Effect of folate oversupplementation on folate uptake by human intestinal and renal epithelial cells.
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.


METHODS
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.
Ashokkumar
Balasubramaniem
B
Department of Medicine, Division of Nephrology, and the Department of Physiology and Biophysics, University of California, Irvine, CA, USA.
Mohammed
Zainab M
ZM
Vaziri
Nosratola D
ND
Said
Hamid M
HM
D015153:Blotting, Western; D018938:Caco-2 Cells; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D019587:Dietary Supplements / Q000506:poisoning*; D015536:Down-Regulation; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D058973:Folate Receptors, GPI-Anchored; D005492:Folic Acid / Q000493:pharmacokinetics* / Q000506:poisoning*; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000187:drug effects; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D058979:Proton-Coupled Folate Transporter; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D058978:Reduced Folate Carrier Protein; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014316:Tritium
D002352:Carrier Proteins; D058973:Folate Receptors, GPI-Anchored; D026901:Membrane Transport Proteins; D058979:Proton-Coupled Folate Transporter; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D058978:Reduced Folate Carrier Protein; C548699:SLC19A1 protein, human; C505058:SLC46A1 protein, human; D014316:Tritium; D005492:Folic Acid