| Folic acid |
 |
 |
 |
(2S)-2-[(4-{[(2-amino-4-hydroxypteridin-6-yl)methyl]amino}phenyl)formamido]pentanedioic acid
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Other names
N-(4-{[(2-amino-4-oxo-1,4-dihydropteridin-6-yl)methyl]amino}benzoyl)-L-glutamic acid; pteroyl-L-glutamic acid; Vitamin B9; Vitamin Bc; Folacin
|
| Identifiers |
| CAS number |
59-30-3  Y |
| PubChem |
6037 |
| ChemSpider |
5815 Y |
| UNII |
935E97BOY8 Y |
| DrugBank |
DB00158 |
| KEGG |
C00504  N |
| ChEBI |
CHEBI:27470 Y |
| ChEMBL |
CHEMBL1622 Y |
| RTECS number |
LP5425000 |
| ATC code |
B03BB01 |
| Jmol-3D images |
Image 1 |
-
c1cc(ccc1C(=O)N[C@@H](CCC(=O)O)C(=O)O)NCc2cnc3c(n2)c(=O)nc([nH]3)N
|
-
InChI=1S/C19H19N7O6/c20-19-25-15-14(17(30)26-19)23-11(8-22-15)7-21-10-3-1-9(2-4-10)16(29)24-12(18(31)32)5-6-13(27)28/h1-4,8,12,21H,5-7H2,(H,24,29)(H,27,28)(H,31,32)(H3,20,22,25,26,30)/t12-/m0/s1 Y
Key: OVBPIULPVIDEAO-LBPRGKRZSA-N Y
InChI=1/C19H19N7O6/c20-19-25-15-14(17(30)26-19)23-11(8-22-15)7-21-10-3-1-9(2-4-10)16(29)24-12(18(31)32)5-6-13(27)28/h1-4,8,12,21H,5-7H2,(H,24,29)(H,27,28)(H,31,32)(H3,20,22,25,26,30)/t12-/m0/s1
Key: OVBPIULPVIDEAO-LBPRGKRZBH
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| Properties |
| Molecular formula |
C19H19N7O6 |
| Molar mass |
441.4 g mol−1 |
| Appearance |
yellow-orange crystalline powder |
| Melting point |
250 °C (523 K), decomp.[1]
|
| Solubility in water |
1.6 mg/L (25 °C)[1] |
| Acidity (pKa) |
1st: 4.65, 2nd: 6.75, 3rd: 9.00[2] |
 N (verify) (what is:  Y/ N?)
Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa) |
| Infobox references |
Folic acid (also known as vitamin B9,[3] vitamin Bc[4] or folacin) and folate (the form naturally occurring in the body), as well as pteroyl-L-glutamic acid, pteroyl-L-glutamate, and pteroylmonoglutamic acid[5] are forms of the water-soluble vitamin B9. Folic acid is itself not biologically active, but its biological importance is due to tetrahydrofolate and other derivatives after its conversion from dihydrofolic acid in the liver.[6]
Vitamin B9 (folic acid and folate inclusive) is essential to numerous bodily functions. The human body needs folate to synthesize DNA, repair DNA, and methylate DNA as well as to act as a cofactor in biological reactions involving folate.[7] It is especially important in aiding rapid cell division and growth, such as in infancy and pregnancy. Children and adults both require folic acid to produce healthy red blood cells and prevent anemia.[8]
Folate and folic acid derive their names from the Latin word folium (which means "leaf"). Leafy vegetables are a principal source, although in Western diets fortified cereals and bread may be a larger dietary source.[citation needed]
A lack of dietary folic acid leads to folate deficiency, which is uncommon in normal Western diets.[citation needed] A complete lack of dietary folate takes months before deficiency develops as normal individuals have about 500–20,000 µg[9] of folate in body stores.[10] This deficiency can result in many health problems, the most notable one being neural tube defects in developing embryos. Common symptoms of folate deficiency include diarrhea, macrocytic anemia with weakness or shortness of breath, nerve damage with weakness and limb numbness (peripheral neuropathy)[citation needed], pregnancy complications, mental confusion, forgetfulness or other cognitive declines, mental depression, sore or swollen tongue, peptic or mouth ulcers, headaches, heart palpitations, irritability, and behavioral disorders. Low levels of folate can also lead to homocysteine accumulation.[7] DNA synthesis and repair are impaired and this could lead to cancer development.[7]
Adequate folate intake during the periconception period, the time right before and just after a woman becomes pregnant, helps protect against a number of congenital malformations, including neural tube defects (which are the most notable birth defects that occur from folate deficiency).[11] Neural tube defects produce malformations of the spine, skull, and brain including spina bifida and anencephaly. The risk of neural tube defects is significantly reduced when supplemental folic acid is consumed in addition to a healthy diet prior to and during the first month following conception.[12][13] Supplementation with folic acid has also been shown to reduce the risk of congenital heart defects, cleft lips,[14] limb defects, and urinary tract anomalies.[15] Folate deficiency during pregnancy may also increase the risk of preterm delivery, infant low birth weight and fetal growth retardation, as well as increasing homocysteine level in the blood, which may lead to spontaneous abortion and pregnancy complications, such as placental abruption and pre-eclampsia.[16] Women who could become pregnant are advised to eat foods fortified with folic acid or take supplements in addition to eating folate-rich foods to reduce the risk of serious birth defects.[17] Taking 400 micrograms of synthetic folic acid daily from fortified foods and/or supplements has been suggested. The RDA for folate equivalents for pregnant women is 600–800 micrograms, twice the normal RDA of 400 micrograms for women who are not pregnant.[18] The mechanisms and reasons why folic acid prevents birth defects is unknown.[19] It is hypothesized that the insulin-like growth factor 2 gene is differentially methylated and these changes in IGF2 result in improved intrauterine growth and development.[19] Approximately 85% of women in an urban Irish study reported using folic acid supplements before they become pregnant, but only 18% used enough folic acid supplements to meet the current folic acid requirements due, it is reported, to socio-economic challenges.[20] Folic acid supplements may also protect the fetus against disease when the mother is battling a disease or taking medications or smoking during pregnancy.[21]
Folic acid may also reduce chromosomal defects in sperm.[22] A benefit is indicated even for more than 700 mcg folate per day, which, though below the tolerable upper intake levels of 1,000 µg/day, was 1.8 times the recommended dietary allowance.[22] Folate is necessary for fertility in both men and women. In men, it contributes to spermatogenesis. In women, on the other hand, it contributes to oocyte maturation, implantation, placentation, in addition to the general effects of folic acid and pregnancy. Therefore, it is necessary to receive sufficient amounts through the diet to avoid subfertility.[23] Also, polymorphisms in genes of enzymes involved in folate metabolism could be one reason for fertility complications in some women with unexplained infertility.[24]
Taking folic acid does not reduce cardiovascular disease even though it reduces homocysteine levels.[25]
Folic acid supplements consumed before and during pregnancy may reduce the risk of heart defects in infants,[26] and may reduce the risk for children to develop metabolic syndrome.[27] That may, however, worsen the outcomes in people with cardiovascular disease such as angina and myocardial infarction.[28]
Folic acid appears to reduce the risk of stroke. The reviews indicate the risk of stroke appears to be reduced only in some individuals, but a definite recommendation regarding supplementation beyond the current RDA has not been established for stroke prevention.[29] Observed stroke reduction is consistent with the reduction in pulse pressure produced by folate supplementation of 5 mg per day, since hypertension is a key risk factor for stroke. Folic supplements are inexpensive and relatively safe to use, which is why stroke or hyperhomocysteinemia patients are encouraged to consume daily B vitamins including folic acid.[30]
Many cancer cells have a high requirement for folic acid and overexpress the folic acid receptor. This finding has led to the development of anti-cancer drugs that target the folic acid receptor.[31]
A meta-analysis published in 2010 failed to find a statistically significant cancer risk due to folic acid supplements.[32]
Some investigations have proposed good levels of folic acid may be related to lower risk of esophageal, stomach, and ovarian cancers, but the benefits of folic acid against cancer may depend on when it is taken and on individual conditions. In addition, folic acid may not be helpful, and could even be damaging, in people already suffering from cancer or from a precancerous condition. Likewise, it has been suggested excess folate may promote tumor initiation.[33] Folate has shown to play a dual role in cancer development; low folate intake protects against early carcinogenesis, and high folate intake promotes advanced carcinogenesis.[34] Therefore, public health recommendations should be careful not to encourage too much folate intake.[34]
Diets high in folate are associated with decreased risk of colorectal cancer; some studies show the association is stronger for folate from foods alone than for folate from foods and supplements,[35] Colorectal cancer is the most studied type of cancer in relation to folate and one carbon metabolism. One study concluded that there was not strong support for an association between prostate cancer risk and circulating concentrations of folate or vitamin B12. The researchers noted that while elevated concentrations of vitamin B12 may be associated with an increased risk for advanced stage prostate cancer, that this was not true of folic acid and that the association between B12 and cancer risk required examination in other large prospective studies.[36]
Most epidemiologic studies suggest diets high in folate are associated with decreased risk of breast cancer, but results are not uniformly consistent. One broad cancer screening trial reported a potential harmful effect of much folate intake on breast cancer risk, suggesting routine folate supplementation should not be recommended as a breast cancer preventive,[37] but a 2007 Swedish prospective study found much folate intake was associated with a lower incidence of postmenopausal breast cancer.[38] A 2008 study has shown no significant effect of folic acid on overall risk of total invasive cancer or breast cancer among women.[39] Folate intake may not have any effect on the risk of breast cancer but may have an effect for women who consume at least 15 g/d of alcohol.[40] Folate intake of more than 300 µg/d may reduce the risk of breast cancer in women who consume alcohol.[40]
Most research studies associate high dietary folate intake with a reduced risk of prostate cancer.[36] Recently, a clinical trial showed daily supplementation of 1 mg of folic acid increased the risk of prostate cancer, while dietary and plasma folate levels among vitamin nonusers actually decreased the risk of prostate cancer.[41] A Finnish study consisting of 29,133 older male smokers observed prostate cancer risk had no relationship with serum folate levels.[7]
Folate is important for cells and tissues that rapidly divide.[42] Cancer cells divide rapidly, and drugs that interfere with folate metabolism are used to treat cancer. The antifolate methotrexate is a drug often used to treat cancer because it inhibits the production of the active form of THF from the inactive dihydrofolate (DHF). However, methotrexate can be toxic,[43][44][45] producing side effects, such as inflammation in the digestive tract that make it difficult to eat normally. Also, bone marrow depression (inducing leukopenia and thrombocytopenia), and acute renal and hepatic failure have been reported.
Folinic acid, under the drug name leucovorin,a form of folate (formyl-THF), can help "rescue" or reverse the toxic effects of methotrexate.[46] Folinic acid is not the same as folic acid. Folic acid supplements have little established role in cancer chemotherapy.[47][48] There have been cases of severe adverse effects of accidental substitution of folic acid for folinic acid in patients receiving methotrexate cancer chemotherapy. It is important for anyone receiving methotrexate to follow medical advice on the use of folic or folinic acid supplements. The supplement of folinic acid in patients undergoing methotrexate treatment is to give cells dividing less rapidly enough folate to maintain normal cell functions. The amount of folate given will be depleted by rapidly dividing cells (cancer) very fast and so will not negate the effects of methotrexate.
Some evidence links a shortage of folate with depression.[49] Limited evidence from randomised controlled trials showed using folic acid in addition to antidepressants, to be specific SSRIs, may have benefits.[50] Research at the University of York and Hull York Medical School has found a link between depression and low levels of folate.[51] One study by the same team involved 15,315 subjects.[52] However, the evidence is probably too limited at present for this to be a routine treatment recommendation. Folic acid supplementation affects noradrenaline and serotonin receptors within the brain, which could be the cause of folic acid's possible ability to act as an antidepressant.[53]
Folate deficiency may increase the risk of schizophrenia because, by increasing homocysteine levels, folate also increases interleukin 6 and tumor necrosis factor alpha levels, and these two cytokines are involved in the development of schizophrenia.[54] The exact mechanisms involved in the development of schizophrenia are not entirely clear, but may have something to do with DNA methylation and one carbon metabolism, and these are the precise roles of folate in the body.[55]
A substudy of the Women's Antioxidant and Folic Acid Cardiovascular Study published in 2009 reported use of a nutritional supplement containing folic acid, pyridoxine, and cyanocobalamin decreased the risk of developing age-related macular degeneration by 34.7%.[56]
[edit] B12 deficiency
There has been concern about the interaction between vitamin B12 and folic acid.[57] The National Institutes of Health has found that "Large amounts of folic acid can mask the damaging effects of vitamin B12 deficiency by correcting the megaloblastic anemia caused by vitamin B12 deficiency without correcting the neurological damage that also occurs", there are also indications that "high serum folate levels not only might mask vitamin B12 deficiency but could also exacerbate the anemia and worsen the cognitive symptoms associated with vitamin B12 deficiency".[58] Due to the fact that in the United States legislation has required enriched flour to contain folic acid to reduce cases of fetal neural-tube defects consumers may be ingesting more than they realize.[59] To counter the masking effect of B12 deficency the NIH recommends "folic acid intake from fortified food and supplements should not exceed 1,000 micrograms (1000 µg = 1 mg) daily in healthy adults."[58]
In fact, to date the evidence such masking actually occurs is scarce, and there is no evidence folic acid fortification in Canada or the U.S. has increased the prevalence of vitamin B12 deficiency or its consequences.[60] However, one recent study has demonstrated high folic acid or folate levels, when combined with low B12 levels, are associated with significant cognitive impairment among the elderly.[61]
In any case, it is important for older adults to be aware of the relationship between folic acid and vitamin B12, because they are at greater risk of having a B12 deficiency. For this reason, a physician may wish to check the vitamin B12 status of patients 50 years of age or older before prescribing them a supplement that contains folic acid.[62]
The risk of toxicity from folic acid is low, because folate is a water-soluble vitamin and is regularly removed from the body through urine.[63] The Institute of Medicine has established a tolerable upper intake level (UL) for folate of 1 mg for adult men and women, and a UL of 800 µg for pregnant and lactating (breast-feeding) women less than 18 years of age. Supplemental folic acid should not exceed the UL to prevent folic acid from masking symptoms of vitamin B12 deficiency.[64] There is growing concern worldwide that prenatal high folic acid in the presence of low vitamin b12 causes epigenetic changes in the unborn predisposing them to metabolic syndromes, central adiposity and adult diseases such as Type 2 diabetes [1]. Another active area of research and concern is that excess folic acid in utero causes epigenetic changes to the brain leading to autism spectrum disorders. http://www.ncbi.nlm.nih.gov/pubmed/21454018
Folate deficiency may lead to glossitis, diarrhea, depression, confusion, anemia, and fetal neural tube defects and brain defects (during pregnancy).[65] Folate deficiency is accelerated by alcohol consumption[66] Folate deficiency is diagnosed by analyzing CBC and plasma vitamin B12 and folate levels.[65] CBC may indicate megaloblastic anemia but this could also be a sign of vitamin B12 deficiency.[65] A serum folate of 3 μg/L or lower indicates deficiency.[65] Serum folate level reflects folate status but erythrocyte folate level better reflects tissue stores after intake.[65] An erythrocyte folate level of 140 μg/L or lower indicates inadequate folate status.[65] Increased homocysteine level suggests tissue folate deficiency but homocysteine is also affected by vitamin B12 and vitamin B6, renal function, and genetics.[65] One way to differentiate between folate deficiency from vitamin B12 deficiency is by testing for methylmalonic acid levels.[65] Normal MMA levels indicate folate deficiency and elevated MMA levels indicate vitamin B12 deficiency.[65] Folate deficiency is treated with supplemental oral folate of 400 to 1000 μg per day.[65] This treatment is very successful in replenishing tissues, even if deficiency was caused by malabsorption.[65] Patients with megaloblastic anemia need to be tested for vitamin B12 deficiency before folate treatment, because if the patient has vitamin B12 deficiency, folate supplementation can remove the anemia, but can also worsen neurologic problems.[65] Morbidly obese patients with BMIs of greater than 50 are more likely to develop folate deficiency.[67] Patients with celiac disease have a higher chance of developing folate deficiency.[67] Cobalamin deficiency may lead to folate deficiency, which, in turn, increases homocysteine levels and may result in the development of cardiovascular disease or birth defects.[68]
Some studies show iron-folic acid supplementation in children under 5 may result in increased mortality due to malaria; this has prompted the World Health Organization to alter their iron-folic acid supplementation policies for children in malaria-prone areas, such as India.[69]
Because of the difference in bioavailability between supplemented folic acid and the different forms of folate found in food, the dietary folate equivalent (DFE) system was established. One DFE is defined as 1 μg (microgram) of dietary folate, or 0.6 μg of folic acid supplement.
National Institutes of Health Nutritional Requirements[70] (µg per day)
| Age |
Infants (RDI) |
Infants (UL) |
Adults (RDI) |
Adults (UL) |
Pregnant women (RDI) |
Pregnant women (UL) |
Lactating women (RDI) |
Lactating women (UL) |
| 0–6 months |
65 |
None set |
– |
– |
– |
– |
– |
– |
| 7–12 months |
80 |
None set |
– |
– |
– |
– |
– |
– |
| 1–3 years |
– |
– |
150 |
300 |
– |
– |
– |
– |
| 4–8 years |
– |
– |
200 |
400 |
– |
– |
– |
– |
| 9–13 years |
– |
– |
300 |
600 |
– |
– |
– |
– |
| 14–18 |
– |
– |
400 |
800 |
600 |
800 |
500 |
800 |
| 19+ |
– |
– |
400 |
1000 |
600 |
1000 |
500 |
1000 |
The Dietary Reference Intake (DRIs) were developed by the United States National Academy of Sciences to set reference values for planning and assessing nutrient intake for healthy people. DRIs incorporate two reference values, the Reference Daily Intake (RDI, the daily intake level that is adequate for 97–98% of the population in the United States where the standards were set) and tolerable upper intake levels (UL, the highest level of intake that is known to avoid toxicity). The UL for folate refers to only synthetic folate, as no health risks have been associated with high intake of folate from food sources.[70]
Certain foods are very high in folate:
Moderate amounts:
- Certain fruits (orange juice, canned pineapple juice, cantaloupe, honeydew melon, grapefruit juice, banana, raspberry, grapefruit and strawberry) and vegetables (beets, corn, tomato juice, vegetable juice, broccoli, brussels sprouts, romaine lettuce and bok choy),[72] beer.[73]
A table of selected food sources of folate and folic acid can be found at the USDA National Nutrient Database for Standard Reference.[74] Folic acid is added to grain products in many countries, and, in these countries, fortified products make up a significant source of the population's folic acid intake.[75] Because of the difference in bioavailability between supplemented folic acid and the different forms of folate found in food, the dietary folate equivalent (DFE) system was established. 1 DFE is defined as 1 μg of dietary folate, or 0.6 μg of folic acid supplement. This is reduced to 0.5 μg of folic acid if the supplement is taken on an empty stomach.[76]
Folate naturally found in food is susceptible to high heat and ultraviolet light, and is soluble in water.[77] It is heat-labile in acidic environments and may also be subject to oxidation.[77]
Some meal replacement products do not meet the folate requirements as specified by the RDAs.[78]
In the 1920s, scientists believed folate deficiency and anemia were the same condition.[79] A key observation by researcher Lucy Wills in 1931 led to the identification of folate as the nutrient needed to prevent anemia during pregnancy. Dr. Wills demonstrated anemia could be reversed with brewer's yeast. Folate was identified as the corrective substance in brewer's yeast in the late 1930s, and was first isolated in and extracted from spinach leaves by Mitchell and others in 1941.[80] Bob Stokstad isolated the pure crystalline form in 1943, and was able to determine its chemical structure while working at the Lederle Laboratories of the American Cyanamid Company.[81] This historical research project, of obtaining folic acid in a pure crystalline form in 1945, was done by the team called the "folic acid boys," under the supervision and guidance of Director of Research Dr. Yellapragada Subbarao, at the Lederle Lab, Pearl River, NY.[82] This research subsequently led to the synthesis of the antifolate aminopterin, the first-ever anticancer drug, the clinical efficacy was proven by Sidney Farber in 1948. In the 1950s and 1960s, scientists began to discover the biochemical mechanisms of action for folate.[79] In 1960, experts first linked folate deficiency to neural tube defects.[79] In the late 1990s, US scientists realized, despite the availability of folate in foods and in supplements, there was still a challenge for people to meet their daily folate requirements, which is when the US implemented the folate fortification program.[79]
A diagram of the chemical structure of folate
Folate is necessary for the production and maintenance of new cells, for DNA synthesis and RNA synthesis, and for preventing changes to DNA, and, thus, for preventing cancer.[42] It is especially important during periods of rapid cell division and growth, such as infancy and pregnancy. Folate is needed to carry one-carbon groups for methylation reactions and nucleic acid synthesis (the most notable one being thymine, but also purine bases).[41] Thus, folate deficiency hinders DNA synthesis and cell division, affecting hematopoietic cells and neoplasms the most because of rapid cell division. RNA transcription, and subsequent protein synthesis, are less affected by folate deficiency, as the mRNA can be recycled and used again (as opposed to DNA synthesis, where a new genomic copy must be created). Since folate deficiency limits cell division, erythropoiesis, production of red blood cells, is hindered and leads to megaloblastic anemia, which is characterized by large immature red blood cells. This pathology results from persistently thwarted attempts at normal DNA replication, DNA repair, and cell division, and produces abnormally large red cells called megaloblasts (and hypersegmented neutrophils) with abundant cytoplasm capable of RNA and protein synthesis, but with clumping and fragmentation of nuclear chromatin. Some of these large cells, although immature (reticulocytes), are released early from the marrow in an attempt to compensate for the anemia.[83] Both adults and children need folate to make normal red and white blood cells and prevent anemia.[84] Deficiency of folate in pregnant women has been implicated in neural tube defects (NTD); therefore, many developed countries have implemented mandatory folic acid fortification in cereals, etc. It must be noted that NTDs occur early in pregnancy (first month), therefore women must have abundant folate upon conception. Folate is required to make red blood cells and white blood cells and folate deficiency may lead to anemia, which further leads to fatigue and weakness and inability to concentrate.[85]
Metabolism of folic acid to produce methyl-vitamin B
12
In the form of a series of tetrahydrofolate (THF) compounds, folate derivatives are substrates in a number of single-carbon-transfer reactions, and also are involved in the synthesis of dTMP (2′-deoxythymidine-5′-phosphate) from dUMP (2′-deoxyuridine-5′-phosphate). It is a substrate for an important reaction that involves vitamin B12 and it is necessary for the synthesis of DNA, and so required for all dividing cells.[86]
The pathway leading to the formation of tetrahydrofolate (FH4) begins when folate (F) is reduced to dihydrofolate (DHF) (FH2), which is then reduced to THF. Dihydrofolate reductase catalyses the last step.[87] Vitamin B3 in the form of NADPH is a necessary cofactor for both steps of the synthesis.
Methylene-THF (CH2FH4) is formed from THF by the addition of methylene groups from one of three carbon donors: formaldehyde, serine, or glycine. Methyl tetrahydrofolate (CH3-THF) can be made from methylene-THF by reduction of the methylene group with NADPH. It is important to note that Vitamin B12 is the only acceptor of methyl-THF. There is also only one acceptor for methyl-B12, which is homocysteine in a reaction catalyzed by homocysteine methyltransferase. This is important because a defect in homocysteine methyltransferase or a deficiency of B12 can lead to a methyl-trap of THF and a subsequent deficiency.[81] Thus, a deficiency in B12 can generate a large pool of methyl-THF that is unable to undergo reactions and will mimic folate deficiency. Another form of THF, formyl-THF or folinic acid, results from oxidation of methylene-THF or is formed from formate donating formyl group to THF. Also, histidine can donate a single carbon to THF to form methenyl-THF.
In other words:
- folate → dihydrofolate → tetrahydrofolate ↔ methylene-THF → methyl-THF
All the biological functions of folic acid are performed by tetrahydrofolate and other derivatives. Their biological availability to the body depends upon dihydrofolate reductase action in the liver. This action is unusually slow in humans, being less than 2% of that in rats. Moreover, in contrast to rats, an almost-5-fold variation in the activity of this enzyme exists between humans.[6] Due to this low activity, it has been suggested this limits the conversion of folic acid into its biologically active forms "when folic acid is consumed at levels higher than the Tolerable Upper Intake Level (1 mg/d for adults)."[6]
A number of drugs interfere with the biosynthesis of folic acid and THF. Among them are the dihydrofolate reductase inhibitors such as trimethoprim, pyrimethamine, and methotrexate; the sulfonamides (competitive inhibitors of 4-aminobenzoic acid in the reactions of dihydropteroate synthetase).
Valproic acid, one of the most commonly prescribed anticonvulsants that is also used to treat certain psychological conditions, is a known inhibitor of folic acid, and as such, has been shown to cause neural tube defects and cases of spina bifida and cognitive impairment in the newborn. Because of this considerable risk, those mothers who must continue to use valproic acid or its derivatives during pregnancy to control their condition (as opposed to stopping the drug or switching to another drug or to a lesser dose) should take folic acid supplements under the direction and guidance of their health care providers.
The National Health and Nutrition Examination Survey (NHANES III 1988–91) and the Continuing Survey of Food Intakes by Individuals (1994–96 CSFII) indicated most adults did not consume adequate folate.[88][89] However, the folic acid fortification program in the United States has increased folic acid content of commonly eaten foods such as cereals and grains, and as a result, diets of most adults now provide recommended amounts of folate equivalents.[90]
In the USA many grain products are fortified with folic acid.
Since the discovery of the link between insufficient folic acid and neural tube defects, governments and health organizations worldwide have made recommendations concerning folic acid supplementation for women intending to become pregnant.
This has led to the introduction in many countries of fortification, where folic acid is added to flour with the intention of benefiting all from the associated rise in blood folate levels. This is controversial, with issues having been raised concerning individual liberty[citation needed], and the masking effect of folate fortification on pernicious anaemia (vitamin B12 deficiency). However, several western countries now fortify their flour, along with a number of Middle Eastern countries and Indonesia. Mongolia and a number of former Soviet republics are among those having widespread voluntary fortification; about five more countries (including Morocco, the first African country) have agreed, but not yet implemented, fortification. To date, no EU country has yet mandated fortification.[91]
Folates can be produced by engineering Lactococcus lactis strains using a rodent depletion-repletion bioassay, and the bioavailabilities of these folates are comparable with those of commercial folic acid currently being used for food fortification.[92] These engineered folates can potentially help alleviate the effects of folate deficiency in the diet.[92] Hematologic studies show an improvement in megaloblastic anemia after the addition of L. lactis strains; this again suggests lactic acid bacteria can potentially reverse some of the harm done by folate deficiency by acting as an essential, bioavailable vitamin.[92]
A study has shown folate fortification will substantially increase in folate status, in particular, for the elderly. In the study group, the subjects that did not use vitamin supplements had increased folate concentrations of 4.6 ng/mL to 10.0 ng/mL (11 to 23 nmol/L) (P<0.001) from the base-line visit to the follow-up visit. The prevalence of low folate concentrations (<3 ng/mL [7 nmol/L]) decreased from 22.0% to 1.7% (P< 0.001). The mean total homocysteine concentration has decreased from a value of 10.1 µmol/L to 9.4 µmol/L during this period (P<0.001), while the prevalence of high homocysteine concentrations (>13 µmol/L) has been reduced from 18.7% to 9.8% (P<0.001). To further clarify the study methods, there were no statistically significant changes in concentrations of folate or homocysteine for the control group.[93]
There has been previous debate in Australia regarding the inclusion of folic acid in products such as bread and flour.[94]
Australia and New Zealand have jointly agreed to fortification though the Food Standards Australia New Zealand. Australia will fortify all flour from 18 September 2009.[95] Although the food standard covers both Australia and New Zealand, an Australian government official has stated it is up to New Zealand to decide whether to implement it there, and they will watch with interest.[96]
The requirement is 0.135 mg of folate per 100g of bread.
In 2003, a Hospital for Sick Children, University of Toronto research group published findings showing the fortification of flour with folic acid in Canada has resulted in a dramatic decrease in neuroblastoma, an early and very dangerous cancer in young children.[97] In 2009, further evidence from McGill University showed a 6.2% decrease per year in the birth prevalence of severe congenital heart defects.[98]
Folic acid used in fortified foods is a synthetic form called pteroylmonoglutamate.[99] It is in its oxidized state and contains only one conjugated glutamate residue.[99] Folic acid therefore enters via a different carrier system from naturally occurring folate, and this may have different effects on folate binding proteins and its transporters.[100] Folic acid has a higher bioavailability than natural folates and are rapidly absorbed across the intestine,[99] therefore it is important to consider the Dietary Folate Equivalent (DFE) when calculating one's intake. Natural occurring folate is equal to 1 DFE, however 0.6 µg of folic acid is equal to 1 DFE.
Folic acid food fortification became mandatory in Canada in 1998, with the fortification of 150 µg of folic acid per 100 grams of enriched flour and uncooked cereal grains.[101] The purpose of fortification was to decrease the risk of neural tube defects in newborns.[101] It is important to fortify grains because it is a widely eaten food and the neural tube closes in the first four weeks of gestation, often before many women even know they are pregnant. Canada's fortification program has been successful with a decrease of neural tube defects by 19% since its introduction.[102] A seven-province study from 1993 to 2002 showed a reduction of 46% in the overall rate of neural tube defects after folic acid fortification was introduced in Canada.[103] The fortification program was estimated to raise a person’s folic acid intake level by 70–130 µg/day, however an increase of almost double that amount was actually observed.[102] This could be from the fact that many foods are over fortified by 160–175% the predicted value.[102] In addition, much of the elder population take supplements that adds 400 µg to their daily folic acid intake. This is a concern because 70–80% of the population have detectable levels of unmetabolized folic acid in their blood and high intakes can accelerate the growth of preneoplasmic lesions.[104] It is still unknown the amount of folic acid supplementation that might cause harm.[101]
According to a Canadian survey, 58% of women said they took a folic acid containing multivitamin or a folic acid supplement as early as three months before becoming pregnant. Women in higher income households and with more years of school education are using more folic acid supplements before pregnancy. Women with planned pregnancies and who are over the age of 25 are more likely to use folic acid supplement Canadian public health efforts are focused on promoting awareness of the importance of folic acid supplementation for all women of childbearing age and decreasing socio-economic inequalities by providing practical folic acid support to vulnerable groups of women.[103]
New Zealand was planning to fortify bread (excluding organic and unleavened varieties) from 18 September 2009, but has opted to wait until more research is done.[95]
The Association of Bakers [105] and the Green Party [106] have opposed mandatory fortification, describing it as "mass medication". Food Safety Minister Kate Wilkinson reviewed the decision to fortify in July 2009, citing links between overconsumption of folate with cancer .[107] The New Zealand Government is reviewing whether it will continue with the mandatory introduction of folic acid to bread.[108]
There has been previous debate in the United Kingdom regarding the inclusion of folic acid in products such as bread and flour.[109]
The Food Standards Agency has recommended fortification.[110][111][112]
The United States Public Health Service recommends an extra 0.4 mg/day for newly pregnant women, which can be taken as a pill. However, many researchers believe supplementation in this way can never work effectively enough, since about half of all pregnancies in the U.S. are unplanned, and not all women will comply with the recommendation. Approximately 53% of the US population uses dietary supplements and 35% uses dietary supplements containing folic acid.[113] Men consume more folate (in dietary folate equivalents) than women, and non-Hispanic whites have higher folate intakes than Mexican Americans and non-Hispanic blacks.[113] Twenty nine percent of black women have inadequate intakes of folate.[113] The age group consuming the most folate and folic acid is the >50 group.[113] Only 5% of the population exceeds the Tolerable Upper Intake Level.[113]
In 1996, the United States Food and Drug Administration (FDA) published regulations requiring the addition of folic acid to enriched breads, cereals, flours, corn meals, pastas, rice, and other grain products.[114][115] This ruling took effect on January 1, 1998, and was specifically targeted to reduce the risk of neural tube birth defects in newborns.[116] There are concerns that the amount of folate added is insufficient .[117] In October 2006, the Australian press claimed that U.S. regulations requiring fortification of grain products were being interpreted as disallowing fortification in non-grain products, specifically Vegemite (an Australian yeast extract containing folate). The FDA later said the report was inaccurate, and no ban or other action was being taken against Vegemite.[118]
As a result of the folic acid fortification program, fortified foods have become a major source of folic acid in the American diet. The Centers for Disease Control and Prevention in Atlanta, Georgia used data from 23 birth defect registries covering about half of United States births, and extrapolated their findings to the rest of the country. These data indicate since the addition of folic acid in grain-based foods as mandated by the FDA, the rate of neural tube defects dropped by 25% in the United States.[119] The results of folic acid fortification on the rate of neural tube defects in Canada have also been positive, showing a 46% reduction in prevalence of NTDs;[120] the magnitude of reduction was proportional to the prefortification rate of NTDs, essentially removing geographical variations in rates of NTDs seen in Canada before fortification.
When the U.S. Food and Drug Administration set the folic acid fortification regulation in 1996, the projected increase in folic acid intake was 100 µg/d.[121] Data from a study with 1480 subjects showed that folic acid intake increased by 190 µg/d and total folate intake increased by 323 µg dietary folate equivalents (DFE)/d.[121] Folic acid intake above the upper tolerable intake level (1000 µg folic acid/d) increased only among those individuals consuming folic acid supplements as well as folic acid found in fortified grain products.[121] Taken together, folic acid fortification has led to a bigger increase in folic acid intake than first projected.[121]
- ^ a b Folic acid in the ChemIDplus database
- ^ R. M. C. Dawson: Data for Biochemical Research, Oxford University Press, Oxford, 1989, 3rd Edition, p. 134, ISBN 0-19-855299-8.
- ^ Ural, Serdar H. (2008-11). "Folic Acid and Pregnancy.". Kid's Health. http://kidshealth.org/parent/pregnancy_newborn/pregnancy/folic_acid.html.
- ^ http://medical-dictionary.thefreedictionary.com/vitamin+Bc
- ^ [Mayo Clinic Web Editors . Folate. http://www.mayoclinic.com/health/folate/NS_patient-folate/DSECTION=synonyms (accessed Nov 15, 2010).],additional text.
- ^ a b c Bailey SW, Ayling JE (September 2009). "The extremely slow and variable activity of dihydrofolate reductase in human liver and its implications for high folic acid intake". Proceedings of the National Academy of Sciences of the United States of America 106 (36): 15424–9. DOI:10.1073/pnas.0902072106. PMC 2730961. PMID 19706381. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2730961.
- ^ a b c d Weinstein, SJ et al. (2003). "Null Association Between Prostate Cancer and Serum Folate, Vitamin B6, Vitamin B12, and Homocysteine" (PDF). Cancer Epidemiology, Biomarkers, & Prevention 12 (11): 1271–1272. http://cebp.aacrjournals.org/content/12/11/1271.full.pdf. Retrieved 1 December 2010.
- ^ "Dietary Supplement Fact Sheet: Folate.". Office of Dietary Supplements, National Institutes of Health. http://ods.od.nih.gov/factsheets/folate.asp.
- ^ Gentili et al, 2009, Folic Acid Deficiency http://emedicine.medscape.com/article/200184-overview
- ^ National Health Service U.K., "Anaemia, vitamin B12 or folate deficiency – Causes" http://www.nhs.uk/Conditions/Anaemia-vitamin-B12-and-folate-deficiency/Pages/Causes.aspx
- ^ Shaw GM, Schaffer D, Velie EM, Morland K, Harris JA (1995). "Periconceptional vitamin use, dietary folate, and the occurrence of neural tube defects". Epidemiology 6 (3): 219–226. DOI:10.1097/00001648-199505000-00005. PMID 7619926.
- ^ Mulinare J, Cordero JF, Erickson JD, Berry RJ (1988). "Periconceptional use of multivitamins and the occurrence of neural tube defects". Journal of the American Medical Association 260 (21): 3141–3145. DOI:10.1001/jama.260.21.3141. PMID 3184392.
- ^ Milunsky A, Jick H, Jick SS, Bruell CL, MacLaughlin DS, Rothman KJ, Willett W (1989). "Multivitamin/folic acid supplementation in early pregnancy reduces the prevalence of neural tube defects". Journal of the American Medical Association 262 (20): 2847–2852. DOI:10.1001/jama.262.20.2847. PMID 2478730. http://www.sjsu.edu/faculty/gerstman/eks/Milunsky1989.pdf.
- ^ Wilcox, AJ; Lie, RT; Solvoll, K; Taylor, J; McConnaughey, DR; Abyholm, F; Vindenes, H; Vollset, SE et al. (2007). "Folic acid supplements and risk of facial clefts: national population based case-control study". BMJ (Clinical research ed.) 334 (7591): 464. DOI:10.1136/bmj.39079.618287.0B. PMC 1808175. PMID 17259187. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1808175.
- ^ Goh, YI; Koren, G (2008). "Folic acid in pregnancy and fetal outcomes". J. Obstet. Gynaecol 28 (1): 3–13. DOI:10.1080/01443610701814195. PMID 18259891.
- ^ Scholl, TO; Johnson, WG (2000). "Folic acid: influence on the outcome of pregnancy". The American journal of clinical nutrition 71 (5 Suppl): 1295S–1303S. PMID 10799405.
- ^ Wilton, DC; Foureur, MJ (2010). "A survey of folic acid use in primigravid women". Women and birth : journal of the Australian College of Midwives 23 (2): 67–73. DOI:10.1016/j.wombi.2009.09.001. PMID 19828392.
- ^ Health Professionals Recommendations, Folic Acid, NCBDDD, CDC
- ^ a b Steegers-Theunissen, RP; Obermann-Borst, SA; Kremer, D; Lindemans, J; Siebel, C; Steegers, EA; Slagboom, PE; Heijmans, BT et al. (2009). Zhang, Cuilin. ed. "Periconceptional Maternal Folic Acid Use of 400 µg per Day Is Related to Increased Methylation of the IGF2 Gene in the Very Young Child". PLoS ONE 4 (11): e7845. DOI:10.1371/journal.pone.0007845. PMC 2773848. PMID 19924280. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2773848.
- ^ McGuire, M; Cleary, B; Sahm, L; Murphy, DJ (2010). "Prevalence and predictors of periconceptional folic acid uptake—prospective cohort study in an Irish urban obstetric population". Human reproduction (Oxford, England) 25 (2): 535–43. DOI:10.1093/humrep/dep398. PMID 19910320.
- ^ Jia, ZL; Li, Y; Chen, CH; Li, S; Wang, Y; Zheng, Q; Shi, B (2010). "Association among polymorphisms at MYH9, environmental factors, and nonsyndromic orofacial clefts in western China". DNA and cell biology 29 (1): 25–32. DOI:10.1089/dna.2009.0935. PMID 19891592.
- ^ a b Young, SS; Eskenazi, B; Marchetti, FM; Block, G; Wyrobek, AJ (2008). "The association of folate, zinc and antioxidant intake with sperm aneuploidy in healthy non-smoking men". Human reproduction (Oxford, England) 23 (5): 1–9. DOI:10.1093/humrep/den036. PMID 18353905. http://www.medpagetoday.com/upload/2008/3/21/den036v1.pdf. Lay summary.
- ^ Ebisch IM, Thomas CM, Peters WH, Braat DD, Steegers-Theunissen RP (2007). "The importance of folate, zinc and antioxidants in the pathogenesis and prevention of subfertility". Hum Reprod Update 13 (2): 163–74. DOI:10.1093/humupd/dml054. PMID 17099205.
- ^ Altmäe, S.; Stavreus-Evers, A.; Ruiz, J.; Laanpere, M.; Syvänen, T.; Yngve, A.; Salumets, A.; Nilsson, T. (2010). "Variations in folate pathway genes are associated with unexplained female infertility". Fertility and Sterility 94 (1): 130–137. DOI:10.1016/j.fertnstert.2009.02.025. PMID 19324355. edit
- ^ Bazzano, LA (2011 Aug). "No effect of folic acid supplementation on cardiovascular events, cancer or mortality after 5 years in people at increased cardiovascular risk, although homocysteine levels are reduced". Evidence-based medicine 16 (4): 117–8. DOI:10.1136/ebm1204. PMID 21402567.
- ^ Bazzano, LA (2009). "Folic acid supplementation and cardiovascular disease: the state of the art". The American journal of the medical sciences 338 (1): 48–9. DOI:10.1097/MAJ.0b013e3181aaefd6. PMID 19593104.
- ^ Stewart, CP; Christian, P; Schulze, KJ; Leclerq, SC; West Jr, KP; Khatry, SK (2009). "Antenatal micronutrient supplementation reduces metabolic syndrome in 6- to 8-year-old children in rural Nepal". The Journal of nutrition 139 (8): 1575–81. DOI:10.3945/jn.109.106666. PMID 19549749.
- ^ Imasa, MS; Gomez, NT; Nevado Jr, JB (2009). "Folic acid-based intervention in non-ST elevation acute coronary syndromes". Asian cardiovascular & thoracic annals 17 (1): 13–21. DOI:10.1177/0218492309102494. PMID 19515873.
- ^ "Folic acid 'reduces stroke risks'". BBC News (London). 31 May 2007. http://news.bbc.co.uk/1/hi/health/6709101.stm.
- ^ Terwecoren, A; Steen, E; Benoit, D; Boon, P; Hemelsoet, D (2009). "Ischemic stroke and hyperhomocysteinemia: truth or myth?". Acta neurologica Belgica 109 (3): 181–8. PMID 19902811.
- ^ Leamon CP, Low PS (July 1991). "Delivery of macromolecules into living cells: a method that exploits folate receptor endocytosis". Proc. Natl. Acad. Sci. U.S.A. 88 (13): 5572–6. DOI:10.1073/pnas.88.13.5572. PMC 51919. PMID 2062838. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=51919.
- ^ Clarke R et. al. (2010). "Effects of Lowering Homocysteine Levels With B Vitamins on Cardiovascular Disease, Cancer, and Cause-Specific Mortality Meta-analysis of 8 Randomized Trials Involving 37 485 Individuals". Archives of Internal Medicine 170 (18): 1622–1631. DOI:10.1001/archinternmed.2010.348. PMID 20937919.
- ^ Kim YI (1 November 2004). "Will mandatory folic acid fortification prevent or promote cancer?". Am J Clin Nutr 80 (5): 1123–8. PMID 15531657. http://www.ajcn.org/cgi/content/full/80/5/1123.
- ^ a b Ulrich, CM (2007). "Folate and cancer prevention: a closer look at a complex picture". The American journal of clinical nutrition 86 (2): 271–273. PMID 17684194.
- ^ Sanjoaquin MA, Allen N, Couto E, Roddam AW, Key TJ (2005). "Folate intake and colorectal cancer risk: a meta-analytical approach". Int J Cancer 113 (5): 825–8. DOI:10.1002/ijc.20648. PMID 15499620.
- ^ a b Johansson, M; Appleby, PN; Allen, NE; Travis, RC; Roddam, AW; Egevad, L; Jenab, M; Rinaldi, S et al. (2008). "Circulating concentrations of folate and vitamin B12 in relation to prostate cancer risk: results from the European Prospective Investigation into Cancer and Nutrition study". Cancer Epidemiology, Biomarkers & Prevention 17 (2): 279–85. DOI:10.1158/1055-9965.EPI-07-0657. PMID 18268110.
- ^ Kim YI (2006). "Does a high folate intake increase the risk of breast cancer?". Nutr Rev 64 (10 Pt 1): 468–75. DOI:10.1301/nr.2006.oct.468-475. PMID 17063929.
- ^ Ericson U, Sonestedt E, Gullberg B, Olsson H, Wirfält E (2007). "High folate intake is associated with lower breast cancer incidence in postmenopausal women in the Malmö Diet and Cancer cohort". Am J Clin Nutr 86 (2): 434–43. PMID 17684216.
- ^ Zhang SM, Cook NR, Albert CM, Gaziano JM, Buring JE, Manson JE (November 2008). "Effect of Combined Folic Acid, Vitamin B6, and Vitamin B12 on Cancer Risk: Results from a Randomized Trial". JAMA 300 (17): 2012–21. DOI:10.1001/jama.2008.555. PMC 2593624. PMID 18984888. http://jama.ama-assn.org/cgi/content/short/300/17/2012.
- ^ a b Zhang, S; Hunter, DJ; Hankinson, SE; Giovannucci, EL; Rosner, BA; Colditz, GA; Speizer, FE; Willett, WC (1999). "A Prospective Study of Folate Intake and the Risk of Breast Cancer". JAMA 281 (17): 1632–1637. DOI:10.1001/jama.281.17.1632. PMID 10235158.
- ^ a b Figueiredo, JC; Grau, MV; Haile, RW; Sandler, RS; Summers, RW; Bresalier, RS; Burke, CA; McKeown-Eyssen, GE et al. (2009). "Folic Acid and Risk of Prostate Cancer: Results From a Randomized Clinical Trial". Journal of the National Cancer Institute 101 (6): 432–5. DOI:10.1093/jnci/djp019. PMC 2657096. PMID 19276452. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2657096.
- ^ a b Kamen B (1997). "Folate and antifolate pharmacology". Seminars in oncology 24 (5 Suppl 18): S18–30–9. PMID 9420019.
- ^ Rubio IT, Cao Y, Hutchins LF, Westbrook KC, Klimberg VS (1998). "Effect of glutamine on methotrexate efficacy and toxicity". Annals of Surgery 227 (5): 772–8. DOI:10.1097/00000658-199805000-00018. PMC 1191365. PMID 9605669. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1191365.
- ^ Wolff JE, Hauch H, Kuhl J, Egeler RM, Jurgens H (1998). "Dexamethasone increases hepatotoxicity of MTX in children with brain tumors". Anticancer Research 18 (4B): 2895–9. PMID 9713483.
- ^ Kepka L, De Lassence A, Ribrag V, Gachot B, Blot F, Theodore C, Bonnay M, Korenbaum C, Nitenberg G (1998). "Successful rescue in a patient with high dose methotrexate-induced nephrotoxicity and acute renal failure". Leukemia & Lymphoma 29 (1–2): 205–9. DOI:10.3109/10428199809058397. PMID 9638991.
- ^ Branda RF, Nigels E, Lafayette AR, Hacker M. (1998). "Nutritional folate status influences the efficacy and toxicity of chemotherapy in rats". Blood 92 (7): 2471–6. PMID 9746787.
- ^ Shiroky JB; Frcp(c) (1997). "The use of folates concomitantly with low-dose pulse methotrexate". Rheumatic Diseases Clinics of North America 23 (4): 969–80. DOI:10.1016/S0889-857X(05)70369-0. PMID 9361164.
- ^ Keshava C, Keshava N, Whong WZ, Nath J, Ong TM (1998). "Inhibition of methotrexate-induced chromosomal damage by folinic acid in V79 cells". Mutation Research 397 (2): 221–8. DOI:10.1016/S0027-5107(97)00216-9. PMID 9541646.
- ^ Coppen A, Bolander-Gouaille C. (2005). "Treatment of depression: time to consider folic acid and vitamin B12". Journal of Psychopharmacology 19 (1): 59–65. DOI:10.1177/0269881105048899. PMID 15671130.
- ^ Taylor MJ, Carney SM, Goodwin GM, Geddes JR. (2004). "Folate for depressive disorders: systematic review and meta-analysis of randomized controlled trials". Journal of Psychopharmacology 18 (2): 251–6. DOI:10.1177/0269881104042630. PMID 15260915.
- ^ Gilbody S, Lewis S, Lightfoot T (January 2007). "Methylenetetrahydrofolate reductase (MTHFR) genetic polymorphisms and psychiatric disorders: a HuGE review". American Journal of Epidemiology 165 (1): 1–13. DOI:10.1093/aje/kwj347. PMID 17074966. http://aje.oxfordjournals.org/cgi/content/full/165/1/1.
- ^ Gilbody S, Lightfoot T, Sheldon T (July 2007). "Is low folate a risk factor for depression? A meta‐analysis and exploration of heterogeneity". Journal of Epidemiology and Community Health 61 (7): 631–637. DOI:10.1136/jech.2006.050385. PMC 2465760. PMID 17568057. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2465760.
- ^ Gaweesh S, Ewies AA. Med Hypotheses. 2009 Sep 29. Folic acid supplementation cures hot flushes in postmenopausal women.
- ^ García-Miss Mdel, R; Pérez-Mutul, J; López-Canul, B; Solís-Rodríguez, F; Puga-Machado, L; Oxté-Cabrera, A; Gurubel-Maldonado, J; Arankowsky-Sandoval, G (2010). "Folate, homocysteine, interleukin-6, and tumor necrosis factor alfa levels, but not the methylenetetrahydrofolate reductase C677T polymorphism, are risk factors for schizophrenia". Journal of Psychiatric Research 44 (7): 441–6. DOI:10.1016/j.jpsychires.2009.10.011. PMID 19939410.
- ^ Krebs, MO; Bellon, A; Mainguy, G; Jay, TM; Frieling, H (2009). "One-carbon metabolism and schizophrenia: current challenges and future directions". Trends in molecular medicine 15 (12): 562–70. DOI:10.1016/j.molmed.2009.10.001. PMID 19896901.
- ^ Christen WG, Glynn RJ, Chew EY, Albert CM, Manson JE (2009). "Folic Acid, Vitamin B6, and Vitamin B12 in Combination and Age-related Macular Degeneration in a Randomized Trial of Women". Arch Intern Med 169 (4): 335–41. DOI:10.1001/archinternmed.2008.574. PMC 2648137. PMID 19237716. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2648137.
- ^ Scott JM (1999 May). "Folate and vitamin B12". Proc Nutr Soc. 58 (2): 441–8. PMID 10466189.
- ^ a b "Dietary Supplement Fact Sheet:Vitamin B12". National Institutes of Health. http://ods.od.nih.gov/factsheets/vitaminb12/.
- ^ Melinda Beck (January 18, 2011). "Sluggish? Confused? Vitamin B12 May Be Low". Wall Street Journal. http://online.wsj.com/article/SB10001424052748703396604576087890340653656.html.
- ^ Mills JL, Von Kohorn I, Conley MR, Zeller JA, Cox C, Williamson RE, Dufour DR (2003 June). "Low vitamin B12 concentrations in patients without anemia: the effect of folic acid fortification of grain". Am J Clin Nutr. 77 (6): 1474–7. PMID 12791626.
- ^ Morris MS, Jacques PF, Rosenberg IH, Selhub J (1 January 2007). "Folate and vitamin B-12 status in relation to anemia, macrocytosis, and cognitive impairment in older Americans in the age of folic acid fortification". Am J Clin Nutr. 85 (1): 193–200. PMC 1828842. PMID 17209196. http://www.ajcn.org/cgi/pmidlookup?view=long&pmid=17209196.
- ^ "Folic acid 'heart boost for elderly'". BBC News. 6 March 2002. http://news.bbc.co.uk/1/hi/health/1856060.stm. Retrieved 2 May 2010.
- ^ Hathcock JN. (1997). "Vitamins and minerals: efficacy and safety". American Journal of Clinical Nutrition 66 (2): 427–37. PMID 9250127.
- ^ Baggott JE, Morgan SL, HaT, Vaughn WH, Hine RJ (1992). "Inhibition of folate-dependent enzymes by non-steroidal anti-inflammatory drugs". Biochemical Journal 282 (Pt 1): 197–202. PMC 1130907. PMID 1540135. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1130907.
- ^ a b c d e f g h i j k l http://www.merck.com
- ^ Diaz, V. H. US Patent 20080020071, Jan 24, 2008.
- ^ a b Malterre T (September 2009). "Digestive and nutritional considerations in celiac disease: could supplementation help?". Alternative Medicine Review 14 (3): 247–57. PMID 19803549. http://www.thorne.com/altmedrev/.fulltext/14/3/247.pdf. [unreliable medical source?]
- ^ Varela-Moreiras G, Murphy MM, Scott JM (May 2009). "Cobalamin, folic acid, and homocysteine". Nutrition Reviews 67 (Suppl 1): S69–72. DOI:10.1111/j.1753-4887.2009.00163.x. PMID 19453682.
- ^ Pasricha S, Shet A, Sachdev HP, Shet AS (October 2009). "Risks of routine iron and folic acid supplementation for young children". Indian Pediatrics 46 (10): 857–66. PMID 19887691. http://www.indianpediatrics.net/oct2009/857.pdf.
- ^ a b "Dietary Supplement Fact Sheet: Folate". National Institutes of Health. http://ods.od.nih.gov/factsheets/folate/.
- ^ a b [KwaZulu-Natal Dietitians: Department of Health . Foods Rich in Folic Acid. http://www.kznhealth.gov.za/nutrition/food6.htm (accessed Nov 15, 2010).], additional text.
- ^ http://www.eatrightontario.ca/en/ViewDocument.aspx?id=109
- ^ http://noticias.uol.com.br/ultnot/cienciaesaude/ultimas-noticias/estado/2010/03/29/cerveja-tem-vitamina-que-combate-anemia-revela-pesquisa.jhtm
- ^ "Reports by Single Nutrients". USDA. 2009-02-13. http://www.ars.usda.gov/Services/docs.htm?docid=9673. Retrieved 2009-03-19.
- ^ Dietrich, M; Brown, CJ; Block, G (2005). "The effect of folate fortification of cereal-grain products on blood folate status, dietary folate intake, and dietary folate sources among adult non-supplement users in the United States". J Am Coll Nutr 24 (4): 266–274. PMID 16093404.
- ^ Suitor, CW; Bailey, LB (2000). "Dietary folate equivalents: interpretation and application". J Am Diet Assoc 100 (1): 88–94. DOI:10.1016/S0002-8223(00)00027-4. PMID 10646010.
- ^ a b http://www.beyondveg.com/tu-j-l/raw-cooked/raw-cooked-2e.shtml
- ^ Cabanillas, M; Moya Chimenti, E; González Candela, C; Loria Kohen, V; Dassen, C; Lajo, T. (2009). "Usefulness of meal replacement: analysis of the principal meal replacement products commercialised in Spain". Nutr Hosp. 24 (5): 535–42. PMID 19893863.
- ^ a b c d Lanska, DJ. (2009). "Chapter 30 Historical aspects of the major neurological vitamin deficiency disorders: the water-soluble B vitamins". Handb Clin Neurol. Handbook of Clinical Neurology 95: 445–76. DOI:10.1016/S0072-9752(08)02130-1. ISBN 978-0-444-52009-8. PMID 19892133.
- ^ Mitchell HK, Snell EE, Williams RJ (1941). "The concentration of "folic acid"". J Am Chem Soc. 63 (8): 2284. DOI:10.1021/ja01853a512. http://pubs.acs.org/doi/abs/10.1021/ja01853a512.
- ^ a b Hoffbrand, AV; Weir, DG (2001). "The history of folic acid". Br J Haematol 113 (3): 579–589. DOI:10.1046/j.1365-2141.2001.02822.x. PMID 11380441.
- ^ Angier, RB; Boothe, JH; Hutchings, BL; Mowat, JH; Semb, J; Stokstad, EL; Subbarow, Y; Waller, CW et al. (1945). "Synthesis of a compound identical with the l. casei factor isolated from liver". Science 102 (2644): 227–228. DOI:10.1126/science.102.2644.227. PMID 17778509.
- ^ Smith C, Lieberman M, Marks DB, Marks AD (2007). Marks' essential medical biochemistry. Hagerstwon, MD: Lippincott Williams & Wilkins. ISBN 0-7817-9340-8.
- ^ Zittoun J (1993). "Anemias due to disorder of folate, vitamin B12 and transcobalamin metabolism". La Revue du praticien 43 (11): 1358–63. PMID 8235383. (French)
- ^ http://www.healthlinkbc.ca/healthfiles/hfile68g.stm
- ^ Goh, YI; Koren, G (2008). "Folic acid in pregnancy and fetal outcomes". J Obstet Gynaecol 28 (1): 3–13. DOI:10.1080/01443610701814195. PMID 18259891.
- ^ EC 1.5.1.3
- ^ Alaimo K, McDowell MA, Briefel RR, Bischof AM, Caughman CR, Loria CM, Johnson CL (1994). "Dietary intake of vitamins, minerals, and fiber of persons ages 2 months and over in the United States: Third National Health and Nutrition Examination Survey, Phase 1, 1988–91". Advance Data (258): 1–28. PMID 10138938.
- ^ Raiten DJ, Fisher KD (1995). "Assessment of folate methodology used in the Third National Health and Nutrition Examination Survey (NHANES III, 1988–1994)". The Journal of Nutrition 125 (5): 1371S–1398S. PMID 7738698.
- ^ Lewis CJ, Crane NT, Wilson DB, Yetley EA (1999). "Estimated folate intakes: data updated to reflect food fortification, increased bioavailability, and dietary supplement use". The American Journal of Clinical Nutrition 70 (2): 198–207. PMID 10426695.
- ^ Russell A (2006). "The UK campaign on folic acid and flour fortification". Cerebrospinal Fluid Res. 3 (Suppl 1): S33. DOI:10.1186/1743-8454-3-S1-S33. PMC 1716791. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1716791.
- ^ a b c Leblanc JG, Sybesma W, Starrenburg M, et al. (November 2009). "Supplementation with engineered Lactococcus lactis improves the folate status in deficient rats". Nutrition 26 (7–8): 835–41. DOI:10.1016/j.nut.2009.06.023. PMID 19931414.
- ^ Jacques PF, Selhub J, Bostom AG, Wilson PW, Rosenberg IH (May 1999). "The effect of folic acid fortification on plasma folate and total homocysteine concentrations". The New England Journal of Medicine 340 (19): 1449–54. DOI:10.1056/NEJM199905133401901. PMID 10320382.
- ^ "Bread fortification 'not justified'". The Sydney Morning Herald. 29 July 2006. http://www.smh.com.au/news/National/Bread-fortification-not-justified/2006/07/29/1153816426688.html.
- ^ a b "Bread to be fortified with folic acid". NZ Herald. 2007-06-22. http://www.nzherald.co.nz/topic/story.cfm?c_id=294&objectid=10447345. Retrieved 2009-07-13.
- ^ "Bread additive call 'up to NZ'". http://www.stuff.co.nz/national/politics/2593949/Bread-additive-call-up-to-NZ. Retrieved 2009-07-15.
- ^ French, AE; Grant, R; Weitzman, S; Ray, JG; Vermeulen, MJ; Sung, L; Greenberg, M; Koren, G. (2003). "Folic acid food fortification is associated with a decline in neuroblastoma". Clin Pharmacol Ther 74 (3): 288–94. DOI:10.1016/S0009-9236(03)00200-5. PMID 12966372.
- ^ Ionescu-Ittu, R.; Marelli, A. J; MacKie, A. S; Pilote, L. (2009). "Prevalence of severe congenital heart disease after folic acid fortification of grain products: time trend analysis in Quebec, Canada". Brit Med J 338 (7705): 1261. DOI:10.1136/bmj.b1673.
- ^ a b c Smith, AD; Kim, YI; Refsum, H (2008). "Is folic acid good for everyone?". American Journal of Clinical Nutrition 87 (3): 517–33. PMID 18326588.
- ^ Ulrich C.M. and Potter, J.D. (2006). "Folate supplementation: Too much of a good thing?". Cancer Epidemiology, Biomarkers & Prevention 15 (2): 189–93. DOI:10.1158/1055-9965.EPI-06-0054 (inactive 2010-01-08). PMID 16492904. http://cebp.aacrjournals.org/content/15/2/189. Retrieved 12 November 2009.
- ^ a b c Mason, J. B.; Dickstein, A.; Jacques, P. F.; Haggarty, P.; Selhub, J.; Dallal, G.; Rosenberg, I. H. (2007). "A temporal association between folic acid fortification and an increase in colorectal cancer rates may be illuminating important biological principles: A hypothesis". Cancer Epidemiology Biomarkers & Prevention 7 (16): 1325. DOI:10.1158/1055-9965.EPI-07-0329.
- ^ a b c Quinlivan, E. P., & Gregory III, J. F. (2003). "Effect of food fortification on folic acid intake in the united states". American Journal of Clinical Nutrition 77 (1): 221–5. PMID 12499345.
- ^ a b http://www.hc-sc.gc.ca
- ^ Chustecka, Z. (2009 Retrieved 11/09, 2009). Folic-acid fortification of flour and increased rates of colon cancer. http://www.medscape.com/viewarticle/591111.
- ^ "Work Starts on Wilkinson’s Mass Medication Plan" (Press release). Association Of Bakers. 2009-07-08. http://www.scoop.co.nz/stories/BU0907/S00210.htm. Retrieved 2009-07-13.
- ^ "NZ should push pause on folic fortification" (Press release). Green Party. 2009-07-09. http://www.scoop.co.nz/stories/PA0907/S00132.htm. Retrieved 2009-07-13.
- ^ "Bakers, Govt battle over folic acid". NZ Herald. 2009-07-08. http://www.nzherald.co.nz/food/news/article.cfm?c_id=206&objectid=10583249. Retrieved 2009-07-13.
- ^ "Govt reviewing folic acid policy". Stuff. http://www.stuff.co.nz/national/politics/2593407/Govt-reviewing-folic-acid-policy. Retrieved 15 July 2009.
- ^ BBC 'Put folic acid in bread' 2000-01-13
- ^ FSA (2007-05-17). "Board recommends mandatory fortification". http://www.food.gov.uk/news/newsarchive/2007/may/folatefort. Retrieved 2007-05-18.
- ^ "Backing for folic acid in bread". BBC News. 17 May 2007. http://news.bbc.co.uk/1/hi/health/6665109.stm. Retrieved 2007-05-18.
- ^ BBC Experts back folic acid in flour 11 May 2007
- ^ a b c d e Bailey, RL; Dodd, KW; Gahche, JJ; Dwyer, JT; McDowell, MA; Yetley, EA; Sempos, CA; Burt, VL et al. (2010). "Total folate and folic acid intake from foods and dietary supplements in the United States: 2003–2006". The American journal of clinical nutrition 91 (1): 231–7. DOI:10.3945/ajcn.2009.28427. PMC 2793110. PMID 19923379. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2793110.
- ^ Malinow MR, Duell PB, Hess DL, Anderson PH, Kruger WD, Phillipson BE, Gluckman RA, Block PC, Upson BM (1998). "Reduction of plasma homocyst(e)ine levels by breakfast cereal fortified with folic acid in patients with coronary heart disease". New England Journal of Medicine 338 (15): 1009–15. DOI:10.1056/NEJM199804093381501. PMID 9535664.
- ^ Daly S, Mills JL, Molloy AM, Conley M, Lee YJ, Kirke PN, Weir DG, Scott JM (1997). "Minimum effective dose of folic acid for food fortification to prevent neural-tube defects". Lancet 350 (9092): 1666–9. DOI:10.1016/S0140-6736(97)07247-4. PMID 9400511.
- ^ Crandall BF, Corson VL, Evans MI, Goldberg JD, Knight G, Salafsky IS (1998). "American College of Medical Genetics statement on folic acid: fortification and supplementation". American Journal of Medical Genetics 78 (4): 381. DOI:10.1002/(SICI)1096-8628(19980724)78:4<381::AID-AJMG16>3.0.CO;2-E. PMID 9714444.
- ^ "FDA muffed chance to reduce birth defects". Boston Globe. 6 January 2004. http://www.boston.com/yourlife/health/women/articles/2004/01/06/fda_muffed_chance_to_prevent_birth_defects/?page=full.
- ^ "US denies Vegemite ban". 25 October 2006. http://www.news.com.au/story/0,23599,20641599-1702,00.html. [dead link]
- ^ Centers for Disease Control and Prevention (CDC) (2004). "Spina bifida and anencephaly before and after folic acid mandate—United States, 1995–1996 and 1999–2000". Morbidity and Mortality Weekly Report 53 (17): 362–5. PMID 15129193.
- ^ De Wals P, Tairou F, Van Allen MI, Uh SH, Lowry RB, Sibbald B, Evans JA, Van den Hof MC, Zimmer P, Crowley M, Fernandez B, Lee NS & Niyonsenga T (2007). "Reduction in neural-tube defects after folic acid fortification in Canada". N Engl J Med 357 (2): 135–142. DOI:10.1056/NEJMoa067103. PMID 17625125.
- ^ a b c d Choumenkovitch, SF; Selhub, J; Wilson, PW; Rader, JI; Rosenberg, IH; Jacques, PF (2002). "Folic acid intake from fortification in United States exceeds predictions". The Journal of nutrition 132 (9): 2792–8. PMID 12221247.
- This article contains information from the public domain resource at http://www.cc.nih.gov/ccc/supplements/folate.html
- Herbert V (1999). "Folic Acid". In Shils ME, Olson J, Shike M, Ross AC. Modern nutrition in health and disease (9th ed.). Baltimore: Williams and Wilkins. ISBN 0-683-30769-X.
- Food and Nutrition Board, Institute of Medicine (1998). Dietary reference intakes for thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12, pantothenic acid, biotin, and choline / a report of the Standing Committee on the Scientific Evaluation of Dietary Reference Intakes and its Panel on Folate, Other B Vitamins, and Choline and Subcommittee on Upper Reference Levels of Nutrients. Washington, D.C.: National Academy Press. ISBN 0-309-06554-2.
- Dietary Guidelines Advisory Committee, Agricultural Research Service, United States Department of Agriculture (USDA). Report of the Dietary Guidelines Advisory Committee on the Dietary Guidelines for Americans, 2000. http://www.ars.usda.gov/dgac
- Biochemistry links
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D2 ( Ergosterol, Ergocalciferol#) · D3 ( 7-Dehydrocholesterol, Previtamin D3, Cholecalciferol, 25-hydroxycholecalciferol, Calcitriol (1,25-dihydroxycholecalciferol), Calcitroic acid) · D4 ( Dihydroergocalciferol) · D5 · D analogues ( Alfacalcidol, Dihydrotachysterol, Calcipotriol, Tacalcitol, Paricalcitol)
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B1 ( Thiamine#) · B2 ( Riboflavin#) · B3 ( Niacin, Nicotinamide#) · B5 ( Pantothenic acid, Dexpanthenol, Pantethine) · B6 ( Pyridoxine#, Pyridoxal phosphate, Pyridoxamine) · B7 ( Biotin) · B9 ( Folic acid, Dihydrofolic acid, Folinic acid) · B12 ( Cyanocobalamin, Hydroxocobalamin, Methylcobalamin, Cobamamide) · Choline
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