Skip to main content
    • Aa
    • Aa
  • Get access
    Check if you have access via personal or institutional login
  • Cited by 96
  • Cited by
    This article has been cited by the following publications. This list is generated based on data provided by CrossRef.

    Alpers, David H. 2016. Absorption and blood/cellular transport of folate and cobalamin: Pharmacokinetic and physiological considerations. Biochimie, Vol. 126, p. 52.

    Chaudhari, Snehal N. Mukherjee, Madhumati Vagasi, Alexandra S. Bi, Gaofeng Rahman, Mohammad M. Nguyen, Christine Q. Paul, Ligi Selhub, Jacob and Kipreos, Edward T. 2016. Bacterial Folates Provide an Exogenous Signal for C. elegans Germline Stem Cell Proliferation. Developmental Cell, Vol. 38, Issue. 1, p. 33.

    Cylwik, Bogdan and Chrostek, Lech 2016. Molecular Aspects of Alcohol and Nutrition.

    Date, Swapneeta S. Chen, Cheng-Yen Charles Chen, Yidong and Jansen, Michaela 2016. Experimentally optimized threading structures of the proton-coupled folate transporter. FEBS Open Bio, Vol. 6, Issue. 3, p. 216.

    Guedes, Marta Araújo, João R. Correia-Branco, Ana Gregório, Inês Martel, Fátima and Keating, Elisa 2016. Modulation of the uptake of critical nutrients by breast cancer cells by lactate: Impact on cell survival, proliferation and migration. Experimental Cell Research, Vol. 341, Issue. 2, p. 111.

    Kue, Chin S. Kamkaew, Anyanee Burgess, Kevin Kiew, Lik V. Chung, Lip Y. and Lee, Hong B. 2016. Small Molecules for Active Targeting in Cancer. Medicinal Research Reviews, Vol. 36, Issue. 3, p. 494.

    Kullak-Ublick, Gerd A. Gubler, Christoph Spanaus, Katharina Ismair, Manfred G. Claro da Silva, Tatiana and Jetter, Alexander 2016. No major effects of vitamin D3 (1,25 dihydroxyvitamin D3) on absorption and pharmacokinetics of folic acid and fexofenadine in healthy volunteers. European Journal of Clinical Pharmacology, Vol. 72, Issue. 7, p. 797.

    Raz, Shachar Stark, Michal and Assaraf, Yehuda G. 2016. Folylpoly-γ-glutamate synthetase: A key determinant of folate homeostasis and antifolate resistance in cancer. Drug Resistance Updates, Vol. 28, p. 43.

    Rossi, Maddalena Raimondi, Stefano Costantino, Luca and Amaretti, Alberto 2016. Industrial Biotechnology of Vitamins, Biopigments, and Antioxidants.

    Saccone, Gabriele Sarno, Laura Roman, Amanda Donadono, Vera Maruotti, Giuseppe Maria and Martinelli, Pasquale 2016. 5-Methyl-tetrahydrofolate in prevention of recurrent preeclampsia. The Journal of Maternal-Fetal & Neonatal Medicine, Vol. 29, Issue. 6, p. 916.

    Araújo, João Ricardo Keating, Elisa and Martel, Fátima 2015. Impact of Gestational Diabetes Mellitus in the Maternal-to-Fetal Transport of Nutrients. Current Diabetes Reports, Vol. 15, Issue. 2,

    Araújo, João Ricardo Martel, Fátima Borges, Nuno Araújo, João Manuel and Keating, Elisa 2015. Folates and aging: Role in mild cognitive impairment, dementia and depression. Ageing Research Reviews, Vol. 22, p. 9.

    Berginc, K. 2015. Dietary Supplements.

    Bispo, Adriana Valéria Sales dos Santos, Luana Oliveira de Barros, Juliana Vieira Duarte, Andrea Rezende Araújo, Jacqueline Muniz, Maria Tereza Cartaxo and Santos, Neide 2015. Polymorphisms in folate pathway genes are not associated with somatic nondisjunction in turner syndrome. American Journal of Medical Genetics Part A, Vol. 167, Issue. 7, p. 1510.

    Kawami, Masashi Miyamoto, Mioka Yumoto, Ryoko and Takano, Mikihisa 2015. Methotrexate influx via folate transporters into alveolar epithelial cell line A549. Drug Metabolism and Pharmacokinetics,

    Keating, Elisa Araújo, João and Martel, Fátima 2015. Human Placental Trophoblasts.

    Lakkakula, Bhaskar Murthy, Jyotsna and Gurramkonda, Venkatesh Babu 2015. Relationship between reduced folate carrier gene polymorphism and non-syndromic cleft lip and palate in Indian population. The Journal of Maternal-Fetal & Neonatal Medicine, Vol. 28, Issue. 3, p. 329.

    Molero-Luis, Marta Serrano, Mercedes O’Callaghan, Maria M Sierra, Cristina Pérez-Dueñas, Belén García-Cazorla, Angels and Artuch, Rafael 2015. Clinical, etiological and therapeutic aspects of cerebral folate deficiency. Expert Review of Neurotherapeutics, Vol. 15, Issue. 7, p. 793.

    Narawa, Tomoya Yano, Toshiaki and Itoh, Tomoo 2015. Stereoselective Recognition of Amethopterin Enantiomers by the Rat Proton-Coupled Folate Transporter. Biological & Pharmaceutical Bulletin, Vol. 38, Issue. 4, p. 545.

    Peñalva, Rebeca Esparza, Irene González-Navarro, Carlos J. Quincoces, Gemma Peñuelas, Ivan and Irache, Juan M. 2015. Zein nanoparticles for oral folic acid delivery. Journal of Drug Delivery Science and Technology, Vol. 30, p. 450.

  • Expert Reviews in Molecular Medicine, Volume 11
  • 2009, e4

Membrane transporters and folate homeostasis: intestinal absorption and transport into systemic compartments and tissues

  • Rongbao Zhao (a1), Larry H. Matherly (a2) and I. David Goldman (a1)
  • DOI:
  • Published online: 01 January 2009

Members of the family of B9 vitamins are commonly known as folates. They are derived entirely from dietary sources and are key one-carbon donors required for de novo nucleotide and methionine synthesis. These highly hydrophilic molecules use several genetically distinct and functionally diverse transport systems to enter cells: the reduced folate carrier, the proton-coupled folate transporter and the folate receptors. Each plays a unique role in mediating folate transport across epithelia and into systemic tissues. The mechanism of intestinal folate absorption was recently uncovered, revealing the genetic basis for the autosomal recessive disorder hereditary folate malabsorption, which results from loss-of-function mutations in the proton-coupled folate transporter gene. It is therefore now possible to piece together how these folate transporters contribute, both individually and collectively, to folate homeostasis in humans. This review focuses on the physiological roles of the major folate transporters, with a brief consideration of their impact on the pharmacological activities of antifolates.

Corresponding author
*Corresponding author: I. David Goldman, Cancer Center, Albert Einstein College of Medicine, Chanin Two, 1300 Morris Park Avenue, Bronx, NY 10461, USA. Tel: +1 718 430 2302; Fax: +1 718 430 8550; E-mail:
Linked references
Hide All

This list contains references from the content that can be linked to their source. For a full set of references and notes please see the PDF or HTML where available.

2P.F. Jacques (1999) The effect of folic acid fortification on plasma folate and total homocysteine concentrations. New England Journal of Medicine 340, 1449-1454

3L.H. Matherly and I.D. Goldman (2003) Membrane transport of folates. Vitamins and Hormones 66, 403-456

5B.A. Kamen and A.K. Smith (2004) A review of folate receptor alpha cycling and 5-methyltetrahydrofolate accumulation with an emphasis on cell models in vitro. Advanced Drug Delivery Reviews 56, 1085-1097

6M.D. Salazar and M. Ratnam (2007) The folate receptor: what does it promise in tissue-targeted therapeutics? Cancer and Metastasis Reviews 26, 141-152

7A. Qiu (2006) Identification of an intestinal folate transporter and the molecular basis for hereditary folate malabsorption. Cell 127, 917-928

8R. Zhao and I.D. Goldman (2007) The molecular identity and characterization of a Proton-coupled Folate Transporter-PCFT; biological ramifications and impact on the activity of pemetrexed. Cancer and Metastasis Reviews 26, 129-139

9R. Zhao (2007) The spectrum of mutations in the PCFT gene, coding for an intestinal folate transporter, that are the basis for hereditary folate malabsorption. Blood 110, 1147-1152

10S.H. Min (2008) The clinical course and genetic defect in the PCFT in a 27-year-old woman with Hereditary folate malabsorption. Journal of Pediatrics 153, 435-437

11J.A. Wessels , T.W. Huizinga and H.J. Guchelaar (2008) Recent insights in the pharmacological actions of methotrexate in the treatment of rheumatoid arthritis. Rheumatology 47, 249-255

12R. Zhao and I.D. Goldman (2003) Resistance to antifolates. Oncogene 22, 7431-7457

13S. Chattopadhyay , R.G. Moran and I.D. Goldman (2007) Pemetrexed: biochemical and cellular pharmacology, mechanisms and clinical applications. Molecular Cancer Therapeutics 6, 404-417

14B. Shane (1989) Folylpolyglutamate synthesis and role in the regulation of one-carbon metabolism. Vitamins and Hormones 45, 263-335

18I.D. Goldman and L.H. Matherly (1985) The cellular pharmacology of methotrexate. Pharmacology and Therapeutics 28, 77-102

19F.M. Sirotnak and B. Tolner (1999) Carrier-mediated membrane transport of folates in mammalian cells. Annual Review of Nutrition 19, 91-122

20G.B. Henderson and E.M. Zevely (1983) Structural requirements for anion substrates of the methotrexate transport system of L1210 cells. Archives of Biochemistry and Biophysics 221, 438-446

21I.D. Goldman (1971) The characteristics of the membrane transport of amethopterin and the naturally occurring folates. Annals of the New York Academy of Sciences 186, 400-422

25B. Dutta (1999) Cloning of the human thiamine transporter, a member of the folate transporter family. Journal of Biological Chemistry 274, 31925-31929

26A. Rajgopal (2001) SLC19A3 encodes a second thiamine transporter, ThTr2. Biochimica et Biophysica Acta 1537, 175-178

27G. Rindi and U. Laforenza (2000) Thiamine intestinal transport and related issues: recent aspects. Proceedings of the Society for Experimental Biology and Medicine 224, 246-255

28R. Zhao (2000) Impact of the reduced folate carrier on the accumulation of active thiamin metabolites in murine leukemia cells. Journal of Biological Chemistry 276, 1114-1118

29R. Zhao , F. Gao and I.D. Goldman (2002) Reduced folate carrier transports thiamine monophosphate: an alternative route for thiamine delivery into mammalian cells. American Journal of Physiology Cell Physiology 282, C1512-C1517

30C.-H. Yang , F.M. Sirotnak and M. Dembo (1984) Interaction between anions and the reduced folate/methotrexate transport system in L1210 cell plasma membrane vesicles: directional symmetry and anion specificity for differential mobility of loaded and unloaded carrier. Journal of Membrane Biology 79, 285-292

33M. Dembo , F.M. Sirotnak and D.M. Moccio (1984) Effects of metabolic deprivation on methotrexate transport in L1210 leukemia cells: further evidence for separate influx and efflux systems with different energetic requirements. Journal of Membrane Biology 78, 9-17

34G.D. Kruh and M.G. Belinsky (2003) The MRP family of drug efflux pumps. Oncogene 22, 7537-7552

35W. Cao and L.H. Matherly (2004) Analysis of the membrane topology for transmembrane domains 7–12 of the human reduced folate carrier by scanning cysteine accessibility methods. Biochemical Journal 378, 201-206

36P.L. Ferguson and W.F. Flintoff (1999) Topological and functional analysis of the human reduced folate carrier by hemagglutinin epitope insertion. Journal of Biological Chemistry 274, 16269-16278

37X. Liu and L. Matherly (2002) Analysis of membrane topology of the human reduced folate carrier protein by hemagglutinin epitope insertion and scanning glycosylation insertion mutagenesis. Biochimica et Biophysica Acta 1564, 333-342

38S.C. Wong (1998) Effects of the loss of capacity for N-glycosylation on the transport activity and cellular localization of the human reduced folate carrier. Biochimica et Biophysica Acta 1375, 6-12

39X.Y. Liu , T.L. Witt and L.H. Matherly (2003) Restoration of high level transport activity by human reduced folate carrier/ThT1 chimeric transporters: Role of the transmembrane domain 6/7 linker region in reduced folate carrier function. Biochemical Journal 369, 31-37

40T.L. Witt , S.E. Stapels and L.H. Matherly (2004) Restoration of transport activity by co-expression of human reduced folate carrier half-molecules in transport-impaired K562 cells: localization of a substrate binding domain to transmembrane domains 7–12. Journal of Biological Chemistry 279, 46755-46763

41Y. Deng (2008) Role of lysine 411 in substrate carboxyl group binding to the human reduced folate carrier, as determined by site-directed mutagenesis and affinity inhibition. Molecular Pharmacology 73, 1274-1281

42Z. Hou (2006) Transmembrane domains 4, 5, 7, 8, and 10 of the human reduced folate carrier are important structural or functional components of the transmembrane channel for folate substrates. Journal of Biological Chemistry 281, 33588-33596

43Z. Hou (2005) Localization of a substrate binding domain of the human reduced folate carrier to transmembrane domain 11 by radioaffinity labeling and cysteine-substituted accessibility methods. Journal of Biological Chemistry 280, 36206-36213

44J. Abramson (2003) Structure and mechanism of the lactose permease of Escherichia coli. Science 301, 610-615

45Y. Huang (2003) Structure and mechanism of the glycerol-3-phosphate transporter from Escherichia coli. Science 301, 616-620

46J.R. Whetstine , R.M. Flatley and L.H. Matherly (2002) The human reduced folate carrier gene is ubiquitously and differentially expressed in normal human tissues: identification of seven non-coding exons and characterization of a novel promoter. Biochemical Journal 367, 629-640

47M. Liu (2005) Structure and regulation of the murine reduced folate carrier gene: identification of four noncoding exons and promoters and regulation by dietary folates. Journal of Biological Chemistry 280, 5588-5597

48S.G. Payton (2007) Effects of 5 untranslated region diversity on the posttranscriptional regulation of the human reduced folate carrier. Biochimica et Biophysica Acta 1769, 131-138

49R.M. Flatley (2004) Primary acute lymphoblastic leukemia cells use a novel promoter and 5noncoding exon for the human reduced folate carrier that encodes a modified carrier translated from an upstream translational start. Clinical Cancer Research 10, 5111-5122

50A. Chango (2000) A polymorphism (80G-> A) in the reduced folate carrier gene and its associations with folate status and homocysteinemia. Molecular Genetics and Metabolism 70, 310-315

52J.R. Whetstine , T.L. Witt and L.H. Matherly (2002) The human reduced folate carrier gene is regulated by the AP2 and Sp1 transcription factor families and a functional 61 base pair polymorphism. Journal of Biological Chemistry 277, 43873-43880

53P. De Marco (2003) Reduced folate carrier polymorphism (80A–>G) and neural tube defects. European Journal of Human Genetics 11, 245-252

54I. Morin (2003) Evaluation of genetic variants in the reduced folate carrier and in glutamate carboxypeptidase II for spina bifida risk. Molecular Genetics and Metabolism 79, 197-200

55C. Laverdiere (2002) Polymorphism G80A in the reduced folate carrier gene and its relationship to methotrexate plasma levels and outcome of childhood acute lymphoblastic leukemia. Blood 100, 3832-3834

56L.H. Matherly (2004) Human reduced Folate carrier gene and transcript variants: functional, physiologic, and pharmacologic consequences. Current Pharmacogenetics 2, 287-298

57V.B. O'Leary (2006) Reduced folate carrier polymorphisms and neural tube defect risk. Molecular Genetics and Metabolism 87, 364-369

58Y. Nakai (2007) Functional characterization of human PCFT/HCP1 heterologously expressed in mammalian cells as a folate transporter. Journal of Pharmacology and Experimental Therapeutics 322, 469-476

59N.S. Umapathy (2007) Cloning and functional characterization of the proton-coupled electrogenic folate transporter and analysis of its expression in retinal cell types. Investigative Ophthalmology and Visual Science 48, 5299-5305

60M. Shayeghi (2005) Identification of an intestinal heme transporter. Cell 122, 789-801

62R. Zhao (2004) A prominent low-pH methotrexate transport activity in human solid tumor cells: Contribution to the preservation of methotrexate pharmacological activity in HeLa cells lacking the reduced folate carrier. Clinical Cancer Research 10, 718-727

63J.M. Kuhnel , J.H. Chiao and F.M. Sirotnak (2000) Contrasting effects of oncogene expression on two carrier-mediated systems internalizing folate compounds in Fisher rat 3T3 cells. Journal of Cellular Physiology 184, 364-372

64E.E. Sierra and I.D. Goldman (1998) Characterization of folate transport mediated by a low pH route in mouse L1210 leukemia cells with defective reduced folate carrier function. Biochemical Pharmacology 55, 1505-1512

65Y.G. Assaraf , S. Babani and I.D. Goldman (1998) Increased activity of a novel low pH folate transporter associated with lipoplilic antifolate resistance in Chinese hamster ovary cells. Journal of Biological Chemistry 273, 8106-8111

66A. Qiu (2007) Rodent intestinal folate transporters (SLC46A1): secondary structure, functional properties, and response to dietary folate restriction. American Journal of Physiology Cell Physiology 293, C1669-C1678

67R. Zhao (2008) The proton-coupled folate transporter (PCFT): impact on pemetrexed transport and on antifolate activities as compared to the reduced folate carrier. Molecular Pharmacology 74, 854-862

68E.E. Sierra (1997) pH dependence of methotrexate transport by the reduced folate carrier and the folate receptor in L1210 leukemia cells - Further evidence for a third route mediated at low pH. Biochemical Pharmacology 53, 223-231

69Y. Wang , R. Zhao and I.D. Goldman (2004) Characterization of a folate transporter in HeLa cells with a low pH optimum and high affinity for pemetrexed distinct from the reduced folate carrier. Clinical Cancer Research 10, 6256-6264

70C.M. Schron , C. Washington Jr. and B.L. Blitzer (1985) The transmembrane pH gradient drives uphill folate transport in rabbit jejunum. Direct evidence for folate/hydroxyl exchange in brush border membrane vesicles. Journal of Clinical Investigation 76, 2030-2033

71B. Mackenzie (2006) Divalent metal-ion transporter DMT1 mediates both H+ -coupled Fe2+ transport and uncoupled fluxes. Pflugers Archiv (European Journal of Physiology) 451, 544-558

72F.M. Sirotnak (1979) Stereospecificity at carbon 6 of formyltetrahydrofolate as a competitive inhibitor of transport and cytotoxicity of methotrexate in vitro. Biochemical Pharmacology 28, 2993-2997

73K. Inoue (2008) Functional characterization of PCFT/HCP1 as the molecular entity of the carrier-mediated intestinal folate transport system in the rat model. American Journal of Physiology Gastrointestinal Liver Physiology 294, G660-G668

75C.H. Yun (1995) Structure/function studies of mammalian Na-H exchangers-an update. Journal of Physiology 482 (Suppl.), 1S-6S

76G.T. McEwan (1990) A combined TDDA-PVC pH and reference electrode for use in the upper small intestine. Journal of Medical Engineering and Technology 14, 16-20

77M. Ikuma (1996) Effects of aging on the microclimate pH of the rat jejunum. Biochimica et Biophysica Acta 1280, 19-26

78H.M. Said , R. Smith and R. Redha (1987) Studies on the intestinal surface acid microclimate: developmental aspects. Pediatric Research 22, 497-499

79J. Yang (2007) Characterization of the pH of folate receptor-containing endosomes and the rate of hydrolysis of internalized acid-labile folate-drug conjugates. Journal of Pharmacology and Experimental Therapeutics 321, 462-468

80Y. Wang (2001) Localization of the murine reduced folate carrier as assessed by immunohistochemical analysis. Biochimica et Biophysica Acta 1513, 49-54

81V.S. Subramanian , J.S. Marchant and H.M. Said (2008) Apical membrane targeting and trafficking of the human proton-coupled transporter in polarized epithelia. American Journal of Physiology Cell Physiology 294, C233-C240

84J.B. Mason (1990) Carrier affinity as a mechanism for the pH-dependence of folate transport in the small intestine. Biochimica et Biophysica Acta 1024, 331-335

87S. Chattopadhyay (2006) The inverse relationship between reduced folate carrier function and pemetrexed activity in a human colon cancer cell line. Molecular Cancer Therapeutics 5, 438-449

88R. Zhao , M. Hanscom and I.D. Goldman (2005) The relationship between folate transport activity at low pH and reduced folate carrier function in human Huh7 hepatoma cells. Biochimica et Biophysica Acta 1715, 57-64

89Y. Wang (2005) Preservation of folate transport activity with a low-pH optimum in rat IEC-6 intestinal epithelial cell lines that lack reduced folate carrier function. American Journal of Physiology Cell Physiology 288, C65-C71

90K. Balamurugan and H.M. Said (2006) Role of reduced folate carrier in intestinal folate uptake. American Journal of Physiology Cell Physiology 291, C189-C193

91Y. Lu and P. Low (2002) Folate-mediated delivery of macromolecular anticancer therapeutic agents. Advanced Drug Delivery Reviews 54, 675-693

93K.E. Brigle (1994) Increased expression and characterization of two distinct folate-binding proteins in murine erythroleukemia cells. Biochemical Pharmacology 47, 337-345

95K.M. Maziarz (1999) Complete mapping of divergent amino acids responsible for differential ligand binding of folate receptors alpha and beta. Journal of Biological Chemistry 274, 11086-11091

97K.G. Rothberg (1990) The glycophospholipid-linked folate receptor internalizes folate without entering the clathrin-coated pit endocytic pathway. Journal of Cell Biology 110, 637-649

98B.A. Kamen , A.K. Smith and R.G.W. Anderson (1991) The folate receptor works in tandem with a probenecid-sensitive carrier in MA104 cells in vitro. Journal of Clinical Investigation 87, 1442-1449

99P.D. Prasad (1994) Functional coupling between a bafilomycin A1-sensitive proton pump and a probenecid-sensitive folate transporter in human placental choriocarcinoma cells. Biochimica et Biophysica Acta Molecular Cell Research 1222, 309-314

100N.C. Andrews (2007) When is a heme transporter not a heme transporter? When it's a folate transporter. Cell Metabolism 5, 5-6

101E.E. Sierra (1995) Comparison of transport properties of the reduced folate carrier and folate receptor in murine L1210 leukemia cells. Biochemical Pharmacology 50, 1287-1294

102M.J. Spinella (1995) Distinguishing between folate receptor-α-mediated transport and reduced folate carrier-mediated transport in L1210 leukemia cells. Journal of Biological Chemistry 270, 7842-7849

103N. Parker (2005) Folate receptor expression in carcinomas and normal tissues determined by a quantitative radioligand binding assay. Analytical Biochemistry 338, 284-293

105C.D. Chancy (2000) Expression and differential polarization of the reduced-folate transporter-1 and the folate receptor alpha in mammalian retinal pigment epithelium. Journal of Biological Chemistry 275, 20676-20684

106G. Toffoli (1997) Overexpression of folate binding protein in ovarian cancers. International Journal of Cancer 74, 193-198

108T. Tran (2005) Enhancement of folate receptor alpha expression in tumor cells through the glucocorticoid receptor: a promising means to improved tumor detection and targeting. Cancer Research 65, 4431-4441

109M. Ratnam (1989) Homologous membrane folate binding proteins in human placenta: Cloning and sequence of cDNA. Biochemistry 28, 8249-8254

112J.F. Ross (1999) Folate receptor type beta is a neutrophilic lineage marker and is differentially expressed in myeloid leukemia. Cancer 85, 348-357

113H. Elnakat (2004) Distribution, functionality and gene regulation of folate receptor isoforms: implications in targeted therapy. Advanced Drug Delivery Reviews 56, 1067-1084

114Y.G. Assaraf (2006) The role of multidrug resistance efflux transporters in antifolate resistance and folate homeostasis. Drug Resistance Updates 9, 227-246

115P. Wielinga (2005) The human multidrug resistance protein MRP5 transports folates and can mediate cellular resistance against antifolates. Cancer Research 65, 4425-4430

119D. Rost (2002) Expression and localization of the multidrug resistance-associated protein 3 in rat small and large intestine. American Journal of Physiology Gastrointestinal Liver Physiology 282, G720-G726

121A. Seithel (2006) Variability in mRNA expression of ABC- and SLC-transporters in human intestinal cells: comparison between human segments and Caco-2 cells. European Journal of Pharmaceutical Sciences 28, 291-299

122H. Koepsell and H. Endou (2004) The SLC22 drug transporter family. Pflugers Archiv (European Journal of Physiology) 447, 666-676

123T. Sekine , H. Miyazaki and H. Endou (2006) Molecular physiology of renal organic anion transporters. American Journal of Physiology. Renal Physiology 290, F251-F261

124B. Hagenbuch and P.J. Meier (2004) Organic anion transporting polypeptides of the OATP/SLC21 family: phylogenetic classification as OATP/SLCO superfamily, new nomenclature and molecular/functional properties. Pflugers Archiv (European Journal of Physiology) 447, 653-665

125S. Masuda (2003) Functional characteristics and pharmacokinetic significance of kidney-specific organic anion transporters, OAT-K1 and OAT-K2, in the urinary excretion of anionic drugs. Drug Metabolism and Pharmacokinetics 18, 91-103

126A.N. Rizwan and G. Burckhardt (2007) Organic anion transporters of the SLC22 family: biopharmaceutical, physiological, and pathological roles. Pharmaceutical Research 24, 450-470

127Y. Uwai (2004) Methotrexate-loxoprofen interaction: involvement of human organic anion transporters hOAT1 and hOAT3. Drug Metabolism and Pharmacokinetics 19, 369-374

128M. Takeda (2002) Characterization of methotrexate transport and its drug interactions with human organic anion transporters. Journal of Pharmacology and Experimental Therapeutics 302, 666-671

129Y. Nozaki (2004) Quantitative evaluation of the drug-drug interactions between methotrexate and nonsteroidal anti-inflammatory drugs in the renal uptake process based on the contribution of organic anion transporters and reduced folate carrier. Journal of Pharmacology and Experimental Therapeutics 309, 226-234

131A.L. VanWert and D.H. Sweet (2008) Impaired clearance of methotrexate in organic anion transporter 3 (Slc22a8) knockout mice: a gender specific impact of reduced folates. Pharmaceutical Research 25, 453-462

132R. Zhao (2001) Rescue of embryonic lethality in reduced folate carrier-deficient mice by maternal folic acid supplementation reveals early neonatal failure of hematopoietic organs. Journal of Biological Chemistry 276, 10224-10228

133J. Gelineau-van Waes (2008) Embryonic development in the reduced folate carrier knockout mouse is modulated by maternal folate supplementation. Birth Defects Research Part A Clinical and Molecular Teratology 82, 494-507

135J. Geller (2002) Hereditary folate malabsorption: family report and review of the literature. Medicine 81, 51-68

136I. Lasry (2008) A novel loss of function mutation in the proton-coupled folate transporter from a patient with hereditary folate malabsorption reveals that Arg 113 is crucial for function. Blood 112, 2055-2061

139I.H. Rosenberg (1969) Absorption of polyglutamic folate: participation of deconjugating enzymes of the intestinal mucosa. New England Journal of Medicine 280, 985-988

140C.E. Butterworth Jr., C.M. Baugh and C. Krumdieck (1969) A study of folate absorption and metabolism in man utilizing carbon-14–labeled polyglutamates synthesized by the solid phase method. Journal of Clinical Investigation 48, 1131-1142

141C.H. Halsted (1989) The intestinal absorption of dietary folates in health and disease. Journal of the American College of Nutrition 8, 650-658

143D.W. Horne and K.A. Reed (1992) Transport of methotrexate in basolateral membrane vesicles from rat liver. Archives of Biochemistry and Biophysics 298, 121-128

144D.W. Horne (1990) Na+ and pH dependence of 5-methyltetrahydrofolic acid and methotrexate transport in freshly isolated hepatocytes. Biochimica et Biophysica Acta Bio-Membranes 1023, 47-55

148C.A. Goresky , H. Watanabe and D.G. Johns (1963) The renal excretion of folic acid. Journal of Clinical Investigation 42, 1841-1849

150J. Selhub and I.H. Rosenberg (1978) Demonstration of high-affinity folate binding activity associated with the brush border membranes of rat kidney. Proceedings of the National Academy of Sciences of the United States of America 75, 3090-3093

152H. Birn (2005) Renal tubular reabsorption of folate mediated by folate binding protein 1. Journal of the American Society of Nephrology 16, 608-615

153S.D. Bhandari , S.K. Joshi and K.E. McMartin (1988) Folate binding and transport by rat kidney brush-border membrane vesicles. Biochimica et Biophysica Acta 937, 211-218

154S.D. Bhandari , T. Fortney and K.E. McMartin (1991) Analysis of the pH dependence of folate binding and transport by rat kidney brush border membrane vesicles. Proceedings of the Society for Experimental Biology and Medicine 196, 451-456

155F. Jaramillo-Juarez , M.M. Aires and G. Malnic (1990) Urinary and proximal tubule acidification during reduction of renal blood flow in the rat. Journal of Physiology 421, 475-483

156P.J. Santiago-Borrero (1973) Congenital isolated defect of folic acid absorption. Journal of Pediatrics 82, 450-455

160S.D. Weitman , K.M. Frazier and B.A. Kamen (1994) The folate receptor in central nervous system malignancies of childhood. Journal of Neuro-Oncology 21, 107-112

161M.D. Kennedy (2003) Evaluation of folate conjugate uptake and transport by the choroid plexus of mice. Pharmaceutical Research 20, 714-719

162D. Wu and W.M. Pardridge (1999) Blood-brain barrier transport of reduced folic acid. Pharmaceutical Research 16, 415-419

163M.B. Segal (2001) Transport of nutrients across the choroid plexus. Microscopy Research and Technique 52, 38-48

164P. Moretti (2008) Brief report: autistic symptoms, developmental regression, mental retardation, epilepsy, and dyskinesias in CNS folate deficiency. Journal of Autism and Developmental Disorders 38, 1170-1177

165P. Moretti (2005) Cerebral folate deficiency with developmental delay, autism, and response to folinic acid. Neurology 64, 1088-1090

166V.T. Ramaekers (2005) Autoantibodies to folate receptors in the cerebral folate deficiency syndrome. New England Journal of Medicine 352, 1985-1991

167R.S. Schwartz (2005) Autoimmune folate deficiency and the rise and fall of “horror autotoxicus”. New England Journal of Medicine 352, 1948-1950

168V.T. Ramaekers (2007) Folate receptor autoimmunity and cerebral folate deficiency in low-functioning autism with neurological deficits. Neuropediatrics 38, 276-281

169R. Spector and A.V. Lorenzo (1975) Folate transport by the choroid plexus in vitro. Science 187, 540-542

174T.A. Patrick (1997) Folate receptors as potential therapeutic targets in choroid plexus tumors of SV40 transgenic mice. Journal of Neuro-Oncology 32, 111-123

175M.B. Segal (2000) The choroid plexuses and the barriers between the blood and the cerebrospinal fluid. Cellular and Molecular Neurobiology 20, 183-196

176R. Zhao (1997) Impact of overexpression of the reduced folate carrier (RFC1), an anion exchanger, on concentrative transport in murine L1210 leukemia cells. Journal of Biological Chemistry 272, 21207-21212

177M. Levitt (1971) Transport characteristics of folates in cerebrospinal fluid; a study utilizing doubly labeled 5-methyltetrahydrofolate and 5-formyltetrahydrofolate. Journal of Clinical Investigation 50, 1301-1308

179J.H. Sweiry and D.L. Yudilevich (1985) Transport of folates at maternal and fetal sides of the placenta: lack of inhibition by methotrexate. Biochimica et Biophysica Acta 821, 497-501

181E. Keating (2006) Comparison of folic acid uptake characteristics by human placental choriocarcinoma cells at acidic and physiological pH. Canadian Journal of Physiology and Pharmacology 84, 247-255

182T. Takahashi (2001) Carrier-mediated transport of folic acid in BeWo cell monolayers as a model of the human trophoblast. Placenta 22, 863-869

183M. Poncz (1981) Therapy of congenital folate malabsorption. Journal of Pediatrics 98, 76-79

184M. Poncz and A. Cohen (1996) Long-term treatment of congenital folate malabsorption. Journal of Pediatrics 129, 948

186S.G. Davey and S. Ebrahim (2005) Folate supplementation and cardiovascular disease. Lancet 366, 1679-1681

188C.M. Ulrich and J.D. Potter (2006) Folate supplementation: too much of a good thing? Cancer Epidemiol Biomarkers Prev 15, 189-193

189M.E. Martínez , J.R. Marshall and E. Giovannucci (2008) Diet and cancer prevention: the roles of observation and experimentation. Nature Reviews Cancer 8, 694-703

190M. Eichholzer , O. Tonz and R. Zimmermann (2006) Folic acid: a public-health challenge. Lancet 367, 1352-1361

191M. Lucock (2000) Folic acid: nutritional biochemistry, molecular biology, and role in disease processes. Molecular Genetics and Metabolism 71, 121-138

192D. Kessel , T.C. Hall and D. Roberts (1965) Uptake as a determinant of methotrexate response in mouse leukemias. Science 150, 752-754

193M.T. Hakala (1965) On the role of drug penetration in amethopterin resistance of Sarcoma-180 cells in vitro. Biochimica et Biophysica Acta 102, 198-209

194G.A. Fischer (1962) Detective transport of amethopterin (methotrexate) as a mechanism of resistance to the antimetabolite in L5178Y leukemic cells. Biochemical Pharmacology 11, 1233-1234

195Y. Ge (2007) Prognostic role of the reduced folate carrier, the major membrane transporter for methotrexate, in childhood acute lymphoblastic leukemia: a report from the Children's Oncology Group. Clinical Cancer Research 13, 451-457

197A.S. Levy (2003) Reduced folate carrier and dihydrofolate reductase expression in acute lymphocytic leukemia may predict outcome: a Children's Cancer Group Study. Journal of Pediatric Hematology/Oncology 25, 688-695

199R. Zhao (2004) Selective preservation of pemetrexed pharmacological activity in HeLa cells lacking the reduced folate carrier; association with the presence of a secondary transport pathway. Cancer Research 64, 3313-3319

200D. Patterson (2008) A humanized mouse model for the reduced folate carrier. Molecular Genetics and Metabolism 93, 95-103

201L.M. Veenhoff , E.H. Heuberger and B. Poolman (2002) Quaternary structure and function of transport proteins. Trends in Biochemical Sciences 27, 242-249

202A. Karlin and M.H. Akabas (1998) Substituted-cysteine accessibility method. Methods in Enzymology 293, 123-145

203M.J. Lemieux (2007) Eukaryotic major facilitator superfamily transporter modeling based on the prokaryotic GlpT crystal structure. Molecular Membrane Biology 24, 333-341

206Y.I. Kim (2008) Folic acid supplementation and cancer risk: point. Cancer Epidemiol Biomarkers Prev. 17, 2220-2225

208A.K. Lawrance (2007) Genetic and nutritional deficiencies in folate metabolism influence tumorigenicity in Apcmin/+ mice. Journal of Nutritional Biochemistry 18, 305-312

209G. Helmlinger (1997) Interstitial pH and pO2 gradients in solid tumors in vivo: high- resolution measurements reveal a lack of correlation. Nature Medicine 3, 177-182

210O. Tredan (2007) Drug resistance and the solid tumor microenvironment. Journal of the National Cancer Institute 99, 1441-1454

211N. Raghunand (1999) Plasmalemmal pH-gradients in drug-sensitive and drug-resistant MCF-7 human breast carcinoma xenografts measured by 31P magnetic resonance spectroscopy. Biochemical Pharmacology 57, 309-312

213E.A. Henderson (2006) Targeting the alpha-folate receptor with cyclopenta[g]quinazoline-based inhibitors of thymidylate synthase. Bioorganic and Medicinal Chemistry 14, 5020-5042

214D.D. Gibbs (2005) BGC 945, a novel tumor-selective thymidylate synthase inhibitor targeted to alpha-folate receptor-overexpressing tumors. Cancer Research 65, 11721-11728

215Y. Deng (2008) Synthesis and Discovery of High Affinity Folate Receptor-Specific Glycinamide Ribonucleotide Formyltransferase Inhibitors with Antitumor Activity. Journal of Medicinal Chemistry 51, 5052-5063

L.H. Matherly , Z. Hou and Y. Deng (2007) Human reduced folate carrier: translation of basic biology to cancer etiology and therapy. Cancer and Metastasis Reviews 26, 111-128

Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Expert Reviews in Molecular Medicine
  • ISSN: -
  • EISSN: 1462-3994
  • URL: /core/journals/expert-reviews-in-molecular-medicine
Please enter your name
Please enter a valid email address
Who would you like to send this to? *