Folic acid — vitamin and panacea or genetic time bomb?

Lucock, Mark; Yates, Zoë

doi:10.1038/nrg1558

Cited by 122 publications

(88 citation statements)

References 59 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…21 Although folic acid is normally found in low concentrations in human serum, folic acid consumed in quantities generally found in multivitamin supplements can be transported in serum in the oxidized form. 24,25 FRa can bind folic acid with 10 times greater affinity than any of the reduced forms of the vitamin 26 or methotrexate. 27 The significance of increased serum folic acid in the presence of FOLR1-expressing tumors is unclear.…”

Section: Folate Receptor Vs Reduced Folate Carrier Transportmentioning

confidence: 99%

The role of folate receptor α in cancer development, progression and treatment: Cause, consequence or innocent bystander?

Kelemen

2006

Intl Journal of Cancer

447

340

View full text Add to dashboard Cite

Folate receptor a (FRa) is a membrane-bound protein with high affinity for binding and transporting physiologic levels of folate into cells. Folate is a basic component of cell metabolism and DNA synthesis and repair, and rapidly dividing cancer cells have an increased requirement for folate to maintain DNA synthesis, an observation supported by the widespread use of antifolates in cancer chemotherapy. FRa levels are high in specific malignant tumors of epithelial origin compared to normal cells, and are positively associated with tumor stage and grade, raising questions of its role in tumor etiology and progression. It has been suggested that FRa might confer a growth advantage to the tumor by modulating folate uptake from serum or by generating regulatory signals. Indeed, cell culture studies show that expression of the FRa gene, FOLR1, is regulated by extracellular folate depletion, increased homocysteine accumulation, steroid hormone concentrations, interaction with specific transcription factors and cytosolic proteins, and possibly genetic mutations. Whether FRa in tumors decreases in vivo among individuals who are folate sufficient, or whether the tumor's machinery sustains FRa levels to meet the increased folate demands of the tumor, has not been studied. Consequently, the significance of carrying a FRa-positive tumor in the era of folic acid fortification and widespread vitamin supplement use in countries such as Canada and the United States is unknown. Epidemiologic and clinical studies using human tumor specimens are lacking and increasingly needed to understand the role of environmental and genetic influences on FOLR1 expression in tumor etiology and progression. This review summarizes the literature on the complex nature of FOLR1 gene regulation and expression, and suggests future research directions. ' 2006 Wiley-Liss, Inc.

show abstract

Section: Folate Receptor Vs Reduced Folate Carrier Transportmentioning

confidence: 99%

The role of folate receptor α in cancer development, progression and treatment: Cause, consequence or innocent bystander?

Kelemen

2006

Intl Journal of Cancer

447

340

View full text Add to dashboard Cite

show abstract

“…Clearly, supplementation of the food supply with folate beginning in the U.S. in 1998 has resulted in a pronounced decrease in the incidence of neural tube defects in newborns. However, the potential long term adverse effects of chronic folate supplementation with respect to other health issues, including cancer, heart disease, and cognitive function are not yet known (Lucock and Yates, 2005;Kim, 2006). (i) Evidence exists that folate supplementation can, under some circumstances, accelerate development of preexisting malignancies, including colorectal cancer and breast cancer (Ulrich and Potter, 2006;Kotsopoulos et al, 2005), two of the most common cancers in humans.…”

Section: Discussionmentioning

confidence: 99%

A humanized mouse model for the reduced folate carrier

Patterson¹,

Graham²,

Cherian³

et al. 2008

Molecular Genetics and Metabolism

View full text Add to dashboard Cite

The ubiquitously expressed reduced folate carrier (RFC) or SLC19A1 is recognized to be an essential transport system for folates in mammalian cells and tissues. In addition to its generalized role as a folate transporter, RFC provides specialized tissue functions including absorption across intestinal/ colonic epithelia, transport across the basolateral membrane of renal proximal tubules, transplacental transport of folates, and folate transport across the blood-brain barrier. The human RFC (hRFC) gene is regulated by 5 major upstream non-coding regions (designated A1/A2, A, B, C, and D), each transcribed from a unique promoter. Altogether, at least 14 distinct hRFC transcripts can be envisaged in which different 5' untranslated regions (UTRs) are fused to a common splice acceptor region (positions -1 to -49) within the first coding exon with a common 1776 bp coding sequence. The 5' non-coding regions are characterized by alternate transcription start sites, multiple splice forms, and selective tissue distributions. Alternate 5'UTRs impact mRNA stabilities and translation efficiencies, and result in synthesis of modified hRFC proteins translated from upstream AUGs. In this report, we describe production and characterization of transgenic mice (TghRFC1) containing a functional hRFC gene and of humanized mice in which the mRFC gene is inactivated and an active hRFC gene has been introduced. The mice appear to be healthy and to breed well. Analysis of tissue specificity of expression in both the TghRFC1 and humanized hRFC mice by real-time RT-PCR demonstrates that the hRFC gene is expressed with a specificity closely resembling that seen in human tissues. For the humanized hRFC mice, levels of B and A1/A2 5'UTRs predominated in all mice/tissues, thus resembling results in normal human tissues. Lower levels of A and C 5'UTRs were also detected. The availability of humanized mouse models for hRFC will permit investigators to address critical unanswered questions pertinent to human health and disease. These include the ability to analyze the hRFC gene in vivo, to control dietary and other environmental conditions that may impact levels of gene expression, and to control the genetics of the mice in order to assess the effects of hRFC gene alterations on tissue folate uptake and distribution, none of which can be easily achieved in human populations.

show abstract

“…Furthermore, an additional consideration remains as to whether supplements should only be targeted at women of child bearing age, or simply to all women. The authors thereby advocate judicious intake based on existing knowledge regarding the bioavailability of native and synthetic forms of this vitamin, as well as recent findings regarding gene-nutrient interactions 17) and the increasing risk for key developmental and degenerative disorders 18) , particularly colorectal cancer rates, where the timing of exposure to synthetic folic acid supplementation seems to be crucial. With the aforementioned points in mind, it may be that the best approach is to initially focus supplementation for those women aiming to become pregnant, and to provide education in support of the use of folic acid at and around the time of conception.…”

mentioning

confidence: 99%

“…Without doubt, 'moderate' intake of folic acid as a supplement or fortificant is known to be beneficial, although it is also important to be aware of some recently-identified negative issues associated with excessive intake. These may include increased rates of positional plagiocephaly, epigenetic modifications that are heritable, genetic selection of deleterious genes, insulin resistance, increased twinning, colorectal cancer, breast cancer, and where vitamin B 12 is low, cognitive decline 17,18) . Other conditions may also be modified by the relationship between native folate and gene variants of proteins which transport or metabolise it.…”

mentioning

confidence: 99%