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

Published online by Cambridge University Press:  28 January 2009

Rongbao Zhao ,
Larry H. Matherly  and
I. David Goldman
Rongbao Zhao
Affiliation:
Departments of Medicine and Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Larry H. Matherly
Affiliation:
Department of Pharmacology and the Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA.
I. David Goldman*
Affiliation:
Departments of Medicine and Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
*
*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: [email protected]
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Abstract

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.

Type
Review Article
Information
Expert Reviews in Molecular Medicine , Volume 11 , July 2009 , e4
Copyright
Copyright © Cambridge University Press 2009

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References

References

1Stokstad, E.L.R. (1990) Historical perspective on key advances in the biochemistry and physiology of folates. In Folic Acid Metabolism in Health and Disease. (Picciano, M.F and Stokstad, E.L.R. eds.), pp. 1-21, Wiley-LissGoogle Scholar
2Jacques, P.F. et al. (1999) The effect of folic acid fortification on plasma folate and total homocysteine concentrations. New England Journal of Medicine 340, 1449-1454CrossRefGoogle ScholarPubMed
3Matherly, L.H. and Goldman, I.D. (2003) Membrane transport of folates. Vitamins and Hormones 66, 403-456CrossRefGoogle ScholarPubMed
4Matherly, L.H., Hou, Z. and Deng, Y. (2007) Human reduced folate carrier: translation of basic biology to cancer etiology and therapy. Cancer and Metastasis Reviews 26, 111-128CrossRefGoogle Scholar
5Kamen, B.A. and Smith, A.K. (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, 1085-1097Google Scholar
6Salazar, M.D. and Ratnam, M. (2007) The folate receptor: what does it promise in tissue-targeted therapeutics? Cancer and Metastasis Reviews 26, 141-152CrossRefGoogle ScholarPubMed
7Qiu, A. et al. (2006) Identification of an intestinal folate transporter and the molecular basis for hereditary folate malabsorption. Cell 127, 917-928CrossRefGoogle ScholarPubMed
8Zhao, R. and Goldman, I.D. (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, 129-139CrossRefGoogle ScholarPubMed
9Zhao, R. et al. (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, 1147-1152CrossRefGoogle ScholarPubMed
10Min, S.H. et al. (2008) The clinical course and genetic defect in the PCFT in a 27-year-old woman with Hereditary folate malabsorption. Journal of Pediatrics 153, 435-437CrossRefGoogle Scholar
11Wessels, J.A., Huizinga, T.W. and Guchelaar, H.J. (2008) Recent insights in the pharmacological actions of methotrexate in the treatment of rheumatoid arthritis. Rheumatology 47, 249-255Google Scholar
12Zhao, R. and Goldman, I.D. (2003) Resistance to antifolates. Oncogene 22, 7431-7457CrossRefGoogle ScholarPubMed
13Chattopadhyay, S., Moran, R.G. and Goldman, I.D. (2007) Pemetrexed: biochemical and cellular pharmacology, mechanisms and clinical applications. Molecular Cancer Therapeutics 6, 404-417Google Scholar
14Shane, B. (1989) Folylpolyglutamate synthesis and role in the regulation of one-carbon metabolism. Vitamins and Hormones 45, 263-335CrossRefGoogle ScholarPubMed
15Matherly, L.H. et al. (1987) The effects of 4-aminoantifolates on 5-formyltetrahydrofolate metabolism in L1210 cells. Journal of Biological Chemistry 262, 710-717Google Scholar
16Seither, R.L. et al. (1989) Folate-pool interconversions and inhibition of biosynthetic processes after exposure of L1210 leukemia cells to antifolates. Journal of Biological Chemistry 264, 17016-17023CrossRefGoogle ScholarPubMed
17Goldman, I.D., Lichtenstein, N.S. and Oliverio, V.T. (1968) Carrier-mediated transport of the folic acid analogue methotrexate, in the L1210 leukemia cell. Journal of Biological Chemistry 243, 5007-5017Google Scholar
18Goldman, I.D. and Matherly, L.H. (1985) The cellular pharmacology of methotrexate. Pharmacology and Therapeutics 28, 77-102Google Scholar
19Sirotnak, F.M. and Tolner, B. (1999) Carrier-mediated membrane transport of folates in mammalian cells. Annual Review of Nutrition 19, 91-122Google Scholar
20Henderson, G.B. and Zevely, E.M. (1983) Structural requirements for anion substrates of the methotrexate transport system of L1210 cells. Archives of Biochemistry and Biophysics 221, 438-446CrossRefGoogle ScholarPubMed
21Goldman, I.D. (1971) The characteristics of the membrane transport of amethopterin and the naturally occurring folates. Annals of the New York Academy of Sciences 186, 400-422CrossRefGoogle ScholarPubMed
22Labay, V. et al. (1999) Mutations in SLC19A2 cause thiamine-responsive megaloblastic anaemia associated with diabetes mellitus and deafness. Nature Genetics 22, 300-304Google Scholar
23Fleming, J.C. et al. (1999) The gene mutated in thiamine-responsive anaemia with diabetes and deafness (TRMA) encodes a functional thiamine transporter. Nature Genetics 22, 305-308Google Scholar
24Diaz, G.A. et al. (1999) Mutations in a new gene encoding a thiamine transporter cause thiamine- responsive megaloblastic anaemia syndrome. Nature Genetics 22, 309-312CrossRefGoogle Scholar
25Dutta, B. et al. (1999) Cloning of the human thiamine transporter, a member of the folate transporter family. Journal of Biological Chemistry 274, 31925-31929CrossRefGoogle ScholarPubMed
26Rajgopal, A. et al. (2001) SLC19A3 encodes a second thiamine transporter, ThTr2. Biochimica et Biophysica Acta 1537, 175-178Google Scholar
27Rindi, G. and Laforenza, U. (2000) Thiamine intestinal transport and related issues: recent aspects. Proceedings of the Society for Experimental Biology and Medicine 224, 246-255CrossRefGoogle ScholarPubMed
28Zhao, R. et al. (2000) Impact of the reduced folate carrier on the accumulation of active thiamin metabolites in murine leukemia cells. Journal of Biological Chemistry 276, 1114-1118CrossRefGoogle Scholar
29Zhao, R., Gao, F. and Goldman, I.D. (2002) Reduced folate carrier transports thiamine monophosphate: an alternative route for thiamine delivery into mammalian cells. American Journal of Physiology Cell Physiology 282, C1512-C1517Google Scholar
30Yang, C.-H., Sirotnak, F.M. and Dembo, M. (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, 285-292Google Scholar
31Goldman, I.D. (1969) Transport energetics of the folic acid analogue, methotrexate, in L1210 cells: Enhanced accumulation by metabolic inhibitors. Journal of Biological Chemistry 244, 3779-3785Google Scholar
32Fry, D.W., White, J.C. and Goldman, I.D. (1980) Effects of 2,4-dinitrophenol and other metabolic inhibitors on the bidirectional carrier fluxes, net transport, and intracellular binding of methotrexate in Ehrlich ascites tumor cells. Cancer Research 40, 3669-3673Google Scholar
33Dembo, M., Sirotnak, F.M. and Moccio, D.M. (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, 9-17CrossRefGoogle ScholarPubMed
34Kruh, G.D. and Belinsky, M.G. (2003) The MRP family of drug efflux pumps. Oncogene 22, 7537-7552Google Scholar
35Cao, W. and Matherly, L.H. (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, 201-206Google Scholar
36Ferguson, P.L. and Flintoff, W.F. (1999) Topological and functional analysis of the human reduced folate carrier by hemagglutinin epitope insertion. Journal of Biological Chemistry 274, 16269-16278CrossRefGoogle ScholarPubMed
37Liu, X. and Matherly, L. (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, 333-342CrossRefGoogle ScholarPubMed
38Wong, S.C. et al. (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, 6-12Google Scholar
39Liu, X.Y., Witt, T.L. and Matherly, L.H. (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, 31-37CrossRefGoogle Scholar
40Witt, T.L., Stapels, S.E. and Matherly, L.H. (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, 46755-46763CrossRefGoogle ScholarPubMed
41Deng, Y. et al. (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, 1274-1281Google Scholar
42Hou, Z. et al. (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, 33588-33596CrossRefGoogle ScholarPubMed
43Hou, Z. et al. (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, 36206-36213Google Scholar
44Abramson, J. et al. (2003) Structure and mechanism of the lactose permease of Escherichia coli. Science 301, 610-615Google Scholar
45Huang, Y. et al. (2003) Structure and mechanism of the glycerol-3-phosphate transporter from Escherichia coli. Science 301, 616-620CrossRefGoogle ScholarPubMed
46Whetstine, J.R., Flatley, R.M. and Matherly, L.H. (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, 629-640CrossRefGoogle ScholarPubMed
47Liu, M. et al. (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, 5588-5597CrossRefGoogle ScholarPubMed
48Payton, S.G. et al. (2007) Effects of 5′ untranslated region diversity on the posttranscriptional regulation of the human reduced folate carrier. Biochimica et Biophysica Acta 1769, 131-138Google Scholar
49Flatley, R.M. et al. (2004) Primary acute lymphoblastic leukemia cells use a novel promoter and 5′noncoding exon for the human reduced folate carrier that encodes a modified carrier translated from an upstream translational start. Clinical Cancer Research 10, 5111-5122Google Scholar
50Chango, A. et al. (2000) A polymorphism (80G-> A) in the reduced folate carrier gene and its associations with folate status and homocysteinemia. Molecular Genetics and Metabolism 70, 310-315CrossRefGoogle ScholarPubMed
51Whetstine, J.R. et al. (2001) Single nucleotide polymorphisms in the human reduced folate carrier: characterization of a high-frequency G/A variant at position 80 and transport properties of the His(27) and Arg(27) carriers. Clinical Cancer Research 7, 3416-3422Google Scholar
52Whetstine, J.R., Witt, T.L. and Matherly, L.H. (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, 43873-43880CrossRefGoogle Scholar
53De Marco, P. et al. (2003) Reduced folate carrier polymorphism (80A–>G) and neural tube defects. European Journal of Human Genetics 11, 245-252CrossRefGoogle Scholar
54Morin, I. et al. (2003) Evaluation of genetic variants in the reduced folate carrier and in glutamate carboxypeptidase II for spina bifida risk. Molecular Genetics and Metabolism 79, 197-200CrossRefGoogle ScholarPubMed
55Laverdiere, C. et al. (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, 3832-3834CrossRefGoogle ScholarPubMed
56Matherly, L.H. (2004) Human reduced Folate carrier gene and transcript variants: functional, physiologic, and pharmacologic consequences. Current Pharmacogenetics 2, 287-298Google Scholar
57O'Leary, V.B. et al. (2006) Reduced folate carrier polymorphisms and neural tube defect risk. Molecular Genetics and Metabolism 87, 364-369Google Scholar
58Nakai, Y. et al. (2007) Functional characterization of human PCFT/HCP1 heterologously expressed in mammalian cells as a folate transporter. Journal of Pharmacology and Experimental Therapeutics 322, 469-476CrossRefGoogle Scholar
59Umapathy, N.S. et al. (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, 5299-5305CrossRefGoogle ScholarPubMed
60Shayeghi, M. et al. (2005) Identification of an intestinal heme transporter. Cell 122, 789-801CrossRefGoogle ScholarPubMed
61Henderson, G.B. and Strauss, B.P. (1990) Characteristics of a novel transport system for folate compounds in wild-type and methotrexate-resistant L1210 cells. Cancer Research 50, 1709-1714Google ScholarPubMed
62Zhao, R. et al. (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, 718-727CrossRefGoogle Scholar
63Kuhnel, J.M., Chiao, J.H. and Sirotnak, F.M. (2000) Contrasting effects of oncogene expression on two carrier-mediated systems internalizing folate compounds in Fisher rat 3T3 cells. Journal of Cellular Physiology 184, 364-3723.0.CO;2-N>CrossRefGoogle ScholarPubMed
64Sierra, E.E. and Goldman, I.D. (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, 1505-1512CrossRefGoogle Scholar
65Assaraf, Y.G., Babani, S. and Goldman, I.D. (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, 8106-8111CrossRefGoogle Scholar
66Qiu, A. et al. (2007) Rodent intestinal folate transporters (SLC46A1): secondary structure, functional properties, and response to dietary folate restriction. American Journal of Physiology Cell Physiology 293, C1669-C1678CrossRefGoogle ScholarPubMed
67Zhao, R. et al. (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, 854-862CrossRefGoogle Scholar
68Sierra, E.E. et al. (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, 223-231CrossRefGoogle ScholarPubMed
69Wang, Y., Zhao, R. and Goldman, I.D. (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, 6256-6264Google Scholar
70Schron, C.M., Washington, C. Jr. and Blitzer, B.L. (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, 2030-2033CrossRefGoogle ScholarPubMed
71Mackenzie, B. et al. (2006) Divalent metal-ion transporter DMT1 mediates both H+ -coupled Fe2+ transport and uncoupled fluxes. Pflugers Archiv (European Journal of Physiology) 451, 544-558CrossRefGoogle Scholar
72Sirotnak, F.M. et al. (1979) Stereospecificity at carbon 6 of formyltetrahydrofolate as a competitive inhibitor of transport and cytotoxicity of methotrexate in vitro. Biochemical Pharmacology 28, 2993-2997CrossRefGoogle ScholarPubMed
73Inoue, K. et al. (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-G668Google Scholar
74Unal, E.S. et al. (2008) N-linked glycosylation and its impact on the electrophoretic mobility and function of the human proton-coupled folate transporter (HsPCFT). Biochimica et Biophysica Acta 1178, 1407-1414CrossRefGoogle Scholar
75Yun, C.H. et al. (1995) Structure/function studies of mammalian Na-H exchangers-an update. Journal of Physiology 482 (Suppl.), 1S-6SCrossRefGoogle ScholarPubMed
76McEwan, G.T. et al. (1990) A combined TDDA-PVC pH and reference electrode for use in the upper small intestine. Journal of Medical Engineering and Technology 14, 16-20CrossRefGoogle ScholarPubMed
77Ikuma, M. et al. (1996) Effects of aging on the microclimate pH of the rat jejunum. Biochimica et Biophysica Acta 1280, 19-26CrossRefGoogle ScholarPubMed
78Said, H.M., Smith, R. and Redha, R. (1987) Studies on the intestinal surface acid microclimate: developmental aspects. Pediatric Research 22, 497-499CrossRefGoogle ScholarPubMed
79Yang, J. et al. (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, 462-468CrossRefGoogle Scholar
80Wang, Y. et al. (2001) Localization of the murine reduced folate carrier as assessed by immunohistochemical analysis. Biochimica et Biophysica Acta 1513, 49-54Google Scholar
81Subramanian, V.S., Marchant, J.S. and Said, H.M. (2008) Apical membrane targeting and trafficking of the human proton-coupled transporter in polarized epithelia. American Journal of Physiology Cell Physiology 294, C233-C240Google Scholar
82Mason, J.B. and Rosenberg, I.H. (1994) Intestinal absorption of folate. In Physiology of the gastrointestinal tract (Third edn) (Johnson, L.R., ed.), pp. 1979-1995, Raven PressGoogle ScholarPubMed
83Selhub, J. and Rosenberg, I.H. (1981) Folate transport in isolated brush border membrane vesicles from rat intestine. Journal of Biological Chemistry 256, 4489-4493CrossRefGoogle ScholarPubMed
84Mason, J.B. et al. (1990) Carrier affinity as a mechanism for the pH-dependence of folate transport in the small intestine. Biochimica et Biophysica Acta 1024, 331-335CrossRefGoogle ScholarPubMed
85Kumar, C.K. et al. (1998) Comparison of intestinal folate carrier clone expressed in IEC-6 cells and in Xenopus oocytes. American Journal of Physiology 274, C289-C294Google Scholar
86Chiao, J.H. et al. (1997) RFC-1 gene expression regulates folate absorption in mouse small intestine. Journal of Biological Chemistry 272, 11165-11170Google Scholar
87Chattopadhyay, S. et al. (2006) The inverse relationship between reduced folate carrier function and pemetrexed activity in a human colon cancer cell line. Molecular Cancer Therapeutics 5, 438-449CrossRefGoogle Scholar
88Zhao, R., Hanscom, M. and Goldman, I.D. (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, 57-64Google Scholar
89Wang, Y. et al. (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-C71Google Scholar
90Balamurugan, K. and Said, H.M. (2006) Role of reduced folate carrier in intestinal folate uptake. American Journal of Physiology Cell Physiology 291, C189-C193Google Scholar
91Lu, Y. and Low, P. (2002) Folate-mediated delivery of macromolecular anticancer therapeutic agents. Advanced Drug Delivery Reviews 54, 675-693Google Scholar
92Jansen, G. (1999) Receptor- and Carrier-Mediated Transport Systems for Folates and Antifolates. (Jackman, A.L. ed.), pp. 293-321, Humana PressGoogle Scholar
93Brigle, K.E. et al. (1994) Increased expression and characterization of two distinct folate-binding proteins in murine erythroleukemia cells. Biochemical Pharmacology 47, 337-345Google Scholar
94Wang, X. et al. (1992) Differential stereospecificities and affinities of folate receptor isoforms for folate compounds and antifolates. Biochemical Pharmacology 44, 1898-1901Google ScholarPubMed
95Maziarz, K.M. et al. (1999) Complete mapping of divergent amino acids responsible for differential ligand binding of folate receptors alpha and beta. Journal of Biological Chemistry 274, 11086-11091Google Scholar
96Kamen, B.A. et al. (1988) Delivery of folates to the cytoplasm of MA104 cells is mediated by a surface membrane receptor that recycles. Journal of Biological Chemistry 263, 13602-13609CrossRefGoogle Scholar
97Rothberg, K.G. et al. (1990) The glycophospholipid-linked folate receptor internalizes folate without entering the clathrin-coated pit endocytic pathway. Journal of Cell Biology 110, 637-649Google Scholar
98Kamen, B.A., Smith, A.K. and Anderson, R.G.W. (1991) The folate receptor works in tandem with a probenecid-sensitive carrier in MA104 cells in vitro. Journal of Clinical Investigation 87, 1442-1449Google Scholar
99Prasad, P.D. et al. (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, 309-314CrossRefGoogle Scholar
100Andrews, N.C. (2007) When is a heme transporter not a heme transporter? When it's a folate transporter. Cell Metabolism 5, 5-6CrossRefGoogle Scholar
101Sierra, E.E. et al. (1995) Comparison of transport properties of the reduced folate carrier and folate receptor in murine L1210 leukemia cells. Biochemical Pharmacology 50, 1287-1294Google Scholar
102Spinella, M.J. et al. (1995) Distinguishing between folate receptor-α-mediated transport and reduced folate carrier-mediated transport in L1210 leukemia cells. Journal of Biological Chemistry 270, 7842-7849Google Scholar
103Parker, N. et al. (2005) Folate receptor expression in carcinomas and normal tissues determined by a quantitative radioligand binding assay. Analytical Biochemistry 338, 284-293Google Scholar
104Smith, S.B. et al. (1999) Expression of folate receptor alpha in the mammalian retinol pigmented epithelium and retina. Investigative Ophthalmology and Visual Science 40, 840-848Google ScholarPubMed
105Chancy, C.D. et al. (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, 20676-20684CrossRefGoogle ScholarPubMed
106Toffoli, G. et al. (1997) Overexpression of folate binding protein in ovarian cancers. International Journal of Cancer 74, 193-198Google Scholar
107Kelley, K.M., Rowan, B.G. and Ratnam, M. (2003) Modulation of the folate receptor alpha gene by the estrogen receptor: mechanism and implications in tumor targeting. Cancer Research 63, 2820-2828Google Scholar
108Tran, T. et al. (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, 4431-4441Google Scholar
109Ratnam, M. et al. (1989) Homologous membrane folate binding proteins in human placenta: Cloning and sequence of cDNA. Biochemistry 28, 8249-8254CrossRefGoogle ScholarPubMed
110Wang, H. et al. (2000) Differentiation-independent retinoid induction of folate receptor type beta, a potential tumor target in myeloid leukemia. Blood 96, 3529-3536Google Scholar
111Reddy, J.A. et al. (1999) Expression and functional characterization of the beta-isoform of the folate receptor on CD34(+) cells. Blood 93, 3940-3948CrossRefGoogle ScholarPubMed
112Ross, J.F. et al. (1999) Folate receptor type beta is a neutrophilic lineage marker and is differentially expressed in myeloid leukemia. Cancer 85, 348-357Google Scholar
113Elnakat, H. (2004) Distribution, functionality and gene regulation of folate receptor isoforms: implications in targeted therapy. Advanced Drug Delivery Reviews 56, 1067-1084Google Scholar
114Assaraf, Y.G. (2006) The role of multidrug resistance efflux transporters in antifolate resistance and folate homeostasis. Drug Resistance Updates 9, 227-246Google Scholar
115Wielinga, P. et al. (2005) The human multidrug resistance protein MRP5 transports folates and can mediate cellular resistance against antifolates. Cancer Research 65, 4425-4430Google Scholar
116Fry, D.W., Yalowich, J.C. and Goldman, I.D. (1982) Rapid formation of poly-gamma-glutamyl derivatives of methotrexate and their association with dihydrofolate reductase as assessed by high pressure liquid chromatography in the Ehrlich ascited tumor cell in vitro. Journal of Biological Chemistry 257, 1890-1896Google Scholar
117Masuda, M. et al. (1997) Methotrexate is excreted into the bile by canalicular multispecific organic anion transporter in rats. Cancer Research 57, 3506-3510Google ScholarPubMed
118Mottino, A.D. et al. (2000) Expression and localization of multidrug resistant protein mrp2 in rat small intestine. Journal of Pharmacology and Experimental Therapeutics 293, 717-723Google ScholarPubMed
119Rost, D. et al. (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-G726Google Scholar
120Taipalensuu, J. et al. (2001) Correlation of gene expression of ten drug efflux proteins of the ATP-binding cassette transporter family in normal human jejunum and in human intestinal epithelial Caco-2 cell monolayers. Journal of Pharmacology and Experimental Therapeutics 299, 164-170Google Scholar
121Seithel, A. et al. (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, 291-299Google Scholar
122Koepsell, H. and Endou, H. (2004) The SLC22 drug transporter family. Pflugers Archiv (European Journal of Physiology) 447, 666-676Google Scholar
123Sekine, T., Miyazaki, H. and Endou, H. (2006) Molecular physiology of renal organic anion transporters. American Journal of Physiology. Renal Physiology 290, F251-F261CrossRefGoogle ScholarPubMed
124Hagenbuch, B. and Meier, P.J. (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, 653-665CrossRefGoogle ScholarPubMed
125Masuda, S. (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, 91-103CrossRefGoogle ScholarPubMed
126Rizwan, A.N. and Burckhardt, G. (2007) Organic anion transporters of the SLC22 family: biopharmaceutical, physiological, and pathological roles. Pharmaceutical Research 24, 450-470Google Scholar
127Uwai, Y. et al. (2004) Methotrexate-loxoprofen interaction: involvement of human organic anion transporters hOAT1 and hOAT3. Drug Metabolism and Pharmacokinetics 19, 369-374CrossRefGoogle ScholarPubMed
128Takeda, M. et al. (2002) Characterization of methotrexate transport and its drug interactions with human organic anion transporters. Journal of Pharmacology and Experimental Therapeutics 302, 666-671Google Scholar
129Nozaki, Y. et al. (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, 226-234Google Scholar
130Cha, S.H. et al. (2001) Identification and characterization of human organic anion transporter 3 expressing predominantly in the kidney. Molecular Pharmacology 59, 1277-1286Google Scholar
131VanWert, A.L. and Sweet, D.H. (2008) Impaired clearance of methotrexate in organic anion transporter 3 (Slc22a8) knockout mice: a gender specific impact of reduced folates. Pharmaceutical Research 25, 453-462Google Scholar
132Zhao, R. et al. (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, 10224-10228Google Scholar
133Gelineau-van Waes, J. et al. (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, 494-507Google Scholar
134Piedrahita, J.A. et al. (1999) Mice lacking the folic acid-binding protein Folbp1 are defective in early embryonic development. Nature Genetics 23, 228-232Google Scholar
135Geller, J. et al. (2002) Hereditary folate malabsorption: family report and review of the literature. Medicine 81, 51-68Google Scholar
136Lasry, I. et al. (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, 2055-2061CrossRefGoogle ScholarPubMed
137Russell, R.M. et al. (1979) Influence of intraluminal pH on folate absorption: studies in control subjects and in patients with pancreatic insufficiency. Journal of Laboratory and Clinical Medicine 93, 428-436Google ScholarPubMed
138Russell, R.M. et al. (1988) Effect of antacid and H2 receptor antagonists on the intestinal absorption of folic acid. Journal of Laboratory and Clinical Medicine 112, 458-463Google Scholar
139Rosenberg, I.H. et al. (1969) Absorption of polyglutamic folate: participation of deconjugating enzymes of the intestinal mucosa. New England Journal of Medicine 280, 985-988CrossRefGoogle ScholarPubMed
140Butterworth, C.E. Jr., Baugh, C.M. and Krumdieck, C. (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, 1131-1142Google Scholar
141Halsted, C.H. (1989) The intestinal absorption of dietary folates in health and disease. Journal of the American College of Nutrition 8, 650-658Google Scholar
142Shafizadeh, T.B. and Halsted, C.H. (2007) gamma-Glutamyl hydrolase not glutamate carboxypeptidase II, hydrolyzes dietary folate in rat small intestine. Journal of Nutrition 137, 1149-1153CrossRefGoogle Scholar
143Horne, D.W. and Reed, K.A. (1992) Transport of methotrexate in basolateral membrane vesicles from rat liver. Archives of Biochemistry and Biophysics 298, 121-128CrossRefGoogle ScholarPubMed
144Horne, D.W. (1990) Na+ and pH dependence of 5-methyltetrahydrofolic acid and methotrexate transport in freshly isolated hepatocytes. Biochimica et Biophysica Acta Bio-Membranes 1023, 47-55CrossRefGoogle ScholarPubMed
145Horne, D.W., Reed, K.A. and Said, H.M. (1992) Transport of 5-methyltetrahydrofolate in basolateral membrane vesicles of rat liver. American Journal of Physiology Gastrointestinal Liver Physiology 262, G150-G158CrossRefGoogle ScholarPubMed
146Horne, D.W. et al. (1993) 5-Methyltetrahydrofolate transport in basolateral membrane vesicles from human liver. American Journal of Clinical Nutrition 58, 80-84CrossRefGoogle ScholarPubMed
147Arias, I.M. and Forgac, M. (1984) The sinusoidal domain of the plasma membrane of rat hepatocytes contains an amiloride-sensitive Na+/H+ antiport. Journal of Biological Chemistry 259, 5406-5408CrossRefGoogle ScholarPubMed
148Goresky, C.A., Watanabe, H. and Johns, D.G. (1963) The renal excretion of folic acid. Journal of Clinical Investigation 42, 1841-1849Google Scholar
149Selhub, J., Nakamura, S. and Carone, F.A. (1987) Renal folate absorption and the kidney folate binding protein. II. Microinfusion studies. American Journal of Physiology 252, F757-F760Google Scholar
150Selhub, J. and Rosenberg, I.H. (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, 3090-3093Google Scholar
151Selhub, J. et al. (1987) Renal folate absorption and the kidney folate binding protein. I. Urinary clearance studies. American Journal of Physiology 252, F750-F756Google Scholar
152Birn, H. et al. (2005) Renal tubular reabsorption of folate mediated by folate binding protein 1. Journal of the American Society of Nephrology 16, 608-615CrossRefGoogle ScholarPubMed
153Bhandari, S.D., Joshi, S.K. and McMartin, K.E. (1988) Folate binding and transport by rat kidney brush-border membrane vesicles. Biochimica et Biophysica Acta 937, 211-218Google Scholar
154Bhandari, S.D., Fortney, T. and McMartin, K.E. (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, 451-456CrossRefGoogle Scholar
155Jaramillo-Juarez, F., Aires, M.M. and Malnic, G. (1990) Urinary and proximal tubule acidification during reduction of renal blood flow in the rat. Journal of Physiology 421, 475-483Google Scholar
156Santiago-Borrero, P.J. et al. (1973) Congenital isolated defect of folic acid absorption. Journal of Pediatrics 82, 450-455Google Scholar
157Lanzkowsky, P., Erlandson, M.E. and Bezan, A.I. (1969) Isolated defect of folic acid absorption associated with mental retardation and cerebral calcification. Blood 34, 452-465Google Scholar
158Birn, H., Nielsen, S. and Christensen, E.I. (1997) Internalization and apical-to-basolateral transport of folate in rat kidney proximal tubule. American Journal of Physiology 272, F70-F78Google Scholar
159Birn, H., Selhub, J. and Christensen, E.I. (1993) Internalization and intracellular transport of folate-binding protein in rat kidney proximal tubule. American Journal of Physiology Cell Physiology 264, C302-C310Google Scholar
160Weitman, S.D., Frazier, K.M. and Kamen, B.A. (1994) The folate receptor in central nervous system malignancies of childhood. Journal of Neuro-Oncology 21, 107-112Google Scholar
161Kennedy, M.D. et al. (2003) Evaluation of folate conjugate uptake and transport by the choroid plexus of mice. Pharmaceutical Research 20, 714-719CrossRefGoogle ScholarPubMed
162Wu, D. and Pardridge, W.M. (1999) Blood-brain barrier transport of reduced folic acid. Pharmaceutical Research 16, 415-419Google Scholar
163Segal, M.B. (2001) Transport of nutrients across the choroid plexus. Microscopy Research and Technique 52, 38-48Google Scholar
164Moretti, P. et al. (2008) Brief report: autistic symptoms, developmental regression, mental retardation, epilepsy, and dyskinesias in CNS folate deficiency. Journal of Autism and Developmental Disorders 38, 1170-1177Google Scholar
165Moretti, P. et al. (2005) Cerebral folate deficiency with developmental delay, autism, and response to folinic acid. Neurology 64, 1088-1090CrossRefGoogle ScholarPubMed
166Ramaekers, V.T. et al. (2005) Autoantibodies to folate receptors in the cerebral folate deficiency syndrome. New England Journal of Medicine 352, 1985-1991Google Scholar
167Schwartz, R.S. (2005) Autoimmune folate deficiency and the rise and fall of “horror autotoxicus”. New England Journal of Medicine 352, 1948-1950CrossRefGoogle ScholarPubMed
168Ramaekers, V.T. et al. (2007) Folate receptor autoimmunity and cerebral folate deficiency in low-functioning autism with neurological deficits. Neuropediatrics 38, 276-281Google Scholar
169Spector, R. and Lorenzo, A.V. (1975) Folate transport by the choroid plexus in vitro. Science 187, 540-542CrossRefGoogle ScholarPubMed
170Spector, R. and Lorenzo, A.V. (1975) Folate transport in the central nervous system. American Journal of Physiology 229, 777-782Google Scholar
171Weitman, S.D. et al. (1992) Distribution of the folate receptor GP38 in normal and malignant cell lines and tissues. Cancer Research 52, 3396-3401Google Scholar
172Weitman, S.D. et al. (1992) Cellular localization of the folate receptor: potential role in drug toxicity and folate homeostasis. Cancer Research 52, 6708-6711Google ScholarPubMed
173Selhub, J. and Franklin, W.A. (1984) The folate-binding protein of rat kidney. Purification, properties, and cellular distribution. Journal of Biological Chemistry 259, 6601-6606CrossRefGoogle ScholarPubMed
174Patrick, T.A. et al. (1997) Folate receptors as potential therapeutic targets in choroid plexus tumors of SV40 transgenic mice. Journal of Neuro-Oncology 32, 111-123Google Scholar
175Segal, M.B. (2000) The choroid plexuses and the barriers between the blood and the cerebrospinal fluid. Cellular and Molecular Neurobiology 20, 183-196Google Scholar
176Zhao, R. et al. (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, 21207-21212CrossRefGoogle ScholarPubMed
177Levitt, M. et al. (1971) Transport characteristics of folates in cerebrospinal fluid; a study utilizing doubly labeled 5-methyltetrahydrofolate and 5-formyltetrahydrofolate. Journal of Clinical Investigation 50, 1301-1308Google Scholar
178Maddox, D.M. et al. (2003) Reduced-folate carrier (RFC) is expressed in placenta and yolk sac, as well as in cells of the developing forebrain, hindbrain, neural tube, craniofacial region, eye, limb buds and heart. BioMed Central Developmental Biology 3, 6Google Scholar
179Sweiry, J.H. and Yudilevich, D.L. (1985) Transport of folates at maternal and fetal sides of the placenta: lack of inhibition by methotrexate. Biochimica et Biophysica Acta 821, 497-501Google Scholar
180Sweiry, J.H. and Yudilevich, D.L. (1988) Characterization of folate uptake in guinea pig placenta. American Journal of Physiology 254, C735-C743CrossRefGoogle ScholarPubMed
181Keating, E. et al. (2006) Comparison of folic acid uptake characteristics by human placental choriocarcinoma cells at acidic and physiological pH. Canadian Journal of Physiology and Pharmacology 84, 247-255Google Scholar
182Takahashi, T. et al. (2001) Carrier-mediated transport of folic acid in BeWo cell monolayers as a model of the human trophoblast. Placenta 22, 863-869CrossRefGoogle Scholar
183Poncz, M. et al. (1981) Therapy of congenital folate malabsorption. Journal of Pediatrics 98, 76-79Google Scholar
184Poncz, M. and Cohen, A. (1996) Long-term treatment of congenital folate malabsorption. Journal of Pediatrics 129, 948Google Scholar
185Kim, Y.I. (2004) Folate and DNA methylation: a mechanistic link between folate deficiency and colorectal cancer? Cancer Epidemiol Biomarkers Prev 13, 511-519Google Scholar
186Davey, S.G. and Ebrahim, S. (2005) Folate supplementation and cardiovascular disease. Lancet 366, 1679-1681Google Scholar
187Mischoulon, D. and Raab, M.F. (2007) The role of folate in depression and dementia. Journal of Clinical Psychiatry 68 (Suppl. 10), 28-33Google Scholar
188Ulrich, C.M. and Potter, J.D. (2006) Folate supplementation: too much of a good thing? Cancer Epidemiol Biomarkers Prev 15, 189-193Google Scholar
189Martínez, M.E., Marshall, J.R. and Giovannucci, E. (2008) Diet and cancer prevention: the roles of observation and experimentation. Nature Reviews Cancer 8, 694-703CrossRefGoogle ScholarPubMed
190Eichholzer, M., Tonz, O. and Zimmermann, R. (2006) Folic acid: a public-health challenge. Lancet 367, 1352-1361CrossRefGoogle ScholarPubMed
191Lucock, M. (2000) Folic acid: nutritional biochemistry, molecular biology, and role in disease processes. Molecular Genetics and Metabolism 71, 121-138CrossRefGoogle ScholarPubMed
192Kessel, D., Hall, T.C. and Roberts, D. (1965) Uptake as a determinant of methotrexate response in mouse leukemias. Science 150, 752-754Google Scholar
193Hakala, M.T. (1965) On the role of drug penetration in amethopterin resistance of Sarcoma-180 cells in vitro. Biochimica et Biophysica Acta 102, 198-209CrossRefGoogle ScholarPubMed
194Fischer, G.A. (1962) Detective transport of amethopterin (methotrexate) as a mechanism of resistance to the antimetabolite in L5178Y leukemic cells. Biochemical Pharmacology 11, 1233-1234Google Scholar
195Ge, Y. et al. (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, 451-457Google Scholar
196Guo, W. et al. (1999) Mechanisms of methotrexate resistance in osteosarcoma. Clinical Cancer Research 5, 621-627Google Scholar
197Levy, A.S. et al. (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, 688-695CrossRefGoogle ScholarPubMed
198Zhang, L. et al. (1998) Reduced folate carrier gene expression in childhood acute lymphoblastic leukemia: relationship to immunophenotype and ploidy. Clinical Cancer Research 4, 2169-2177Google Scholar
199Zhao, R. et al. (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, 3313-3319CrossRefGoogle ScholarPubMed
200Patterson, D. et al. (2008) A humanized mouse model for the reduced folate carrier. Molecular Genetics and Metabolism 93, 95-103Google Scholar
201Veenhoff, L.M., Heuberger, E.H. and Poolman, B. (2002) Quaternary structure and function of transport proteins. Trends in Biochemical Sciences 27, 242-249Google Scholar
202Karlin, A. and Akabas, M.H. (1998) Substituted-cysteine accessibility method. Methods in Enzymology 293, 123-145Google Scholar
203Lemieux, M.J. (2007) Eukaryotic major facilitator superfamily transporter modeling based on the prokaryotic GlpT crystal structure. Molecular Membrane Biology 24, 333-341Google Scholar
204Song, J. et al. (2000) Effects of dietary folate on intestinal tumorigenesis in the apcMin mouse. Cancer Research 60, 5434-5440Google ScholarPubMed
205Song, J. et al. (2000) Chemopreventive effects of dietary folate on intestinal polyps in Apc+/− Msh2−/− mice. Cancer Research 60, 3191-3199Google Scholar
206Kim, Y.I. (2008) Folic acid supplementation and cancer risk: point. Cancer Epidemiol Biomarkers Prev. 17, 2220-2225Google Scholar
207Ma, D.W. et al. (2005) Folate transport gene inactivation in mice increases sensitivity to colon carcinogenesis. Cancer Research 65, 887-897Google Scholar
208Lawrance, A.K. et al. (2007) Genetic and nutritional deficiencies in folate metabolism influence tumorigenicity in Apcmin/+ mice. Journal of Nutritional Biochemistry 18, 305-312Google Scholar
209Helmlinger, G. et al. (1997) Interstitial pH and pO2 gradients in solid tumors in vivo: high- resolution measurements reveal a lack of correlation. Nature Medicine 3, 177-182Google Scholar
210Tredan, O. et al. (2007) Drug resistance and the solid tumor microenvironment. Journal of the National Cancer Institute 99, 1441-1454Google Scholar
211Raghunand, N. et al. (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, 309-312Google Scholar
212Theti, D.S. et al. (2003) Selective delivery of CB300638, a cyclopenta[g]quinazoline-based thymidylate synthase inhibitor into human tumor cell lines overexpressing the alpha-isoform of the folate receptor. Cancer Research 63, 3612-3618Google ScholarPubMed
213Henderson, E.A. et al. (2006) Targeting the alpha-folate receptor with cyclopenta[g]quinazoline-based inhibitors of thymidylate synthase. Bioorganic and Medicinal Chemistry 14, 5020-5042Google Scholar
214Gibbs, D.D. et al. (2005) BGC 945, a novel tumor-selective thymidylate synthase inhibitor targeted to alpha-folate receptor-overexpressing tumors. Cancer Research 65, 11721-11728Google Scholar
215Deng, Y. et al. (2008) Synthesis and Discovery of High Affinity Folate Receptor-Specific Glycinamide Ribonucleotide Formyltransferase Inhibitors with Antitumor Activity. Journal of Medicinal Chemistry 51, 5052-5063Google Scholar
216Zhao, R. et al. (2008) A role for the proton-coupled folate transporter (PCFT - SLC46A1) in folate receptor-mediated endocytosis. Journal of Biological Chemistry Dec 11; [Epub ahead of print]Google Scholar
217Hou, Z. and Matherly, L.H. (2008) Oligomeric structure of the human reduced folate carrier: Identification of homo-oligomers and dominant-negative effects on carrier expression and function. Journal of Biological Chemistry Nov 19; [Epub ahead of print]Google Scholar

Further reading, resources and contacts

For an in-depth up-to-date review of hereditary folate malabsorption from the clinical and genetic perspectives see:

Matherly, L.H., Hou, Z. and Deng, Y. (2007) Human reduced folate carrier: translation of basic biology to cancer etiology and therapy. Cancer and Metastasis Reviews 26, 111-128Google Scholar
Salazar, M.D. and Ratnam, M. (2007) The folate receptor: what does it promise in tissue-targeted therapeutics? Cancer and Metastasis Reviews 26, 141-152Google Scholar
Chattopadhyay, S., Moran, R.G. and Goldman, I.D. (2007) Pemetrexed: biochemical and cellular pharmacology, mechanisms, and clinical applications. Molecular Cancer Therapeutics 6, 404-417Google Scholar
Geller, J. et al. (2002) Hereditary folate malabsorption: family report and review of the literature. Medicine 81, 51-68Google Scholar
http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=folate-malGoogle Scholar
http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=folate-malGoogle Scholar