Folic Acid

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Folic Acid
2D structure for Folic Acid
Chemical Name 2-[ [4-[(2-amino-4-hydroxy-pteridin-6-yl) methylamino]benzoyl]amino] pentanedioic acid
Chemical Formula C19H19N7O6
CAS Number 59-30-3
Chemical Information HMDB00121
Biochemical Taxonomy
Functional Taxonomy 1-C metabolism
Nutritional Taxonomy Water-Soluble Vitamins
Metabolic Pathways Folate biosynthesis
One carbon pool by folate
Biofluid Location
Tissue Location
Normal Biofluid Concentrations Urine:
0 (not detectable)
Plasma:
0.0063-0.0306 uM
Normal Tissue Concentrations
Diseases / Conditions Related to Nutrition megaloblastic anemia, neural tube defects, cardiovascular disease, cancer, cognitive function and dementia.
Other (Monogenic Disorders)
Abnormal Biofluid Concentrations
Abnormal Tissue Concentrations
Physiological Processes
Authors:
Affiliations:


Contents

Introduction

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Folate is the generic term for a large family of chemically-similar, highly labile trace compounds involved in a range of biosynthetic pathways. Folate is a water-soluble member of the B group of vitamins, deriving its name from the Latin folium, meaning leaf. Diet and plasma predominantly consist of 5'-methyltetrahydrofolate and formyltetrahydrofolate, while in supplements the synthetic oxidized form of folate, folic acid, is used. Folate coenzymes are acceptors and donors of one-carbon units and are involved in the transfer of these 1-C units in key synthetic pathways such as methionine, purine, and pyrimidine biosynthesis. Additionally, they play an important role in the interconversion of serine and glycine, and in histidine catabolism. The folate molecule consists of a 2-amino-4-hydroxy-pteridine moiety linked via a methylene group at the C-6 position to p-aminobenzoic acid (pteroic acid) combined with a variable number of glutamic acid residues. Folate derivatives differ in the oxidation state of the pteridine ring, the type of the one carbon substituent at N5 and/or N10 positions, and the number of conjugated glutamic acid residues (1).

Biological Function

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Folate one-carbon metabolism

The principal function of folate coenzymes is to accept or donate one-carbon units in key metabolic pathways. These reactions involve various electron transfer steps, catalysed and accompanied by specific enzyme systems and coenzymes such as FADH2 and NADPH (1). Check the pathway wiki.

DNA precursor synthesis

One of the major one-carbon transfer reactions occurring within the cell is the synthesis of purines and the pyrimidine thymidine for DNA synthesis and repair. The biosynthesis of purines involves construction of the purine ring system via addition of functional groups sequentially onto a pre-existing ribose phosphate. A nucleotide is the final product. Aminoimidazole-4-carboxamide ribonucleotide (AICAR) and glycinamide ribonucleotide (GAR) each receive a one-carbon unit from 10-formyltetrahydrofolate during the biosynthesis which become carbon atoms 2 and 8, respectively, of the developing purine ring. The enzymes responsible are AICAR transformylase and GAR transformylase. The transfer of one-carbon units is also crucial in biosynthesis of the pyrimidine thyminidine. Folate, in the form of 5,10-methylenetetrahydrofolate, acts as methyl donor for the enzyme thymidylate synthase, which converts deoxyuridine monophosphate to thymidine monophosphate (1).

Remethylation of homocysteine to methionine

The requirement of methyl groups for cellular metabolism exceeds the normal dietary supply. Insufficiency is prevented by de novo methyl synthesis via one carbon donation from the folate pool. Homocysteine acquires a methyl group from 5-methyltetrahydrofolate to form methionine. The transfer of the methyl group of 5-methyltetrahydrofolate to homocysteine is catalysed by vitamin B12-dependent methionine synthase. During the first step of the reaction the methyl group is transferred from 5-methyltetrahydrofolate to the cofactor to form methylcyanocobalamin. In the second step the methyl group is then transferred to homocysteine to yield methionine and tetrahydrofolate. De novo synthesised methionine is activated by ATP to form the methyl donor S-adenosylmethionine (SAM). This reaction is facilitated by the enzyme methionine adenosyl transferase. SAM acts as a methyl donor to a variety of acceptors, including nucleic acids, neurotransmitters, phospholipids, and hormones. During this process SAM is converted to S-adenosylhomocysteine (SAH). SAH is subsequently hydrolysed back to homocysteine, which then becomes available to start a new cycle of methyl-group transfer. This reaction is catalysed by S-adenosylhomocysteine hydrolase, producing adenosine and homocysteine. This pathway is known as the remethylation cycle. A second pathway in which homocysteine is involved is the homocysteine transsulfuration pathway. The first step in this pathway is the vitamin B6-dependent condensation of homocysteine with serine to form cystathionine. This irreversible reaction is catalysed by the enzyme cystathionine β-synthase. Cystathionine is then hydrolysed to cysteine and α-ketobutyrate by a second vitamin B6-dependent enzyme, γ-cystathionase. Excess cysteine is oxidised to taurine and eventually to inorganic sulfates. The transsulfuration pathway effectively catabolises potentially toxic homocysteine, which is not required for methylation (1).

Catabolism

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Diseases / Conditions Related to Nutrition

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Folates in health and disease

It has been suggested that folate deficiency is the most common vitamin deficiency in the world, with 40% of 15-18 year olds in the UK exhibiting marginal folate status and folate deficiency common in people over 65 years of age, especially in the institutionalised elderly [www.nutrition.org.uk]. In excess of 80% of women (in different age groups) do not achieve the RNI for women who could become pregnant (even accounting for supplement use), while 85% of men and women do not consume the recommended number of fruit and vegetable portions as detailed in the “5 a day” campaign issued by the Department of Health in the UK [www.dh.gov.uk]. Folate is crucial for human health and disease. A range of diseases or conditions is associated with poor folate status.

Folate and megaloblastic anemia

Folate deficiency results in a specific type of anemia, megaloblastic anemia. Megaloblasts are large, abnormal, nucleated cells that are precursors of erythrocytes. These cells arise as a consequence of folate deficiency due to failure of the red blood cell precursors to divide normally and accumulate in the bone marrow.

Folate and Pregnancy

Folate is crucial in pregnancy due to its key function in maintaining normal cell growth and division. A positive association has been reported for maternal folate status and birth weight and an inverse association between maternal homocysteine and birth weight.

Folate and Neural Tube Defects (NTD)

Neural tube defects (NTD) refer to malformations of the embryonic brain and/or spinal cord. NTDs are characterised by incomplete development of the central nervous system and the related surrounding structures. Development and closure of the neural tube are normally completed within 28 days after conception. Periconceptional intake of folic acid is of major importance in the development of NTDs. Periconceptional folic acid supplementation can reduce the risk of occurrence as well as the recurrence risk of NTD (7). An association between elevated homocysteine levels and increased risk of NTD has been observed. Many countries, including the UK, recommend periconceptional folic acid supplementation. Women planning a pregnancy are advised to take 400 μg folate daily while attempting to become pregnant and during early pregnancy (see RNI above).

Folate, mental health and Alzheimers dementia

Folate, vitamin B12 and vitamin B6 are essential in maintaining normal nervous system function in the adult. Acute clinical deficiencies of these vitamins are associated with severe depression, paranoia, neuropathy and psychosis, possibly as a result of pathological changes in the peripheral and central nervous system (8). Low serum and/or red blood cell folate have been associated with greater symptom severity among depressed patients (9). Intervention with folate supplements appears to reduce symptom severity. Elevated homocysteine is associated with risk of Alzheimers disease, although it remains to be established whether this is linked or acts independently of folate status.

Folate and vascular disease

Epidemiological (prospective and case-control studies) and human intervention trials in patients either with pre-existing cardiovascular lesions or in healthy volunteers have demonstrated an inverse relationship between folate status and relative risk of cardiovascular disease. Several potential mechanisms through which folate status influences vascular health have been proposed (reviewed in 10). Folate deficiency may induce vascular dysfunction indirectly through increased cellular homocysteine, which itself may be cytotoxic to vascular epithelia or which may act to induce oxidative stress via autoxidation and generation of reactive oxygen species (ROS). Folate deficiency may also induce abnormal DNA methylation and gene expression in the vascular tissue via impaired metabolism of SAM and altered SAM to SAH ratios. Conversely, folate sufficiency, (associated with a high intake of folate via fruit and vegetable consumption) has been hypothesised to positively influence vascular cell integrity and function either by stabilising endothelial cell nitric oxide synthetase with downstream effects on endothelial cell function and vasodilation or via its ability to directly scavenging ROS such as superoxide dismutase generated by normal cellular metabolism. Even a mild elevation of total plasma homocysteine is associated with an increased risk of vascular disease. A meta analysis of 17 studies examining the relationship between total plasma homocysteine and cardiovascular disease observed that 14 studies showed a positive association, with an increased risk of 60% for men and 80% for women for each 5μmol/L increase in total homocysteine (11). Decreased folate levels are associated with an increased risk of cardiovascular disease. Individuals in the lowest serum folate tertile compared with the highest are at more than twice the risk of cardiovascular disease (12).

Folate and cancer

Poor folate status is associated with the development of cancer of the cervix, colorectum, lung, esophagus, brain, pancreas and breast (reviewed in 13). Support for a protective role for folate is most compelling for colorectal cancer. Cigarette smoke may cause localised folate deficiency in the bronchial epithelium, thereby making lung cells more susceptible to carcinogens in tobacco smoke. Serum folate levels are lower in smokers than in non-smokers (14). Chemical components of cigarette smoke may convert certain folate metabolites into biologically inactive compounds. One case-control study investigating the association between dietary folate intake and risk of lung cancer found no significant association (15). Conversely, a larger study demonstrated a significant protective effect of dietary folate against the development of squamous cell carcinoma in the lungs in men who smoked heavily (16). Additionally, two studies have shown that folate supplementation in smokers can reverse bronchial metaplasia, a purported precursor of bronchial squamous cell carcinoma (17,18). The epidemiological evidence linking folate intake with cervical dysplasia or cervical cancer is conflicting. Folate intake and red blood cell folate concentrations are inversely associated with cervical dysplasia but are not associated with more advanced stages of cervical neoplasia (19,20). A small intervention study demonstrated that folate supplementation can regress cervical dysplasia (21). However, a double-blind, placebo-controlled trial with a larger number of subjects failed to confirm this finding (22). A similar situation exists at present for the association between dietary folate deficiency and cancer of the esophagus, stomach, pancreas, liver and breast. No conclusions can be drawn for these associations due to insufficient data available in the literature to date (13). However, convincing evidence exists suggesting that poor folate status is associated with an increased risk of colorectal cancer. Colorectal cancer is a significant health problem in the Western world. Both sexes are affected equally, with about 401 000 new cases in men annually and 381 000 in women. Worldwide, colorectal cancer represents 9.4% of all incident cancer in men and 10.1% in women (23). Several questionnaire-based human case-control studies have shown an inverse association between reported dietary folate intake and colorectal cancer incidence (reviewed in13). Individuals with high alcohol and low methyl (methionine and folate) intake are at a significantly higher risk of colorectal cancer than subjects with adequate methyl intake (24). Similarly, high alcohol, low folate and low protein intakes are inversely associated with colon cancer risk in men (25).

Mechanisms for folate deficiency and carcinogenesis

There are currently two principal mechanisms by which folate deficiency may increase the risk of cancer, namely by altering normal DNA methylation and/or by inducing an imbalance in DNA precursors leading to impaired DNA synthesis and repair (extensively reviewed in 26).

Altered DNA methylation

Folate is essential for synthesis of SAM, which serves as methyl donor in a variety of biochemical reactions including methylation of DNA. DNA methylation in mammals is seen as a covalent modification at the fifth carbon position of cytosine residues within CpG dinucleotides. Approximately 4% of cytosines in DNA are modified to 5-methylcytosine, of which most are found in the palindromic sequence, CpG. The genome methylation pattern is precisely inherited during mitosis and is highly tissue- and species-specific. In general, genes methylated at specific sites, e.g. upstream of a promoter, are either not transcribed or are transcribed at a reduced rate. The absence of methyl groups is associated with increased gene expression. Site-specific DNA methylation therefore controls gene expression. Alterations in DNA methylation as a result of folate deficiency may affect the expression both of oncogenes and tumour suppressor genes. There is evidence that DNA methylation plays an important role in carcinogenesis (13,26). Decreased genomic methylation is a consistent finding in tumorigenesis and has been observed in cancers of the colon, stomach, uterine cervix, prostate, thyroid and breast. DNA both from benign colon polyps and malignant carcinomas is substantially unermethylated (hypomethylated) when compared with DNA from adjacent normal tissue. This decrease in genomic methylation appears early in carcinogenesis and appears to precede mutation and deletion events that occur later in the process. Animal studies have shown that DNA methylation is altered by dietary folate status (29). Although folate deficiency is associated with an increased risk of cancer in man, there is no consistent or convincing evidence from human studies to suggest that folate can influence DNA hypomethylation. Slattery et al. (30) in a population-based case-control study found no association between dietary intake of micronutrients (methionine, folate, vitamin B12 and vitamin B6) and colon cancer risk. Only a slight trend of increasing risk between individuals with a high or low composite dietary profile based on alcohol, methionine, folate, vitamin B12 and vitamin B6 intake was observed. Subclinical folate deficiency causes lymphocyte DNA hypomethylation in healthy postmenopausal women (31). Furthermore, DNA hypomethylation can be reversed by repletion with 516 μg/day of folate (31). This was the first study to show that marginal folate deficiency could alter DNA methylation in normal healthy individuals and that this was modification was reversible by supplemental folate.

Altered DNA synthesis and repair

The second mechanism through which folate may modulate cancer risk is through chromosomal instability. 5,10-methylenetetrahydrofolate is required for the synthesis of both purine residues in DNA and also for the conversion of deoxyuridine monophosphate to thymidine monophosphate. Limited 5,10-methylenetetrahydrofolate impairs thymidylate synthase activity, blocking the methylation of deoxyuridine monophosphate to thymidine monophosphate and disrupting the balance of DNA for DNA synthesis and repair. This results in an increase in uracil available for misincorporation into DNA in place of thymidine. Uracil is misincorporated into DNA due to the fact that DNA polymerase does not distinguish between deoxyuridine monophosphate and thymidine monophosphate. Under normal conditions, misincorporated uracil is quickly repaired. However, under conditions of continual folate deficiency, misincorporation of uracil and repair may occur repeatedly in what has been termed a 'futile' or 'catastrophic' repair cycle. Strand breaks, as intermediates in excision repair, destabilise the DNA molecule, leading to chromosome aberrations and malignant transformation. Folate acid deficiency in vitro can increase uracil misincorporation into DNA. DNA extracted from cultured human myeloid cells (HL60) grown in medium deficient in folate and/or B12 contained increased amounts of uracil and decreased levels of thymidine compared with DNA from cells grown in supplemented medium. Normal human lymphocyte DNA contains small but detectable amounts of uracil while folate deficiency in vitro destabilised the DNA of cultured lymphocytes further, resulting in increased DNA strand breakage and uracil misincorporation. Folate deficiency can alter nucleotide pools and induce uracil misincorporation and strand breakage in vivo. Folate deficiency alone or in combination with methionine and choline deficiency increased uracil levels significantly in rat livers. DNA strand breaks were induced in genomic DNA and moreover, specifically within the p53 tumour suppressor gene in liver from methyl-deficient (methionine, choline and folate deficient) rats. Few comparable studies have been undertaken in humans. In a small study DNA obtained from the bone marrow and blood of splenectomised folate-deficient individuals incorporated 8-9 times more uracil than subjects with normal folate levels (32). Supplementation with folic acid (5mg/daily for 8 weeks) significantly increased plasma and red blood cell folate levels and significantly decreased uracil levels in individuals previously with low folate concentration. This study suggests that folate deficiency does induce uracil misincorporation and chromosomal damage in humans, and that supplementation can reduce these lesions. In a recent human intervention study to determine whether increasing folate intake can improve DNA stability biomarkers in subjects with blood folate levels in the normal range, volunteers were given 1.2mg folate for 12 weeks and genomic stability measured in isolated lymphocytes. Folate supplementation increased total folate and 5-methylTHF concentrations in the experimental group. Uracil misincorporation was significantly and specifically decreased in lymphocytes from folate-supplemented subjects (33).

Associated decreased protein/metabolite profile

Associated increased protein/metabolite profile

Other (Monogenic) Disorders

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Nutritional Information

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Nutritional information: dietary sources and absorption of folates

The Reference Nutrient Intake (RNI) for folate can vary for different age groups, by gender and by country. Currently, in the UK the RNI for folate is 200mg/day for most groups, rising to 400mg/day (prior to conception and until the 12th week of pregnancy) for all women who could become pregnant (2).

Mammals are unable to produce folate de novo, as they cannot attach the initial glutamate to pteroic acid or synthesise the p-aminobenzoic acid residue. Therefore, mammals rely primarily on dietary sources of folate, (although some folate is obtained via microbial breakdown in the gut). Naturally occurring forms are reduced derivatives of folate, while the fully oxidised derivative, folic acid, is only found in supplemented food sources. Reduced folates are less stable than the oxidised form (1). As little as 20-50% of food folates are bioavailable compared with synthetic folic acid. The unstable nature of naturally-occurring folates causes significant loss of activity during harvesting, storage, processing and preparation. Boiling can reduce the folate content of vegetables such as broccoli by as much as 50%, while steaming has little detrimental effect. Freezing before cooking in most species has no negative effect and folate concentrations remains stable for 12 months.

Rich sources of folate in the diet are primarily leafy green vegetables, liver, kidney, citrus fruits (and juices) and yeast extracts. Sources of the vitamin contributing to the total folate intake of the diet are bread, potatoes, cereal (very often fortified with folic acid) and dairy products. Cereal and cereal products provide 23% of mean daily intake overall, with vegetables a further 15%. Meat, fish, eggs and milk account for 24%, beverages 12% and potatoes 15% (2). The most abundant folate compounds present in food are 5-methyltetrahydrofolate and 10-formyltetrahydrofolate and their derivatives. Dietary folates are absorbed into the portal circulation. The first step in this process is passage through the mucosal cells of the small intestine where the polyglutamyl chain is removed in the brush border of the mucosal cells, leaving a single glutamic acid remaining. As a result of this absorbed dietary folate is primarily converted to 5-methyltetrahydrofolate during its passage through the intestinal mucosa before release into the portal circulation. Plasma folate is subsequently transported to peripheral tissues. To enable the retention and concentration of folates in mammalian tissues, the folate forms are converted to polyglutamate derivatives, catalysed by folypolyglutamate synthetase. Erythrocytes, or red blood cells, contain higher levels of folate than plasma, primarily 5-methyltetrahydrofolate and formyl-tetrahydrofolate. Folate is incorporated into the developing erythroblast during erythropoiesis in the marrow, and retained throughout the lifespan of the cell. Although fasted plasma folate levels are also a good indicator for folate status, plasma levels are affected by recent dietary intake. For this reason red cell folate levels are often used as an indicator of long-term folate status. Transport of folates across cell membranes is facilitated in two ways: membrane carrier-and folate-binding protein-mediated systems. Several membrane carrier-mediated folate transporters have been identified in mammalian tissues, exhibiting different affinities for various folate derivatives (1).

Toxicity

Folic acid is a water-soluble vitamin, enabling excess amounts to be excreted from the body. It is generally considered safe, even at relatively high intakes (>5mg/day), but an upper limit has been recommended at 1mg/day. However, high folate levels may mask B12 deficiency anaemia leading to irreversible peripheral nerve damage. The long-term effects of high folic acid intake are unknown at this time.

Genetic and lifestyle modifiers of folate status

Under conditions of folate deficiency all one-carbon reactions will be affected and compromised to varying extents. Consequently, various substrates and metabolic intermediates are either depleted or accumulate. Folate deficiency causes an imbalance in the precursor pool essential for normal DNA synthesis and repair and also for DNA methylation with negative consequences for genomic stability (see Folate and Cancer below). Folate deficiency is also associated with the accumulation of homocysteine, which is implicated in the aetiology of several diseases, such as heart disease, dementia and neural tube defects. In addition to nutritional factors influencing one-carbon metabolism, genetic defects in the enzymes involved in folate metabolism can have a profound effect on disease risk. The most well reported polymorphism in a folate metabolising enzyme associated with disease risk is the methylenetetrahydrofolate reductase (MTHFR) gene. MTHFR is a flavoprotein that consists of two identical subunits of approximately 70 kDa. The enzyme contains an N-terminal catalytic region with determinants for binding flavin-adenine dinucleotide, for binding nicotinamide-adenine dinucleotide phosphate and for binding 5,10-methylenetetrahdrofolate. The human methylenetetrahydrofolate reductase gene is located on chromosome 1p36 and catalyses the conversion of 5,10-methylenetetrahydrofolate, required for pyrimidine biosynthesis, to 5-methyltetrahydrofolate, required for methionine synthesis. Two common genetic polymorphisms associated with a reduced methylenetetrahydrofolate reductase activity have been identified. The first variant identified, C677T, is located in exon 4 at the folate binding site, resulting in a C to T substitution and convertion of an alanine to a valine residue (3). This mutation causes thermolability of the enzyme. Homozygous individuals for this mutation (677TT) exhibit a temperature-related-loss of function, which correlates with reduced enzyme activity. Homozygous individuals for the mutation have altered distribution of red cell folates, with accumulation of formylated tetrahydrofolate polyglutamates in addition to methylated derivatives. In healthy individuals the 677TT genotype is associated with a significantly higher total homocysteine plasma level than in heterozygotes (677CT) or individuals with wild-type C alleles (677CC) (3) and decreased red blood cell folate levels (4). The second polymorphism (A1298C) is in exon 7, resulting in a A to C substitution and convertion of a glutamine to an alanine residue (4). This substitution lowers the enzyme activity in individuals homozygous (1298CC) for the mutant allele to approximately 60% of control values (5,6). Combined heterozygosity for the 677T and the 1298C alleles is associated with reduced enzyme activity (50-60%), higher homocysteine and decreased plasma folate levels, compared to individuals homozygous for the 677TT mutation (5). Biological and lifestyle factors factors can influence both folate and homocysteine levels. Old age and gender are determinants of total plasma homocysteine levels independently of folate status. Race and ethnicity also influence homocysteine concentrations. Coffee consumption is associated with increased homocysteine levels, while protein consumption (>75 g/day) lowers homocysteine levels Both associations are independent of folate, vitamin B12 and B6 levels. Cigarette smoking is associated with low folate levels and higher homocysteine. Consumption of ethanol in the diet increases folate deficiency.

Drivers for biological variation

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Vulnerable groups

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Markers of homeostasis and / or health

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Folic acid in physiological doses

Category Markers sign yes/no/? Inverse(I)/Direct(D) Status(S)/Intake(I) ref score
inflammation, immune response CRP / hsCRP Yes & No I S & I 1,91,100,107
fibrinogen
Albumin
White blood cell count Yes I S 72
TNF-alpha
Il-6
Il1-beta
Il-10
Prostaglandin F2alpha
Prostaglandin E1 (PGE1)
Prostaglandin E2 (PGE2)
Thromboxane B2
Nitric Oxide (NO) Yes I S 65
Serum Amyloid A (SAA)
NfkB
alpha1-antichymotrypsin
oxidative stress 8(OH)-DG
F2-isoprostanes
8-iso-prostaglandin F2alpha
oxidized LDL No S & I 100
SOD No I 2
TBARS
myeloperoxidase
nitrotyrosine
Metabolic stress diastolic BP Yes I S & I 81,90,102  ?
systolic BP Yes I S & I 81,90,101,102  ?
total cholesterol
LDL Yes I I 77
HDL Yes D I 77
HDL/TC
triglycerides
homocysteine Yes  ? S & I 1-76,78-80,82-89,91-99,103-106,108-117 5
tPA/PAI-1
Fibrin fragment D-dimer
Factor VIIa No I 1
sICAM
Monocyte chemotactic protein 1 (MCP1) Yes I I 107
fasting glucose
fasting insulin
OGTT
insulin tolerance test
HbA1c
fructosamine

References (double click in this box and insert your references list)*:

  1. Klerk M, Durga J, Schouten EG, Kluft C, Kok FJ, Verhoef P. : No effect of folic acid supplementation in the course of 1 year on haemostasis markers and C-reactive protein in older adults. Thromb Haemost. 2005 Jul;94(1):96-100.
  2. Moat SJ, Hill MH, McDowell IF, Pullin CH, Ashfield-Watt PA, Clark ZE, Whiting JM, Newcombe RG, Lewis MJ, Powers HJ. Reduction in plasma total homocysteine through increasing folate intake in healthy individuals is not associated with changes in measures of antioxidant activity or oxidant damage. Eur J Clin Nutr. 2003 Mar;57(3):483-9.
  3. Ubbink JB, Vermaak WJ, van der Merwe A, Becker PJ. Vitamin B-12, vitamin B-6, and folate nutritional status in men with hyperhomocysteinemia. Am J Clin Nutr. 1993 Jan;57(1):47-53.
  4. Selhub J, Jacques PF, Wilson PW, Rush D, Rosenberg IH. Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. JAMA. 1993 Dec 8;270(22):2693-8.
  5. Ubbink JB, Vermaak WJ, van der Merwe A, Becker PJ, Delport R, Potgieter HC. Vitamin requirements for the treatment of hyperhomocysteinemia in humans. J Nutr. 1994 Oct;124(10):1927-33.
  6. O'Keefe CA, Bailey LB, Thomas EA, Hofler SA, Davis BA, Cerda JJ, Gregory JF 3rd. Controlled dietary folate affects folate status in nonpregnant women. J Nutr. 1995 Oct;125(10):2717-25.
  7. Selhub J, Jacques PF, Bostom AG, D'Agostino RB, Wilson PW, Belanger AJ, O'Leary DH, Wolf PA, Rush D, Schaefer EJ, Rosenberg IH. Relationship between plasma homocysteine, vitamin status and extracranial carotid-artery stenosis in the Framingham Study population. J Nutr. 1996 Apr;126(4 Suppl):1258S-65S.
  8. Koehler KM, Romero LJ, Stauber PM, Pareo-Tubbeh SL, Liang HC, Baumgartner RN, Garry PJ, Allen RH, Stabler SP. Vitamin supplementation and other variables affecting serum homocysteine and methylmalonic acid concentrations in elderly men and women. J Am Coll Nutr. 1996 Aug;15(4):364-76.
  9. Guttormsen AB, Ueland PM, Nesthus I, Nygård O, Schneede J, Vollset SE, Refsum H. Determinants and vitamin responsiveness of intermediate hyperhomocysteinemia (> or = 40 micromol/liter). The Hordaland Homocysteine Study. J Clin Invest. 1996 Nov 1;98(9):2174-83.
  10. Tucker KL, Selhub J, Wilson PW, Rosenberg IH. Dietary intake pattern relates to plasma folate and homocysteine concentrations in the Framingham Heart Study.J Nutr. 1996 Dec;126(12):3025-31.
  11. Tucker KL, Mahnken B, Wilson PW, Jacques P, Selhub J. Folic acid fortification of the food supply. Potential benefits and risks for the elderly population. JAMA. 1996 Dec 18;276(23):1879-85. Erratum in: JAMA 1997 Mar 5;277(9):714.
  12. Shimakawa T, Nieto FJ, Malinow MR, Chambless LE, Schreiner PJ, Szklo M. Vitamin intake: a possible determinant of plasma homocyst(e)ine among middle-aged adults. Ann Epidemiol. 1997 May;7(4):285-93.
  13. Verhoef P, Kok FJ, Kluijtmans LA, Blom HJ, Refsum H, Ueland PM, Kruyssen DA. The 677C-->T mutation in the methylenetetrahydrofolate reductase gene: associations with plasma total homocysteine levels and risk of coronary atherosclerotic disease. Atherosclerosis. 1997 Jul 11;132(1):105-13.
  14. Ward M, McNulty H, McPartlin J, Strain JJ, Weir DG, Scott JM. Plasma homocysteine, a risk factor for cardiovascular disease, is lowered by physiological doses of folic acid. QJM. 1997 Aug;90(8):519-24.
  15. Houghton LA, Green TJ, Donovan UM, Gibson RS, Stephen AM, O'Connor DL.: Association between dietary fiber intake and the folate status of a group of female adolescents. Am J Clin Nutr. 1997 Dec;66(6):1414-21.
  16. Nygård O, Refsum H, Ueland PM, Vollset SE. Major lifestyle determinants of plasma total homocysteine distribution: the Hordaland Homocysteine Study. Am J Clin Nutr. 1998 Feb;67(2):263-70.
  17. Brouwer DA, Welten HT, van Doormaal JJ, Reijngoud DJ, Muskiet FA. [Recommended dietary allowance of folic acid is insufficient for optimal homocysteine levels] Ned Tijdschr Geneeskd. 1998 Apr 4;142(14):782-6. [Article in Dutch]
  18. Schorah CJ, Devitt H, Lucock M, Dowell AC. The responsiveness of plasma homocysteine to small increases in dietary folic acid: a primary care study Eur J Clin Nutr. 1998 Jun;52(6):407-11.
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  20. Brouwer IA, van Dusseldorp M, Thomas CM, Duran M, Hautvast JG, Eskes TK, Steegers-Theunissen RP. Low-dose folic acid supplementation decreases plasma homocysteine concentrations: a randomized trial. Am J Clin Nutr. 1999 Jan;69(1):99-104
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  22. McQuillan BM, Beilby JP, Nidorf M, Thompson PL, Hung J. Hyperhomocysteinemia but not the C677T mutation of methylenetetrahydrofolate reductase is an independent risk determinant of carotid wall thickening. The Perth Carotid Ultrasound Disease Assessment Study (CUDAS) Circulation. 1999 May 11;99(18):2383-8.
  23. Jacques PF, Selhub J, Bostom AG, Wilson PW, Rosenberg IH. The effect of folic acid fortification on plasma folate and total homocysteine concentrations.N Engl J Med. 1999 May 13;340(19):1449-54.
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  72. Folsom AR, Desvarieux M, Nieto FJ, Boland LL, Ballantyne CM, Chambless LE. B vitamin status and inflammatory markers. Atherosclerosis. 2003 Jul;169(1):169-74.
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Folic acid in megadoses

Category Markers sign yes/no/? I/D S/I ref score
inflammation, immune response fibrinogen Yes I S & I 1, 7
oxidation SOD Yes D I 1
metabolic stress systolic BP Yes I I 6
homocysteine Yes I I 1-6,8-10
Fibrin fragment D-dimer Yes I S 7

References (double click in this box and insert your references list)*:

  1. Mayer O Jr, Simon J, Rosolová H, Hromádka M, Subrt I, Vobrubová I: The effects of folate supplementation on some coagulation parameters and oxidative status surrogates. Eur J Clin Pharmacol. 2002 Apr;58(1):1-5. Epub 2002 Feb 19.
  2. Woo KS, Chook P, Lolin YI, Sanderson JE, Metreweli C, Celermajer DS. Folic acid improves arterial endothelial function in adults with hyperhomocystinemia.J Am Coll Cardiol. 1999 Dec;34(7):2002-6.
  3. Woo KS, Chook P, Chan LL, Cheung AS, Fung WH, Qiao M, Lolin YI, Thomas GN, Sanderson JE, Metreweli C, Celermajer DS. Long-term improvement in homocysteine levels and arterial endothelial function after 1-year folic acid supplementation. Am J Med. 2002 May;112(7):535-9
  4. Cafolla A, Dragoni F, Girelli G, Tosti ME, Costante A, De Luca AM, Funaro D, Scott CS. Effect of folic acid and vitamin C supplementation on folate status and homocysteine level: a randomised controlled trial in Italian smoker-blood donors. Atherosclerosis. 2002 Jul;163(1):105-11.
  5. Neal B, MacMahon S, Ohkubo T, Tonkin A, Wilcken D; PACIFIC Study Group. Dose-dependent effects of folic acid on plasma homocysteine in a randomized trial conducted among 723 individuals with coronary heart disease. Eur Heart J. 2002 Oct;23(19):1509-15.
  6. Mangoni AA, Sherwood RA, Swift CG, Jackson SH. Folic acid enhances endothelial function and reduces blood pressure in smokers: a randomized controlled trial. J Intern Med. 2002 Dec;252(6):497-503.
  7. Mangoni AA, Arya R, Ford E, Asonganyi B, Sherwood RA, Ouldred E, Swift CG, Jackson SH. Effects of folic acid supplementation on inflammatory and thrombogenic markers in chronic smokers. A randomised controlled trial. Thromb Res. 2003 Apr 15;110(1):13-7.
  8. Woodman RJ, Celermajer DE, Thompson PL, Hung J. Folic acid does not improve endothelial function in healthy hyperhomocysteinaemic subjects. Clin Sci (Lond). 2004 Apr;106(4):353-8.
  9. Sheu WH, Chin HM, Lee WJ, Wan CJ, Su HY, Lang HF. Prospective evaluation of folic acid supplementation on plasma homocysteine concentrations during weight reduction: a randomized, double-blinded, placebo-controlled study in obese women. Life Sci. 2005 Mar 18;76(18):2137-45. Epub 2005 Jan 25.
  10. Miyaki K, Murata M, Kikuchi H, Takei I, Nakayama T, Watanabe K, Omae KAssessment of tailor-made prevention of atherosclerosis with folic acid supplementation: randomized, double-blind, placebo-controlled trials in each MTHFR C677T genotype. J Hum Genet. 2005;50(5):241-8. Epub 2005 May 14.


.

Determinants of variation in requirement

guidelines

Category Determinants of status sign yes/no/? help independent of intake yes/no/?
general gender Yes No
age (adults) Yes Yes
age (children)
ethnicity Yes Yes & No
physiological status polymorphisms Yes Yes & No
pregnancy Yes  ?
lactation Yes  ?
menopause
physical fitness
gut flora Yes
anthropometric variables body weight
BMI Yes Yes & No
waist circumference
fat free mass
Lifestyle variables smoking Yes & No Yes & No
physical activity
alcohol use Yes & No Yes & No
medication use (incl. contraceptive pill) Yes & No  ?
stress

Other resources

guidelines
Cited references:

  1. Shane, B. Folate chemistry and metabolism. In Folate in Health and Disease (Bailey LB, Ed). New York: Marcel Dekker, pp 1-22, 1995.
  2. NDNS Adults aged 19 to 64 (2004); 5.
  3. Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, Boers GJH, den Hejer M, Klijtmans LAJ, van den Heuvel LP, Rozen R. A candidate genetic risk factor for vascular disease: A common mutation in methylenetetrahydrofolate reductase. Nature Genetics 10: 111-113, 1995.
  4. Molloy AM, Daly S, Mills JL, Kirke PN, Whitehead AS, Ramsbottom D, Conley MR, Weir DG, Scott JM. Thermolabile variant of 5,10-methylenetetrahydrofolate reductase associated with low red-cell folates: implications for folate intake recommendations. Lancet 349: 1591-1593, 1997.
  5. Van der Put NM, Gabreels F, Stevens EM, Smeitink JA, Trijbels F, Eskes TK, van den Heuvel LP, Blom HJ. A second common mutation in the methylenetetrahydrofolate reductase gene: An additional factor for neural-tube defects? American Journal of Human Genetics 62: 1044-1051, 1998.
  6. Weisberg I, Tran P, Christensen B, Sibani S, Rozen R. A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity. Molecular Genetetics and Metabolism 64: 169-172, 1998.
  7. MRC Vitamin Study Research Group. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. Lancet 338: 131-137, 1991.
  8. Rosenberg IH and Miller JW. Nutritional factors in physical and cognitive functions of elderly people. American Journal of Clinical Nutrition 55: 1237s-1243s, 1992.
  9. Abou-Saleh MT and Coppen A. Serum and red blood cell folate in depression. Acta Psychiatrica Scandinavia 80: 78-82, 1989.
  10. Verhaar et al., Arterioscler Thromb Vasc Biol., 22: 6-13, 2002.
  11. Boushey CJ, Beresford SAA, Omenn GS, Motulsky AG. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folate intakes. JAMA 274: 1049-1057, 1995.
  12. Loria CM, Ingram DD, Feldman JJ, Wright JD, Madans JH. Serum folate and cardiovascular disease mortality among US men and women. Archives of Internal Medicine 160: 3258-3262, 2000.
  13. Kim YI. Folate and carcinogenesis: Evidence, mechanisms, and implications. Journal of Nutritional Biochemistry 10: 66-88, 1999.
  14. Heimburger DC, Krumdieck CL, Alexander CB, Birch R, Dill SR, Bailey WC. Localised folic acid deficiency and bronchial metaplasia in smokers: Hypothesis and preliminary report. Nutrition International 3: 54-60, 1987.
  15. Le Marchand L, Yoshizawa CN, Kolonel LN, Hankin JH, Goodman MT. Vegetable consumption and lung cancer risk: A population-based case-control study in Hawaii. Journal of the National Cancer Institute 81: 1158-1164, 1989.
  16. Bandera EV, Freudenheim JL, Marshall JR, Zielezny M, Priore RL, Brasure J, Baptiste M, Graham S. Diet and alcohol consumption and lung cancer risk in the New York State Cohort. Cancer Causes Control 8: 828-840, 1997.
  17. Heimburger DC, Alexander CB, Birch R, Butterworth Jr. CE, Bailey WC, Krumdieck CL. Improvement in bronchial squamous metaplasia in smokers treated with folate and vitamin B12. Report of a preliminary randomised, double-blind intervention trial. JAMA 259: 1525-1530, 1988.
  18. Saito M, Kato H, Tsuchida T, Konaka C. Chemoprevention effects of bronchial squamous metaplasia by folate and vitamin B12 in heavy smokers. Chest 106: 496-499, 1994.
  19. McPherson RS. Nutritional factors and the risk of cervical dysplasia. American journal of Epidemiology 130: 830, 1989.
  20. Potischman N, Brinton LA, Laiming VA, Reevers WC, Brenes MM, Herroro R, Tenorino F, de Britton RC, Gaitan E. A case-control study of serum folate levels and invasive cervical cancer. Cancer Research 51: 4785-4789, 1991.
  21. Butterworth Jr. CE, Hatch KD, Gore H, Müller H, Krumdieck CL. Improvement in cervical dysplasia associated with folic acid therapy in users of oral contraceptives. American Journal of Clinical Nutrition 35: 73-82, 1982.
  22. Childers JM, Chu J, Voigt LF, Feigl P, Tamimi HK, Franklin EW, Alberts DS, Meyskens FL. Chemoprevention of cervical cancer with folic acid: A phase III Soutwest Oncology Group Intergroup study Cancer Epidemiology, Biomarkers & Prevention 4: 155-159, 1995.
  23. Boyle P and Langman MJS. Epidemiology. In ABC of colorectal cancer (Kerr DJ, Young AM, Hobbs FDR, Ed) London: BMJ Publishing Group, pp 1-4, 2001.
  24. Giovannucci E, Rimm EB, Ascherio A, Stampfer MJ, Colditz GA, Willett WC. Alcohol, low-methionine-low-folate diets, and risk of colon cancer in men. Journal of the National Cancer Institute 87(4): 265-273, 1995.
  25. Glynn SA, Albanes D, Pietinen P, Brown CC, Rautalahti M, Tangera JA, Gunter EW, Barrett MJ, Virtamo J, Taylor PR. Colorectal Cancer and folate status: A nested case-control study among male smokers. Cancer Epidemiology, Biomarkers & Prevention 5: 487-494, 1996.
  26. Duthie SJ. Proc Nutr Soc 63: 571-578, 2004.
  27. Wainfain E and Poirier LA. Methyl groups in carcinogenesis: Effects on DNA methylation and gene expression. Cancer Research 52: 20170s-20177s, 1992.
  28. Christman JK, Sheikhnejad G, Dizik M, Abileah S, Wainfain E. Reversibility of changes in nucleic acid methylation and gene expression induced in rat liver by severe dietary methyl deficiency. Carcinogenesis 14(4): 551-557, 1993.
  29. Balaghi M and Wagner C. DNA methylation in folate deficiency: use of CpG methylase. Biochemical and Biophysical Research Communications 193(3): 1184-1190, 1993.
  30. Slattery ML, Schaffer D, Edwards SL, M KN, Potter JD. Are dietary factors involved in DNA methylation associated with colon cancer? Nutrition and Cancer 28(1): 52-62, 1997.
  31. Jacob RA, Gretz DM; Taylor PC, James SJ, Pogribny IP, Miller BJ, Henning SM, Swendseid ME. Moderate folate depletion increases plasma homocysteine and decreases lymphocyte DNA methylation in postmenopausal women. Journal of Nutrition 128: 1204-1212, 1998.
  32. Blount BC, Mack MM, Wehr CM, MacGregor JT, Hiatt RA, Wang G, Wickramasinghe SN, Everson RB, Ames BN. Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: Implications for cancer and neuronal damage. Proceedings of the National Academy of Sciences USA 94: 3290-3295, 1997.
  33. Basten, GP, et al., (2006). Brit J Cancer 94: 1942-1947, 2006.

Thesis: More detailed information on the topic of folate, the MTHFR genotype and colon cancer, can be found in the thesis of Dr Sabrina Narayanan "The Effect of Folic Acid and Genetic Polymorphisms on DNA Stability and Colorectal Cancer", which contributed to this webpage. This is available from the Rowett Research Institute, Aberdeen, Scotland, UK. Alternatively, please search Web of Science using the author and supervisors names [Dr SJ Duthie, Professor J Little and Dr L Sharpe] for recent publications on various topics related to folate in human health.

Links

guidelines

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