Genetic polymorphisms in low-dose methotrexate transporters: Current relevance as methotrexate therapeutic outcome biomarkers

Pharmacogenomics

Volumn 15, Issue 12, 2014, Pages 1611-1635

  Lima, Aurea ^a,b,c   Sousa, Hugo ^b,d   Monteiro, Joaquim ^a   Azevedo, Rita ^b,d   Medeiros, Rui ^b,c,e   Seabra, Vitor ^a  

^a INSTITUTO DE INVESTIGAÇÃO E FORMAÇÃO AVANÇADA EM CIÊNCIAS E TECNOLOGIAS DA SAÚDE   (Portugal)

^b PORTUGUESE ONCOLOGY INSTITUTE   (Portugal)

^c UNIVERSITY OF PORTO   (Portugal)

^d University of Porto   (Portugal)

^e LPCC Portuguese League Against Cancer (NRNorte)   (Portugal)

Author keywords

ABCs; ATP binding cassette transporters; low dose; methotrexate; personalized medicine; pharmacogenomics; single nucleotide polymorphisms; SLCs; SNPs; solute carriers; therapeutic outcome; transporters

Indexed keywords

BREAST CANCER RESISTANCE PROTEIN; CARRIER PROTEIN; METHOTREXATE; MONOCARBOXYLATE TRANSPORTER 2; MULTIDRUG RESISTANCE ASSOCIATED PROTEIN 1; MULTIDRUG RESISTANCE ASSOCIATED PROTEIN 2; MULTIDRUG RESISTANCE ASSOCIATED PROTEIN 3; MULTIDRUG RESISTANCE ASSOCIATED PROTEIN 4; MULTIDRUG RESISTANCE PROTEIN 1; ORGANIC ANION TRANSPORTER 1; ORGANIC ANION TRANSPORTER 3; ORGANIC ANION TRANSPORTER 4; PROTON COUPLED FOLATE TRANSPORTER; REDUCED FOLATE CARRIER; SOLUTE CARRIER ORGANIC ANION TRANSPORTER 1A2; SOLUTE CARRIER ORGANIC ANION TRANSPORTER 1B1; SOLUTE CARRIER ORGANIC ANION TRANSPORTER 1B3; ABC TRANSPORTER;

ABCB1 GENE; ABCC1 GENE; ABCC2 GENE; ABCC3 GENE; ABCC4 GENE; ABCG2 GENE; DRUG ABSORPTION; DRUG BIOAVAILABILITY; DRUG CLEARANCE; DRUG HALF LIFE; DRUG MECHANISM; DRUG METABOLISM; DRUG TRANSPORT; ENTERAL DRUG ADMINISTRATION; FOLR1 GENE; GENE; GENE EXPRESSION; GENETIC POLYMORPHISM; HUMAN; LOW DRUG DOSE; PHARMACOGENOMICS; REVIEW; SINGLE NUCLEOTIDE POLYMORPHISM; SLC16A7 GENE; SLC19A1 GENE; SLC22A11 GENE; SLC22A6 GENE; SLC22A8 GENE; SLC46A1 GENE; SLCO1A2 GENE; SLCO1B1 GENE; SLCO1B3 GENE; ADVERSE DRUG REACTION; DOSE RESPONSE; GENETICS; PHARMACOGENETICS;

ATP-BINDING CASSETTE TRANSPORTERS; DOSE-RESPONSE RELATIONSHIP, DRUG; DRUG-RELATED SIDE EFFECTS AND ADVERSE REACTIONS; HUMANS; MEMBRANE TRANSPORT PROTEINS; METHOTREXATE; PHARMACOGENETICS; POLYMORPHISM, SINGLE NUCLEOTIDE;

EID: 84908131959     PISSN: 14622416     EISSN: 17448042     Source Type: Journal    
DOI: 10.2217/pgs.14.116     Document Type: Review

References (83)

1. Farber S, Diamond LK. Temporary remissions in acute leukemia in children produced by folic acid antagonist, 4-Aminopteroyl-glutamic acid. N. Engl. J. Med. 238(23), 787-793 (1948).
2. Gubner R, August S, Ginsberg V. Therapeutic suppression of tissue reactivity. II. Effect of aminopterin in rheumatoid arthritis and psoriasis. Am. J. Med. Sci. 221(2), 176-182 (1951).
3. Giannini EH, Cawkwell GD. Drug treatment in children with juvenile rheumatoid arthritis. Past, present, and future. Pediatr. Clin. North Am. 42(5), 1099-1125 (1995).
4. Creemers MC, Franssen MJ, Van De Putte LB, Gribnau FW, Van Riel PL. Methotrexate in severe ankylosing spondylitis: an open study. J. Rheumatol. 22(6), 1104-1107 (1995).
5. Haustein UF, Rytter M. Methotrexate in psoriasis: 26 years' experience with low-dose long-Term treatment. J. Eur. Acad. Dermatol. Venereol. 14(5), 382-388 (2000).
6. Swierkot J, Szechinski J. Methotrexate in rheumatoid arthritis. Pharmacol. Rep. 58(4), 473-492 (2006
7. Tian H, Cronstein BN. Understanding the mechanisms of action of methotrexate: implications for the treatment of rheumatoid arthritis. Bull. NYU Hosp. Jt Dis. 65(3), 168-173 (2007).
8. Rowland M, Tozer TN. Clinical Pharmacokinetics and Pharmacodynamics: Concepts and Applications. (4th Edition). Wolters Kluwer, PA, USA (2011).
9. Inoue K, Yuasa H. Molecular basis for pharmacokinetics and pharmacodynamics of methotrexate in rheumatoid arthritis therapy. Drug Metab. Pharmacokinet. 29(1), 12-19 (2014).
10. Mikkelsen TS, Thorn CF, Yang JJ, et al. PharmGKB summary: methotrexate pathway. Pharmacogenet. Genomics 21(10), 679-686 (2011).
11. Kremer JM, Lee JK. The safety and efficacy of the use of methotrexate in long-Term therapy for rheumatoid arthritis. Arthritis Rheum. 29(7), 822-831 (1986).
12. Giacomini KM, Sugiyama Y. Membrane transporters and drug response. In: Goodman & Gilman's the Pharmacological Basis Of Therapeutics. Brunton LL, Lazo JS, Parker KL (Eds). McGraw-Hill, NY, USA, 41-70 (2006).
13. Nies AT, Schwab M, Keppler D. Interplay of conjugating enzymes with OATP uptake transporters and ABCC/MRP efflux pumps in the elimination of drugs. Expert Opin. Drug Metab. Toxicol. 4(5), 545-568 (2008).
14. Qiu A, Jansen M, Sakaris A, et al. Identification of an intestinal folate transporter and the molecular basis for hereditary folate malabsorption. Cell 127(5), 917-928 (2006).
15. Korell J, Duffull SB, Dalrymple JM, et al. Comparison of intracellular methotrexate kinetics in red blood cells with the kinetics in other cell types. Br. J. Clin. Pharmacol. 77(3), 493-497 (2014).
16. Van De Ven R, Oerlemans R, Van Der Heijden JW, et al. ABC drug transporters and immunity: novel therapeutic targets in autoimmunity and cancer. J. Leukoc. Biol.86(5), 1075-1087 (2009).
17. Halestrap AP. The SLC16 gene family-structure, role and regulation in health and disease. Mol. Aspects Med. 34(2-3), 337-349 (2013).
18. Moncrieffe H, Hinks A, Ursu S, et al. Generation of novel pharmacogenomic candidates in response to methotrexate in juvenile idiopathic arthritis: correlation between gene expression and genotype. Pharmacogenet. Genomics 20(11), 665-676 (2010).
19. National Center for Biotechnology Information: dbSNP-Short Genetic Variations. www.ncbi.nlm.nih.gov/SNP/
20. Hinken M, Halwachs S, Kneuer C, Honscha W. Subcellular localization and distribution of the reduced folate carrier in normal rat tissues. Eur. J. Histochem. 55(1), e3 (2011).
21. Baslund B, Gregers J, Nielsen CH. Reduced folate carrier polymorphism determines methotrexate uptake by B cells and CD4+ T cells. Rheumatology (Oxford) 47(4), 451-453 (2008).
22. Chatzikyriakidou A, Georgiou I, Voulgari PV, Papadopoulos CG, Tzavaras T, Drosos AA. Transcription regulatory polymorphism-43T C in the 5-flanking region of SLC19A1 gene could affect rheumatoid arthritis patient response to methotrexate therapy. Rheumatol. Int. 27(11), 1057-1061 (2007).
23. Hilgendorf C, Ahlin G, Seithel A, Artursson P, Ungell AL, Karlsson J. Expression of thirty-six drug transporter genes in human intestine, liver, kidney, and organotypic cell lines. Drug Metab. Dispos. 35(8), 1333-1340 (2007).
24. Bleasby K, Hall LA, Perry JL, Mohrenweiser HW, 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).
25. 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), F905-912 (2006).
26. Vormfelde SV, Schirmer M, Hagos Y, et al. Torsemide renal clearance and genetic variation in luminal and basolateral organic anion transporters. Br. J. Clin. Pharmacol. 62(3), 323-335 (2006).
27. Kalliokoski A, Niemi M. Impact of OATP transporters on pharmacokinetics. Br. J. Pharmacol. 158(3), 693-705 (2009).
28. Badagnani I, Castro RA, Taylor TR, et al. Interaction of methotrexate with organic-Anion transporting polypeptide 1A2 and its genetic variants. J. Pharmacol. Exp. Ther. 318(2), 521-529 (2006).
29. Ramsey LB, Bruun GH, Yang W, et al. Rare versus common variants in pharmacogenetics: SLCO1B1 variation and methotrexate disposition. Genome Res. 22(1), 1-8 (2012).
30. Niemi M, Pasanen MK, Neuvonen PJ. Organic anion transporting polypeptide 1B1: a genetically polymorphic transporter of major importance for hepatic drug uptake. Pharmacol. Rev. 63(1), 157-181 (2011).
31. Konig J, Cui Y, Nies AT, Keppler D. A novel human organic anion transporting polypeptide localized to the basolateral hepatocyte membrane. Am. J. Physiol. Gastrointest. Liver Physiol. 278(1), G156-G164 (2000).
32. Tirona RG, Leake BF, Merino G, Kim RB. Polymorphisms in OATP-C: identification of multiple allelic variants associated with altered transport activity among European-And African-Americans. J. Biol. Chem. 276(38), 35669-35675 (2001).
33. O'Byrne MR, Au KS, Morrison AC, et al. Association of folate receptor (FOLR1, FOLR2, FOLR3) and reduced folate carrier (SLC19A1) genes with meningomyelocele. Birth Defects Res. A Clin. Mol. Teratol. 88(8), 689-694 (2010
34. Wang D, Johnson AD, Papp AC, Kroetz DL, Sadee W. Multidrug resistance polypeptide 1 (MDR1, ABCB1) variant 3435CT affects mRNA stability. Pharmacogenet. Genomics 15(10), 693-704 (2005).
35. 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).
36. Berggren S, Gall C, Wollnitz N, et al. Gene and protein expression of P-glycoprotein, MRP1, MRP2, and CYP3A4 in the small and large human intestine. Mol. Pharm. 4(2), 252-257 (2007).
37. Lee SH, Lee MS, Lee JH, et al. MRP1 polymorphisms associated with citalopram response in patients with major depression. J. Clin. Psychopharmacol. 30(2), 116-125 (2010).
38. Fromm MF, Kauffmann HM, Fritz P, et al. The effect of rifampin treatment on intestinal expression of human MRP transporters. Am. J. Pathol. 157(5), 1575-1580 (2000).
39. Deo AK, Prasad B, Balogh L, Lai Y, Unadkat JD. Interindividual variability in hepatic expression of the multidrug resistance-Associated protein 2 (MRP2/ABCC2): quantification by liquid chromatography/tandem mass spectrometry. Drug Metab. Dispos. 40(5), 852-855 (2012).
40. 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).
41. 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 efflux pump for urinary cAMP and cGMP. J. Am. Soc. Nephrol. 13(3), 595-603 (2002).
42. Zhang L, Spencer KL, Voruganti VS, et al. Association of functional polymorphism rs2231142 (Q141K) in the ABCG2 gene with serum uric acid and gout in 4 US populations: the PAGE study. Am. J. Epidemiol. 177(9), 923-932 (2013).
43. Owen SA, Hider SL, Martin P, Bruce IN, Barton A, Thomson W. Genetic polymorphisms in key methotrexate pathway genes are associated with response to treatment in rheumatoid arthritis patients. Pharmacogenomics J. 13(3), 227-234 (2013).
44. Dervieux T, Furst D, Lein DO, et al. Polyglutamation of methotrexate with common polymorphisms in reduced folate carrier, aminoimidazole carboxamide ribonucleotide transformylase, and thymidylate synthase are associated with methotrexate effects in rheumatoid arthritis. Arthritis Rheum. 50(9), 2766-2774 (2004).
45. Dervieux T, Greenstein N, Kremer J. Pharmacogenomic and metabolic biomarkers in the folate pathway and their association with methotrexate effects during dosage escalation in rheumatoid arthritis. Arthritis Rheum. 54(10), 3095-3103 (2006).
46. Takatori R, Takahashi KA, Tokunaga D, et al. ABCB1 C3435T polymorphism influences methotrexate sensitivity in rheumatoid arthritis patients. Clin. Exp. Rheumatol. 24(5), 546-554 (2006).
47. Drozdzik M, Rudas T, Pawlik A, Gornik W, Kurzawski M, Herczynska M. Reduced folate carrier-1 80GA polymorphism affects methotrexate treatment outcome in rheumatoid arthritis. Pharmacogenomics J. 7(6), 404-407 (2007).
48. Bohanec Grabar P, Logar D, Lestan B, Dolzan V. Genetic determinants of methotrexate toxicity in rheumatoid arthritis patients: a study of polymorphisms affecting methotrexate transport and folate metabolism. Eur. J. Clin. Pharmacol. 64(11), 1057-1068 (2008).
49. James HM, Gillis D, Hissaria P, et al. Common polymorphisms in the folate pathway predict efficacy of combination regimens containing methotrexate and sulfasalazine in early rheumatoid arthritis. J. Rheumatol. 35(4), 562-571 (2008).
50. Warren RB, Smith RL, Campalani E, et al. Genetic variation in efflux transporters influences outcome to methotrexate therapy in patients with psoriasis. J. Invest. Dermatol. 128(8), 1925-1929 (2008).
51. Hayashi H, Fujimaki C, Daimon T, Tsuboi S, Matsuyama T, Itoh K. Genetic polymorphisms in folate pathway enzymes as a possible marker for predicting the outcome of methotrexate therapy in Japanese patients with rheumatoid arthritis. J. Clin. Pharm. Ther. 34(3), 355-361 (2009).
52. Stamp LK, Chapman PT, O'Donnell JL, et al. Polymorphisms within the folate pathway predict folate concentrations but are not associated with disease activity in rheumatoid arthritis patients on methotrexate. Pharmacogenet. Genomics 20(6), 367-376 (2010).
53. de Rotte MC, Bulatovic M, Heijstek MW, et al. ABCB1 and ABCC3 gene polymorphisms are associated with first-year response to methotrexate in juvenile idiopathic arthritis. J. Rheumatol. 39(10), 2032-2040 (2012).
54. Bohanec Grabar P, Leandro-Garcia LJ, Inglada-Perez L, Logar D, Rodriguez-Antona C, Dolzan V. Genetic variation in the SLC19A1 gene and methotrexate toxicity in rheumatoid arthritis patients. Pharmacogenomics 13(14), 1583-1594 (2012).
55. Kato T, Hamada A, Mori S, Saito H. Genetic polymorphisms in metabolic and cellular transport pathway of methotrexate impact clinical outcome of methotrexate monotherapy in Japanese patients with rheumatoid arthritis. Drug Metab. Pharmacokinet. 27(2), 192-199 (2012).
56. Plaza-Plaza JC, Aguilera M, Canadas-Garre M, et al. Pharmacogenetic polymorphisms contributing to toxicity induced by methotrexate in the southern Spanish population with rheumatoid arthritis. OMICS 16(11), 589-595 (2012).
57. Lima A, Bernardes M, Sousa H, et al. SLC19A1 80G allele as a biomarker of methotrexate-related gastrointestinal toxicity in Portuguese rheumatoid arthritis patients. Pharmacogenomics 15(6), 807-820 (2014).
58. Lynch M, Scofield DG, Hong X. The evolution of transcription-initiation sites. Mol. Biol. Evol. 22(4), 1137-1146 (2005
59. Chango A, Emery-Fillon N, De Courcy GP, et al. A polymorphism (80G-A) in the reduced folate carrier gene and its associations with folate status and homocysteinemia. Mol. Genet. Metab.70(4), 310-315 (2000).
60. Dervieux T, Kremer J, Lein DO, et al. Contribution of common polymorphisms in reduced folate carrier and gamma-glutamylhydrolase to methotrexate polyglutamate levels in patients with rheumatoid arthritis. Pharmacogenetics 14(11), 733-739 (2004).
61. Giannini EH, Ruperto N, Ravelli A, Lovell DJ, Felson DT, Martini A. Preliminary definition of improvement in juvenile arthritis. Arthritis Rheum. 40(7), 1202-1209 (1997).
62. Wang GS, Cooper TA. Splicing in disease: disruption of the splicing code and the decoding machinery. Nat. Rev. Genet. 8(10), 749-761 (2007).
63. Spaapen RM, De Kort RA, Van Den Oudenalder K, et al. Rapid identification of clinical relevant minor histocompatibility antigens via genome-wide zygosity-genotype correlation analysis. Clin. Cancer Res. 15(23), 7137-7143 (2009).
64. Uwai Y, Taniguchi R, Motohashi H, Saito H, Okuda M, Inui K. Methotrexate-loxoprofen interaction: involvement of human organic anion transporters hOAT1 and hOAT3. Drug Metab. Pharmacokinet. 19(5), 369-374 (2004).
65. Glaeser H, Bailey DG, Dresser GK, et al. Intestinal drug transporter expression and the impact of grapefruit juice in humans. Clin. Pharmacol. Ther. 81(3), 362-370 (2007).
66. Abe T, Unno M, Onogawa T, et al. LST-2, a human liver-specific organic anion transporter, determines methotrexate sensitivity in gastrointestinal cancers. Gastroenterology 120(7), 1689-1699 (2001).
67. Spinella MJ, Brigle KE, Sierra EE, Goldman ID. Distinguishing between folate receptor-Alpha-mediated transport and reduced folate carrier-mediated transport in L1210 leukemia cells. J. Biol. Chem. 270(14), 7842-7849 (1995).
68. Strand V, Cohen S, Schiff M, et al. Treatment of active rheumatoid arthritis with leflunomide compared with placebo and methotrexate. Leflunomide Rheumatoid Arthritis Investigators Group. Arch. Intern. Med. 159(21), 2542-2550 (1999).
69. Pawlik A, Wrzesniewska J, Fiedorowicz-Fabrycy I, Gawronska-Szklarz B. The MDR1 3435 polymorphism in patients with rheumatoid arthritis. Int. J. Clin. Pharmacol. Ther. 42(9), 496-503 (2004).
70. Drozdzik M, Rudas T, Pawlik A, et al. The effect of 3435CT MDR1 gene polymorphism on rheumatoid arthritis treatment with disease-modifying antirheumatic drugs. Eur. J. Clin. Pharmacol. 62(11), 933-937 (2006).
71. Ranganathan P, Culverhouse R, Marsh S, et al. Methotrexate (MTX) pathway gene polymorphisms and their effects on MTX toxicity in Caucasian and African American patients with rheumatoid arthritis. J. Rheumatol. 35(4), 572-579 (2008).
72. Kooloos WM, Wessels JA, Van Der Straaten T, Allaart CF, Huizinga TW, Guchelaar HJ. Functional polymorphisms and methotrexate treatment outcome in recent-onset rheumatoid arthritis. Pharmacogenomics 11(2), 163-175 (2010).
73. Takano M, Yumoto R, Murakami T. Expression and function of efflux drug transporters in the intestine. Pharmacol. Ther. 109(1-2), 137-161 (2006).
74. Kim RB. Drugs as P-glycoprotein substrates, inhibitors, and inducers. Drug Metab. Rev. 34(1-2), 47-54 (2002).
75. Llorente L, Richaud-Patin Y, Diaz-Borjon A, et al. Multidrug resistance-1 (MDR-1) in rheumatic autoimmune disorders. Part I: increased P-glycoprotein activity in lymphocytes from rheumatoid arthritis patients might influence disease outcome. Joint Bone Spine 67(1), 30-39 (2000).
76. Fung KL, Gottesman MM. A synonymous polymorphism in a common MDR1 (ABCB1) haplotype shapes protein function. Biochim. Biophys. Acta 1794(5), 860-871 (2009).
77. Van Der Heijden JW, Oerlemans R, Tak PP, et al. Involvement of breast cancer resistance protein expression on rheumatoid arthritis synovial tissue macrophages in resistance to methotrexate and leflunomide. Arthritis Rheum. 60(3), 669-677 (2009).
78. Breuninger LM, Paul S, Gaughan K, et al. Expression of multidrug resistance-Associated protein in NIH/3T3 cells confers multidrug resistance associated with increased drug efflux and altered intracellular drug distribution. Cancer Res. 55(22), 5342-5347 (1995).
79. Vlaming ML, Pala Z, Van Esch A, et al. Functionally overlapping roles of Abcg2 (Bcrp1) and Abcc2 (Mrp2) in the elimination of methotrexate and its main toxic metabolite 7-hydroxymethotrexate in vivo. Clin. Cancer Res. 15(9), 3084-3093 (2009).
80. Vlaming ML, Pala Z, Van Esch A, et al. Impact of Abcc2 (Mrp2) and Abcc3 (Mrp3) on the in vivo elimination of methotrexate and its main toxic metabolite 7-hydroxymethotrexate. Clin. Cancer Res. 14(24), 8152-8160 (2008).
81. Chen ZS, Lee K, Walther S, et al. Analysis of methotrexate and folate transport by multidrug resistance protein 4 (ABCC4): MRP4 is a component of the methotrexate efflux system. Cancer Res. 62(11), 3144-3150 (2002).
82. Volk EL, Schneider E. Wild-Type breast cancer resistance protein (BCRP/ABCG2) is a methotrexate polyglutamate transporter. Cancer Res. 63(17), 5538-5543 (2003).
83. Fransen J, Kooloos WM, Wessels JA, et al. Clinical pharmacogenetic model to predict response of MTX monotherapy in patients with established rheumatoid arthritis after DMARD failure. Pharmacogenomics 13(9), 1087-1094 (2012