. Adv. Ther. 27(1), 1-16 (2010).
186. Deval J: Antimicrobial strategies: inhibition of viral polymerases by 3́-hydroxyl nucleosides. Drugs 69(2), 151-166 (2009).
187. Vanpouille C, Lisco A, Derudas M et al.: A new class of dual-targeted antivirals: monophosphorylated acyclovir prodrug derivatives suppress both human immunodefciency virus type 1 and herpes simplex virus type 2. J. Infect Dis. 201(4), 635-643 (2010).
188. Sharma SD: Hepatitis C virus: molecular biology and current therapeutic options. Indian J. Med. Res. 131, 17-34 (2010).
189. Kimberlin DW, Jacobs RF, Weller S et al.: Pharmacokinetics and safety of extemporaneously compounded valacyclovir oral suspension in pediatric patients from 1 month through 11 years of age. Clin. Infect Dis. 50(2), 221-228 (2010).
190. Jenh AM, Thio CL, Pham PA: Tenofovir for the treatment of hepatitis B virus. Pharmacotherapy 29(10), 1212-1227 (2009).
191. Cihlar T, Lafamme G, Fisher R et al.: Novel nucleotide human immunodefciency virus reverse transcriptase inhibitor GS-9148 with a low nephrotoxic potential: characterization of renal transport and accumulation. Antimicrob. Agents Chemother. 53(1), 150-156 (2009).
192. Molina-Arcas M, Moreno-Bueno G, Cano-Soldado P et al.: Human equilibrative nucleoside transporter-1 (hENT1) is required for the transcriptomic response of the nucleoside-derived drug 5́-DFUR in breast cancer MCF7 cells. Biochem. Pharmacol. 72(12), 1646-1656 (2006).
193. Smith KM, Ng AM, Yao SY et al.: Electrophysiological characterization of a recombinant human Na+-coupled nucleoside transporter (hCNT1) produced in xenopus oocytes. J. Physiol. 558(Pt 3), 807-823 (2004).
194. Clarke ML, Damaraju VL, Zhang J et al.: The role of human nucleoside transporters in cellular uptake of 4́-thio-b-D-arabinofuranosylcytosine and b-D-arabinosylcytosine. Mol. Pharmacol. 70(1), 303-310 (2006).
195. Endo Y, Obata T, Murata D et al.: Cellular localization and functional characterization of the equilibrative nucleoside transporters of antitumor nucleosides. Cancer Sci. 98(10), 1633-1637 (2007).
196. Rius M, Stresemann C, Keller D et al.: Human concentrative nucleoside transporter 1-mediated uptake of 5-azacytidine enhances DNA demethylation. Mol. Cancer Ther. 8(1), 225-231 (2009).
197. Huang Y, Anderle P, Bussey KJ et al.: Membrane transporters and channels: role of the transportome in cancer chemosensitivity and chemoresistance. Cancer Res. 64(12), 4294-4301 (2004).
198. King KM, Damaraju VL, Vickers MF et al.: A comparison of the transportability, and its role in cytotoxicity, of clofarabine, cladribine, and fudarabine by recombinant human nucleoside transporters produced in three model expression systems. Mol. Pharmacol. 69(1), 346-353 (2006).
199. Molina-Arcas M, Bellosillo B, Casado FJ et al.: Fludarabine uptake mechanisms in B-cell chronic lymphocytic leukemia. Blood 101(6), 2328-2334 (2003). (Pubitemid 36304669)
200. Huang M, Wang Y, Gu J et al.: Determinants of sensitivity of human t-cell leukemia CCRF-CEM cells to immucillin-h. Leuk. Res. 32(8), 1268-1278 (2008).
201. Zhang J, Tackaberry T, Ritzel MW et al.: Cysteine-accessibility ana lysis of transmembrane domains 11-13 of human concentrative nucleoside transporter 3. Biochem. J. 394(Pt 2), 389-398 (2006).
202. Prus KL, Averett DR, Zimmerman TP: Transport and metabolism of 9-b-D-arabinofuranosylguanine in a human T-lymphoblastoid cell line: nitrobenzylthioinosine-sensitive and-insensitive infux. Cancer Res. 50(6), 1817-1821 (1990).
203. Ishida K, Takaai M, Yotsutani A, Taguchi M, Hashimoto Y: Membrane transport mechanisms of mizoribine in the rat intestine and human epithelial ls180 cells. Biol. Pharm. Bull 32(4), 741-745 (2009).
204. Mori N, Yokooji T, Kamio Y, Murakami T: Study on intestinal absorption sites of mizoribine and ribavirin, substrates for concentrative nucleoside transporter(s), in rats. Eur. J. Pharmacol. 628(1-3), 214-219 (2010).
205. Mori S, Ohtsuki S, Takanaga H, Kikkawa T, Kang YS, Terasaki T: Organic anion transporter 3 is involved in the brain-to-blood effux transport of thiopurine nucleobase analogs. J. Neurochem 90(4), 931-941 (2004).
206. Yao SY, Ng AM, Sundaram M, Cass CE, Baldwin SA, Young JD: Transport of antiviral 3́-deoxy-nucleoside drugs by recombinant human and rat equilibrative, nitrobenzylthioinosine (NBMPR)-insensitive (ENT2) nucleoside transporter proteins produced in xenopus oocytes. Mol. Membr. Biol. 18(2), 161-167 (2001).
207. Jung N, Lehmann C, Rubbert A et al.: Relevance of the organic cation transporters 1 and 2 for antiretroviral drug therapy in human immunodefciency virus infection. Drug Metab. Dispos. 36(8), 1616-1623 (2008).
208. Jin MJ, Han HK: Interaction of zalcitabine with human organic anion transporter 1. Pharmazie 61(5), 491-492 (2006).
209. Truong DM, Kaler G, Khandelwal A, Swaan PW, Nigam SK: Multi-level ana lysis of organic anion transporters 1, 3, and 6 reveals major differences in structural determinants of antiviral discrimination. J. Biol. Chem. 283(13), 8654-8663 (2008).
210. Morita N, Kusuhara H, Sekine T, Endou H, Sugiyama Y: Functional characterization of rat organic anion transporter 2 in LLC-PK1 cells. J. Pharmacol. Exp. Ther. 298(3), 1179-1184 (2001). (Pubitemid 32761937)
211. Li JY, Boado RJ, Pardridge WM: Differential kinetics of transport of 2́,3́-dideoxyinosine and adenosine via concentrative Na+ nucleoside transporter CNT2 cloned from rat blood-brain barrier. J. Pharmacol. Exp. Ther. 299(2), 735-740 (2001).
212. Wada S, Tsuda M, Sekine T et al.: Rat multispecifc organic anion transporter 1 (rOAT1) transports zidovudine, acyclovir, and other antiviral nucleoside analogs. J. Pharmacol. Exp. Ther. 294(3), 844-849 (2000).
213. Govindarajan R, Endres CJ, Whittington D et al.: Expression and hepatobiliary transport characteristics of the concentrative and equilibrative nucleoside transporters in sandwich-cultured human hepatocytes. Am. J. Physiol. Gastrointest. Liver Physiol. 295(3), G570-580 (2008).
214. Yamamoto T, Sugawara M, Kikukawa T et al.: Kinetic study of anti-viral ribavirin uptake mediated by hCNT3 and hENT1 in Xenopus laevis oocytes. Biophys. Chem. 147(1-2), 59-65 (2010).
215. Sekine T, Cha SH, Tsuda M et al.: Identifcation of multispecifc organic anion transporter 2 expressed predominantly in the liver. FEBS Lett. 429(2), 179-182 (1998).
216. Friedrichsen GM, Chen W, Begtrup M, Lee CP, Smith PL, Borchardt RT: Synthesis of analogs of l-valacyclovir and determination of their substrate activity for the oligopeptide transporter in Caco-2 cells. Eur. J. Pharm. Sci. 16(1-2), 1-13 (2002).
217. Uwai Y, Ida H, Tsuji Y, Katsura T, Inui K: Renal transport of adefovir, cidofovir, and tenofovir by SLC22A family members (hOAT1, hOAT3, and hOCT2). Pharm. Res. 24(4), 811-815 (2007).
218. Mahony WB, Domin BA, Daluge SM, Zimmerman TP: Membrane permeation characteristics of abacavir in human erythrocytes and human T-lymphoblastoid CD4+ CEM cells: comparison with (-)-carbovir. Biochem. Pharmacol. 68(9), 1797-1805 (2004).
219. Xu AS, Chu CK, London RE: 19F NMR study of the uptake of 2́-fuoro-5-methyl-b-l-arabinofuranosyluracil in erythrocytes: evidence of transport by facilitated and nonfacilitated pathways. Biochem. Pharmacol. 55(10), 1611-1619 (1998).
220. Brandl M, Wu X, Holper M et al.: Physicochemical properties of the nucleoside prodrug r1626 leading to high oral bioavailability. Drug Dev. Ind. Pharm. 34(7), 683-691 (2008).
221. Guo Y, Kotova E, Chen ZS et al.: MRP8, ATP-binding cassette C11 (ABCC11), is a cyclic nucleotide effux pump and a resistance factor for fuoropyrimidines 2́,3́-dideoxycytidine and 9́-(2́-phosphonylmethoxyethyl) adenine. J. Biol. Chem. 278(32), 29509-29514 (2003).
222. Zeng H, Lin ZP, Sartorelli AC: Resistance to purine and pyrimidine nucleoside and nucleobase analogs by the human MDR1 transfected murine leukemia cell line l1210/vMDRc.06. Biochem. Pharmacol. 68(5), 911-921 (2004).
223. Oguri T, Bessho Y, Achiwa H et al.: MRP8/ABCC11 directly confers resistance to 5-fuorouracil. Mol. Cancer Ther. 6(1), 122-127 (2007).
224. Pratt S, Shepard RL, Kandasamy RA, Johnston PA, Perry W, 3rd, Dantzig AH: The multidrug resistance protein 5 (ABCC5) confers resistance to 5-fuorouracil and transports its monophosphorylated metabolites. Mol. Cancer Ther. 4(5), 855-863 (2005).
225. Guo Y, Kock K, Ritter CA et al.: Expression of ABCC-type nucleotide exporters in blasts of adult acute myeloid leukemia: relation to long-term survival. Clin. Cancer Res. 15(5), 1762-1769 (2009).
226. Ritter CA, Jedlitschky G, Meyer Zu Schwabedissen H, Grube M, Kock K, Kroemer HK: Cellular export of drugs and signaling molecules by the ATP-binding cassette transporters MRP4 (ABCC4) and MRP5 (ABCC5). Drug Metab. Rev. 37(1), 253-278 (2005).
227. Oguri T, Achiwa H, Sato S et al.: The determinants of sensitivity and acquired resistance to gemcitabine differ in non-small cell lung cancer: a role of ABCC5 in gemcitabine sensitivity. Mol. Cancer Ther. 5(7), 1800-1806 (2006).
228. De Wolf C, Jansen R, Yamaguchi H et al.: Contribution of the drug transporter ABCG2 (breast cancer resistance protein) to resistance against anticancer nucleosides. Mol. Cancer Ther. 7(9), 3092-3102 (2008).
229. Reid G, Wielinga P, Zelcer N et al.: Characterization of the transport of nucleoside analog drugs by the human multidrug resistance proteins MRP4 and MRP5. Mol. Pharmacol. 63(5), 1094-1103 (2003).
230. Eilers M, Roy U, Mondal D: MRP (ABCc) transporters-mediated effux of anti-HIV drugs, saquinavir and zidovudine, from human endothelial cells. Exp. Biol. Med. (Maywood) 233(9), 1149-1160 (2008).
231. Wang X, Baba M: The role of breast cancer resistance protein (BCRP/ABCG2) in cellular resistance to HIV-1 nucleoside reverse transcriptase inhibitors. Antivir. Chem. Chemother. 16(4), 213-216 (2005).
232. Janneh O, Owen A, Bray PG, Back DJ, Pirmohamed M: The accumulation and metabolism of zidovudine in 3T3-F442A pre-adipocytes. Br. J. Pharmacol. 159(2), 484-493 (2010).
233. Wang X, Furukawa T, Nitanda T et al.: Breast cancer resistance protein (BCRP/ABCG2) induces cellular resistance to HIV-1 nucleoside reverse transcriptase inhibitors. Mol. Pharmacol. 63(1), 65-72 (2003).
234. Kim HS, Sunwoo YE, Ryu JY et al.: The effect of ABCG2 V12M, Q141K and Q126X, known functional variants in vitro, on the disposition of lamivudine. Br. J. Clin. Pharmacol. 64(5), 645-654 (2007).
235. Karla PK, Quinn TL, Herndon BL, Thomas P, Pal D, Mitra A: Expression of multidrug resistance associated protein 5 (MRP5) on cornea and its role in drug effux. J. Ocul Pharmacol. Ther. 25(2), 121-132 (2009).
236. Wijnholds J, Mol CA, Van Deemter L et al.: Multidrug-resistance protein 5 is a multispecifc organic anion transporter able to transport nucleotide analogs. Proc. Natl Acad. Sci. USA 97(13), 7476-7481 (2000).
237. Ming X, Thakker DR: Role of basolateral effux transporter MRP4 in the intestinal absorption of the antiviral drug adefovir dipivoxil. Biochem. Pharmacol. 79(3), 455-462 (2010).
238. Brody SR, Humphreys MH, Gambertoglio JG, Schoenfeld P, Cundy KC, Aweeka FT: Pharmacokinetics of cidofovir in renal insuffciency and in continuous ambulatory peritoneal dialysis or high-fux hemodialysis. Clin. Pharmacol. Ther. 65(1), 21-28 (1999).
239. Imaoka T, Kusuhara H, Adachi M, Schuetz JD, Takeuchi K, Sugiyama Y: Functional involvement of multidrug resistance-associated protein 4 (MRP4/ABCC4) in the renal elimination of the antiviral drugs adefovir and tenofovir. Mol. Pharmacol. 71(2), 619-627 (2007).
240. Shaik N, Giri N, Pan G, Elmquist WF: P-glycoprotein-mediated active effux of the anti-HIV1 nucleoside abacavir limits cellular accumulation and brain distribution. Drug Metab. Dispos. 35(11), 2076-2085 (2007).
241. Pan G, Giri N, Elmquist WF: ABCG2/BCRP1 mediates the polarized transport of antiretroviral nucleosides abacavir and zidovudine. Drug Metab. Dispos. 35(7), 1165-1173 (2007).
242. Ngo LY, Patil SD, Unadkat JD: Ontogenic and longitudinal activity of Na+-nucleoside transporters in the human intestine. Am. J. Physiol. Gastrointest. Liver Physiol. 280(3), G475-G481 (2001).
243. Govindarajan R, Bakken AH, Hudkins KL et al.: In situ hybridization and immunolocalization of concentrative and equilibrative nucleoside transporters in the human intestine, liver, kidneys, and placenta. Am. J. Physiol. Regul. Integr. Comp. Physiol. 293(5), R1809-R1822 (2007).
244. Damaraju VL, Elwi AN, Hunter C et al.: Localization of broadly selective equilibrative and concentrative nucleoside transporters, hENT1 and hCNT3, in human kidney. Am. J. Physiol. Renal Physiol. 293(1), F200-F211 (2007).
245. Koehler MR, Wissinger B, Gorboulev V, Koepsell H, Schmid M: The two human organic cation transporter genes SLC22A1 and SLC22A2 are located on chromosome 6q26. Cytogenet. Cell Genet. 79(3-4), 198-200 (1997).
246. Lips KS, Volk C, Schmitt BM et al.: Polyspecifc cation transporters mediate luminal release of acetylcholine from bronchial epithelium. Am. J. Respir Cell Mol. Biol. 33(1), 79-88 (2005).
247. Wessler I, Roth E, Deutsch C et al.: Release of non-neuronal acetylcholine from the isolated human placenta is mediated by organic cation transporters. Br. J. Pharmacol. 134(5), 951-956 (2001).
248. Motohashi H, Sakurai Y, Saito H et al.: Gene expression levels and immunolocalization of organic ion transporters in the human kidney. J. Am. Soc. Nephrol. 13(4), 866-874 (2002).
249. Busch AE, Karbach U, Miska D et al.: Human neurons express the polyspecifc cation transporter hOCT2, which translocates monoamine neurotransmitters, amantadine, and memantine. Mol. Pharmacol. 54(2), 342-352 (1998).
250. Muller J, Lips KS, Metzner L, Neubert RH, Koepsell H, Brandsch M: Drug specifcity and intestinal membrane localization of human organic cation transporters (OCT). Biochem. Pharmacol. 70(12), 1851-1860 (2005).
251. Sata R, Ohtani H, Tsujimoto M et al.: Functional ana lysis of organic cation transporter 3 expressed in human placenta. J. Pharmacol. Exp. Ther. 315(2), 888-895 (2005).
252. Shang T, Uihlein AV, Van Asten J, Kalyanaraman B, Hillard CJ: 1-methyl-4-phenylpyridinium accumulates in cerebellar granule neurons via organic cation transporter 3. J. Neurochem 85(2), 358-367 (2003).
253. Alebouyeh M, Takeda M, Onozato ML et al.: Expression of human organic anion transporters in the choroid plexus and their interactions with neurotransmitter metabolites. J. Pharmacol. Sci. 93(4), 430-436 (2003).
254. Enomoto A, Takeda M, Shimoda M et al.: Interaction of human organic anion transporters 2 and 4 with organic anion transport inhibitors. J. Pharmacol. Exp. Ther. 301(3), 797-802 (2002). (Pubitemid 34595067)
255. Simonson GD, Vincent AC, Roberg KJ, Huang Y, Iwanij V: Molecular cloning and characterization of a novel liver-specifc transport protein. J. Cell Sci. 107(Pt 4), 1065-1072 (1994).
256. Walker D, Thwaites DT, Simmons NL, Gilbert HJ, Hirst BH: Substrate upregulation of the human small intestinal peptide transporter, hPepT1. J. Physiol. 507(Pt 3), 697-706 (1998).
257. Thiebaut F, Tsuruo T, Hamada H, Gottesman MM, Pastan I, Willingham MC: Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues. Proc. Natl Acad. Sci. USA 84(21), 7735-7738 (1987).
258. Sugawara I, Kataoka I, Morishita Y et al.: Tissue distribution of P-glycoprotein encoded by a multidrug-resistant gene as revealed by a monoclonal antibody, MRK 16. Cancer Res. 48(7), 1926-1929 (1988).
259. Cordon-Cardo C, O'Brien JP, Casals D et al.: Multidrug-resistance gene (P-glycoprotein) is expressed by endothelial cells at blood-brain barrier sites. Proc. Natl Acad. Sci. USA 86(2), 695-698 (1989).
260. Ceckova-Novotna M, Pavek P, Staud F: P-glycoprotein in the placenta: expression, localization, regulation and function. Reprod. Toxicol. 22(3), 400-410 (2006).
261. Hemauer SJ, Nanovskaya TN, Abdel-Rahman SZ, Patrikeeva SL, Hankins GD, Ahmed MS: Modulation of human placental P-glycoprotein expression and activity by MDR1 gene polymorphisms. Biochem. Pharmacol. 79(6), 921-925 (2010).
262. Bellusci CP, Rocco CA, Aulicino PC et al.: MDR1 3435T and 1236T alleles delay disease progression to pediatric aids but have no effect on HIV-1 vertical transmission. AIDS 24(6), 833-840 (2010).
263. Yang YL, Lin DT, Chang SK et al.: Pharmacogenomic variations in treatment protocols for childhood acute lymphoblastic leukemia. Pediatr. Blood Cancer 54(2), 206-211 (2010).
264. Khedri A, Nejat-Shokouhi A, Salek R et al.: Association of the colorectal cancer and MDR1 gene polymorphism in an iranian population. Mol. Biol. Rep. DOI: 10.1007/s11033-010-9957-9959 (2010) (Epub ahead of print).
265. Rabascio C, Laszlo D, Andreola G et al.: Expression of the human concentrative nucleotide transporter 1 (hCNT1) gene correlates with clinical response in patients affected by Waldenström's macroglobulinemia (WM) and small lymphocytic lymphoma (SLL) undergoing a combination treatment with 2-chloro-2́-deoxyadenosine (2-CDA) and rituximab. Leuk. Res. 34(4), 454-457 (2010).
266. Mackey JR, Galmarini CM, Graham KA et al.: Quantitative ana lysis of nucleoside transporter and metabolism gene expression in chronic lymphocytic leukemia (CLL): identifcation of fudarabine-sensitive and-insensitive populations. Blood 105(2), 767-774 (2005).
267. Tsang RY, Santos C, Ghosh S et al.: Immunohistochemistry for human concentrative nucleoside transporter 3 protein predicts fudarabine sensitivity in chronic lymphocytic leukemia. Mod. Pathol. 21(11), 1387-1393 (2008).
268. Lai R, Bartlett NL, Mackey JR et al.: High expression of nucleoside transporter protein hENT1 in reed-sternberg cells is associated with treatment failure in relapsed/refractory hodgkin lymphoma patients treated with gemcitabine, vinorelbine and liposomal doxorubicin-a CALGB 59804 correlative study. Leuk. Lymphoma 49(6), 1202-1205 (2008).
269. Al-Massaeid AL, Craik JD: Decreased nucleoside transport and hENT1 transporter expression in b-thalassemia major. Med. Princ. Pract. 18(3), 180-186 (2009).
270. Santini D, Vincenzi B, Fratto ME et al.: Prognostic role of human equilibrative transporter 1 (hENT1) in patients with resected gastric cancer. J. Cell Physiol. 223(2), 384-388 (2010).
271. Hallermann C, Niermann C, Fischer RJ, Schulze HJ: New prognostic relevant factors in primary cutaneous diffuse large B-cell lymphomas. J. Am. Acad. Dermatol. 56(4), 588-597 (2007).
272. Yokoo S, Masuda S, Yonezawa A, Terada T, Katsura T, Inui K: Signifcance of organic cation transporter 3 (SLC22A3) expression for the cytotoxic effect of oxaliplatin in colorectal cancer. Drug Metab. Dispos. 36(11), 2299-2306 (2008).
273. Damiani D, Tiribelli M, Michelutti A et al.: Fludarabine-based induction therapy does not overcome the negative effect of ABCG2 (BCRP) over-expression in adult acute myeloid leukemia patients. Leuk. Res. DOI:10.1016/j.leukres.2010. 01.008 (2010) (Epub ahead of print).
274. Meuwis MA, Fillet M, Geurts P et al.: Biomarker discovery for infammatory bowel disease, using proteomic serum profling. Biochem. Pharmacol. 73(9), 1422-1433 (2007).