← Back to Search
Effect Of Folate Oversupplementation On Folate Uptake By Human Intestinal And Renal Epithelial Cells.
B. Ashokkumar, Zainab M. Mohammed, N. Vaziri, H. Said
Published 2007 · Medicine, Biology
Download PDFAnalyze on Scholarcy
BACKGROUND Folic acid [corrected] plays an essential role in cellular metabolism. Its deficiency can lead to neural tube defects. However, optimization of body folate homeostasis can reduce the incidence of neural tube defects and may decrease the risk of Alzheimer and cardiovascular diseases and cancer. Hence, food fortification and intake of supplemental folate are widespread. OBJECTIVE We examined the effects of long-term folate oversupplementation on the physiologic markers of intestinal and renal folate uptake processes. DESIGN Human-derived intestinal Caco-2 and renal HK-2 epithelial cells were maintained (5 generations) in a growth medium oversupplemented (100 micromol folic acid/L) or maintained under sufficient conditions (0.25 and 9 micromol folic acid/L). RESULTS Carrier-mediated uptake of (3)H-folic acid (2 micromol/L) at buffer pH 5.5 (but not buffer pH 7.4) by Caco-2 and HK-2 cells maintained under the folate-oversupplemented condition was significantly (P<0.01) and specifically lower than in cells maintained under the folate-sufficient condition. This reduction in folic acid uptake was associated with a significant decrease in the protein and mRNA levels of the human reduced-folate carrier (hRFC) and a decrease in the activity of the hRFC promoter. It was also associated with a decrease in mRNA levels of the proton-coupled folate transporter/heme carrier protein 1 (PCFT/HCP1) and folate receptor (FR). CONCLUSIONS Long-term oversupplementation with folate leads to a specific and significant down-regulation in intestinal and renal folate uptake, which is associated with a decrease in message levels of hRFC, PCFT/HCP1, and FR. This regulation appears to be mediated via a transcriptional mechanism, at least for the hRFC system.
This paper references
Determination of folate transport pathways in cultured rat proximal tubule cells.
P. K. Sikka (1998)
Recent advances in carrier-mediated intestinal absorption of water-soluble vitamins.
H. Said (2004)
Folic acid: nutritional biochemistry, molecular biology, and role in disease processes.
M. Lucock (2000)
Role of reduced folate carrier in intestinal folate uptake.
K. Balamurugan (2006)
Carrier-mediated membrane transport of folates in mammalian cells.
F. Sirotnak (1999)
Roles of USF, Ikaros and Sp proteins in the transcriptional regulation of the human reduced folate carrier B promoter.
Mingjun Liu (2004)
High dietary folate supplementation affects gestational development and dietary protein utilization in rats.
M. Achón (1999)
Occurrence of omphalocele in relation to maternal multivitamin use: a population-based study.
L. Botto (2002)
Folate supplementation: too much of a good thing?
C. Ulrich (2006)
One hundred and twenty-seven cultured human tumor cell lines producing tumors in nude mice.
J. Fogh (1977)
Folate transport proteins mediate the bidirectional transport of 5-methyltetrahydrofolate in cultured human proximal tubule cells.
K. M. Morshed (1997)
Enterocyte-like differentiation and polarization of the human colon carcinoma cell line Caco-2 in culture
M. Pinto (1983)
Folic acid supplements and fortification affect the risk for neural tube defects, vascular disease and cancer: evolving science.
L. Bailey (2003)
The Basal Promoters for the Human Reduced Folate Carrier Gene Are Regulated by a GC-box and a cAMP-response Element/AP-1-like Element
J. Whetstine (2001)
Folic acid and the prevention of birth defects.
C. Butterworth (1996)
Colorectal cancer and folate status: a nested case-control study among male smokers.
S. Glynn (1996)
The dubious use of vitamin-mineral supplements in relation to cardiovascular disease.
D. Mccormick (2006)
Properties of a folate binding protein (FBP) isolated from porcine kidney.
B. Kamen (1986)
Folate uptake in the human intestine: Promoter activity and effect of folate deficiency
V. S. Subramanian (2003)
Distribution of the folate receptor GP38 in normal and malignant cell lines and tissues.
S. Weitman (1992)
Folate transport and binding by cultured human proximal tubule cells.
K. McMartin (1992)
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.
J. Whetstine (2002)
Physiology of folic acid in health and disease.
O. Stanger (2002)
Folic Acid Supplementation in Dementia: A Preliminary Report
B. R. Sommer (2003)
The transport of vitamin B12 through polarized monolayers of Caco-2 cells.
C. Dix (1990)
The effect of folic acid supplementation on the risk for cancer or dysplasia in ulcerative colitis.
B. Lashner (1997)
Modern nutrition in health and disease
R. S. Goodhart (1980)
The human colon carcinoma cell lines HT-29 and Caco-2: two in vitro models for the study of intestinal differentiation.
M. Rousset (1986)
Carrier affinity as a mechanism for the pH-dependence of folate transport in the small intestine.
J. Mason (1990)
Identification of an Intestinal Folate Transporter and the Molecular Basis for Hereditary Folate Malabsorption
A. Qiu (2006)
Extracellular glutathione peroxidase is secreted basolaterally by human renal proximal tubule cells.
J. Whitin (2002)
Analysis of the pH Dependence of Folate Binding and Transport by Rat Kidney Brush Border Membrane Vesicles
S. Bhandari (1991)
Folic acid supplementation for 4 weeks affects liver morphology in aged rats.
María Roncalés (2004)
Unmetabolized folic acid in plasma is associated with reduced natural killer cell cytotoxicity among postmenopausal women.
A. Troen (2006)
Primary Prevention of Neural-Tube Defects and Some Other Major Congenital Abnormalities
A. Czeizel (2000)
The effect of folate supplementation on the risk of cancer or dysplasia in ulcerative colitis
BA Lashner (1997)
This paper is referenced by
Increased synthesis of folate transporters regulates folate transport in conditions of ethanol exposure and folate deficiency
S. Thakur (2015)
Classical Antifolates: Synthesis of 5-Substituted, 6-Substituted and 7-Substituted Pyrrolo[2,3-d]Pyrimidines as Targeted Anticancer Therapies
Y. Wang (2013)
Differentiation-dependent regulation of the intestinal folate uptake process: studies with Caco-2 cells and native mouse intestine.
V. S. Subramanian (2008)
A Candidate Gene Study of Folate-Associated One Carbon Metabolism Genes and Colorectal Cancer Risk
A. Levine (2010)
Effects of folic acid supplementation on the pharmacokinetics and anticoagulant effect of warfarin: an open-label, prospective study of long-term administration in adults.
M. Muszkat (2010)
Optimizing the Pharmacology of Periconceptional and Prenatal Multivitamin Supplementation
Patricia Nguyen (2009)
The intestinal absorption of folates.
M. Visentin (2014)
Factors Influencing the Input Side of Folate Nutrition
Yen-Ming Chan (2016)
Folates in bread: retention during bread-making and in vitro bioaccessibility
V. Öhrvik (2010)
Enhanced efficacy of chemotherapeutic drugs against colorectal cancer using ligand-decorated self-breakable agents
M. Tsai (2015)
Polysaccharide-based micro/nanohydrogels for delivering macromolecular therapeutics.
K. Ganguly (2014)
Folate Absorption Across the Colon: And the Modulation of Bacterial Folate Synthesis by Diet
S. Aufreiter (2012)
The effect of dietary folic acid on flesh quality and muscle antioxidant status referring to Nrf2 signalling pathway in young grass carp (Ctenopharyngodon idella)
L. Shi (2020)
INFLUENCE OF B-VITAMINS ON ONE-CARBON METABOLISM AND ASSOCIATIONS WITH CANCER RISK AND REPRODUCTIVE STATE
Sajin Bae (2017)
Transport characteristics of L‐citrulline in renal apical membrane of proximal tubular cells
Keisuke Mitsuoka (2009)
The adverse effects of an excessive folic acid intake
K. Patel (2017)
Post-hatching ontogeny of intestinal proton-coupled folate transporter and reduced folate carrier in broiler chickens.
M. Jing (2013)
Folate receptor-targeted antioxidant therapy ameliorates renal ischemia-reperfusion injury.
Sarah F Knight (2012)
Unmetabolized folic acid and total folate concentrations in breast milk are unaffected by low-dose folate supplements.
L. Houghton (2009)
Is High Folic Acid Intake a Risk Factor for Autism?—A Review
Darrell J. Wiens (2017)
Folate malabsorption and its influence on DNA methylation during cancer development.
A. Hamid (2012)
Apical membrane targeting and trafficking of the human proton-coupled transporter in polarized epithelia.
V. S. Subramanian (2008)
Folic Acid and Pathogenesis of Cardiovascular Disease
James D House (2012)
International Journal of Nanomedicine Dovepress Open Access to Scientific and Medical Research Open Access Full Text Article
Yelda Buyru Özkurt ()
Overview of Methods of Making Polyester Nano- and Microparticulate Systems for Drug Delivery
M. Kumar (2017)
An optimal periconception maternal folate status for embryonic size: the Rotterdam Predict study
EM Uitert (2014)
Folate status in various pathophysiological conditions
N. A. Wani (2008)
Vitamin/mineral supplements: of questionable benefit for the general population.
D. Mccormick (2010)
Vitamin contents in rat milk and effects of dietary vitamin intakes of dams on the vitamin contents in their milk.
Mika Endo (2011)
More than 50% of pregnant Japanese women with an intake of 150 μg dietary folate per 1,000 kcal can maintain values above the cut-off.
K. Shibata (2014)
Effects of folic acid supplementation on growth performance and hepatic folate metabolism-related gene expressions in weaned piglets
B. Yu (2010)
Maternal One-carbon Nutrients Status and Effects on DNA Methylation and Hydroxymethylation in Newborn Infants
Lesley Plumptre (2016)See more