Human intestinal folate transport: Cloning, expression, and distribution of complementary RNA

Nguyen, Toai T.; Dyer, David L.; Dunning, Daniel D.; Rubin, Stanley A.; Grant, Kenneth E.; Said, Hamid M.

doi:10.1053/gast.1997.v112.pm9041240

Cited by 120 publications

(92 citation statements)

References 3 publications

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“…Consequently, this may trigger a (sub)clinical folate deficiency, especially when dietary intake, absorption, or cellular retention of folates is poor. With respect to folate absorption, it is important to note that the intestinal folate transporter is structurally and functionally identical to the RFC expressed in CEM cells (62)(63)(64). Thus, original reports of impaired intestinal folate absorption following SSZ treatment (25)(26)(27) can be attributed to direct inhibition of intestinal RFC by SSZ.…”

Section: Discussionmentioning

confidence: 99%

Sulfasalazine is a potent inhibitor of the reduced folate carrier: Implications for combination therapies with methotrexate in rheumatoid arthritis

Jansen¹,

Heijden²,

Oerlemans³

et al. 2004

Arthritis & Rheumatism

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Objective. To investigate whether interactions of sulfasalazine (SSZ) with reduced folate carrier (RFC), the dominant cell membrane transporter for natural folates and methotrexate (MTX), may limit the efficacy of combination therapy with MTX and SSZ in patients with rheumatoid arthritis. Conclusion. At clinically relevant plasma concentrations, interactions of SSZ with RFC provide a biochemical rationale for 2 important clinical observations: 1) the onset of (sub)clinical folate deficiency during SSZ treatment, and 2) the lack of additivity/synergism of the combination of SSZ and MTX when these diseasemodifying antirheumatic drugs are administered simultaneously. Thus, when considering use of these drugs in combination therapies, the present results provide a rationale both for the use of folate supplementation and for spacing administration of these drugs over time.

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Section: Discussionmentioning

confidence: 99%

Sulfasalazine is a potent inhibitor of the reduced folate carrier: Implications for combination therapies with methotrexate in rheumatoid arthritis

Jansen¹,

Heijden²,

Oerlemans³

et al. 2004

Arthritis & Rheumatism

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“…Using these cells we then tested the possible involvement of specific protein kinase-and Ca 2ϩ /calmodulin-mediated pathways in the regulation of folic acid uptake by colonocytes. We focused on pathways that involve protein kinases (PKC and PKA) for which consensus sequences have been shown to exist in the recently cloned folate carriers (13)(14)(15)32) as well as those pathways that have been shown to play an important role in the regulation of uptake of other nutrients by epithelial cells (PTK-and Ca 2ϩ /calmodulin-mediated pathways) (33)(34)(35)(36)(37)(38)(39)(40)(41). When specific modulators of these pathways were used, we found that PKC-mediated pathways had no role in regulating folic acid uptake by NCM460 cells.…”

Section: Discussionmentioning

confidence: 99%

A Protein-tyrosine Kinase-regulated, pH-dependent, Carrier-mediated Uptake System for Folate in Human Normal Colonic Epithelial Cell Line NCM460

Kumar

Moyer

Dudeja

et al. 1997

Journal of Biological Chemistry

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A significant proportion of the bacterially synthesized folate in the large intestine exists in the form of folate monoglutamate. Recent studies in our laboratory using human colonic apical membrane vesicles have shown the existence of an efficient carrier-mediated system for folate uptake. Nothing, however, is known about the cellular regulation of the colonic uptake process. In this study, we used a recently established human normal colonic epithelial cell line NCM460 to address this issue. Uptake of folic acid by NCM460 cells was: 1) linear with time for 4 min of incubation and occurred with minimal metabolic alterations, 2) temperature-and pH-(but not Na ؉ ) dependent, 3) saturable as a function of concentration (apparent K m of 1.4 M), 4) inhibited by structural analogs and anion transport inhibitors, and 5) energydependent. These characteristics of folic acid uptake by NCM460 cells are similar to those seen with apical membrane vesicles derived from human native colonic tissue. Using these cells, we found that protein kinase Cand Ca 2؉ /calmodulin-mediated pathways have no role in regulating folic acid uptake. On the other hand, cAMP (through a mechanism independent of protein kinase A) and protein-tyrosine kinase-mediated pathways were found to play a role in the regulation of folic acid uptake by these cells. These results establish the suitability of NCM460 cells as an in vitro model system for investigating the details of the mechanism of colonic folate uptake and its regulation. Folic acid uptake by these cells appears to involve a carrier-mediated system, which is temperature-, pH-, and energy-dependent and appears to be under the regulation of cAMP and protein tyrosine kinase.Folate is an essential micronutrient, which acts as a coenzyme in the synthesis of DNA and RNA and the interconversion and degradation of several amino acids (1-4). An adequate supply of folate is therefore necessary for normal cellular function, growth, and development. Folate deficiency has been suggested as one of the most common vitamin deficiencies in the Western Hemisphere (5, 6). Humans and other mammals cannot synthesize folate and rely on exogenous sources to meet their metabolic requirements. Folates are presented to the host from the diet and are also synthesized in the large intestine by normal microflora. The mechanism of absorption of dietary folate has been intensively examined over the past two decades at the tissue, cellular, subcellular, and more recently, molecular levels (6 -15). Absorption of dietary folate has been shown to occur mainly in the proximal small intestine and involves a specialized, carrier-mediated system (6 -12).As to the bacterially synthesized folate in the large intestine, a significant amount of that folate exists in the monoglutamate, i.e. the absorbable form. Using [ 3 H]p-aminobenzoic acid to label the newly synthesized folate by the intestinal flora, Rong et al. (16) have shown that a portion of this folate is indeed absorbed by the rat and is incorporated into its various tissues. ...

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“…The enzyme acts as a catalyst in the reduction of 5,10-methylenetetrahydrofolate to produce 5-methyltetrahydrofolate, which in turn acts as the methyl donor for the remethylation of homocysteine to methionine. 10,11 MTHFR deficiency has been found to be also associated with increased risk of myocardial infarction, cancers, inherited bleeding disorders and neural tube defects and Down syndrome. [12][13][14][15] The common polymorphism, i.e., MTHFR C677T (rs1801133: C>T) which is associated with mild deficiency of the enzyme, persists with high prevalence in different populations even in homozygous state.…”

Section: Introductionmentioning

confidence: 99%

Possible selection of host folate pathway gene polymorphisms in patients with malaria from a malaria endemic region in North East India

Mirgal

Ghosh²,

Mahanta

et al. 2016

Trans R Soc Trop Med Hyg

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Background: Recent studies in experimental mice have shown that mild deficiency of methylenetetrahydrofolate reductase (MTHFR) enzyme confers protection against malaria, thus providing an important basis for the hypothesis that MTHFR polymorphism, i.e. C677T, might have been subjected to selection pressure against malaria. The present study was undertaken in a malaria endemic region in North East India to assess whether a similar selection advantage exists for other genes in folate metabolism pathway.Methods: A total of 401 subjects including 131 symptomatic malaria, 97 asymptomatic malaria and 173 normal healthy controls were analysed for nine polymorphisms (single-nucleotide polymorphisms [SNPs] in eight genes and insertion/deletion in one gene): MTHFR C677T, methionine synthase reductase (MTRR) A66G, glutamate carboxypeptidase II (GCPII) C1561T, cystathionine beta-synthase (CBS) 844ins68, reduced folate carrier-1 (RFC-1) G80A, serine hydroxymethyltransferase (SHMT) C1420T, methionine synthase (MTR) A2756G, MTHFR G1793A (D 919G), glycine N-methyltransferase (GNMT) 1289 by PCR-RFLP technique. Differences in frequencies of genotype distribution of each polymorphic marker between these groups were evaluated.Results: MTRR A2756G, SHMT C1420T, GCPII C1561T, MTRR A2756G and GNMT C1289T and RFC1 G80A polymorphisms showed significantly different prevalence between different groups analyzed. No significant differences were seen in the distribution of other polymorphisms. Conclusions:The study gives a clue for the possible selection of specific polymorphisms in the genes involved in the folate metabolism pathway by malaria parasite.

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Human intestinal folate transport: Cloning, expression, and distribution of complementary RNA

Cited by 120 publications

References 3 publications

Sulfasalazine is a potent inhibitor of the reduced folate carrier: Implications for combination therapies with methotrexate in rheumatoid arthritis

Sulfasalazine is a potent inhibitor of the reduced folate carrier: Implications for combination therapies with methotrexate in rheumatoid arthritis

A Protein-tyrosine Kinase-regulated, pH-dependent, Carrier-mediated Uptake System for Folate in Human Normal Colonic Epithelial Cell Line NCM460

Possible selection of host folate pathway gene polymorphisms in patients with malaria from a malaria endemic region in North East India

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