folic acid

Folic acid
IUPAC name (2S)-2-[(4-{[(2-amino-4-hydroxypteridin-6-yl)methyl]amino}phenyl)formamido]pentanedioic acid
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;Vitamin M; 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
SMILES c1cc(ccc1C(=O)N[C@@H](CCC(=O)O)C(=O)O)NCc2cnc3c(n2)c(=O)nc([nH]3)N
InChI 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
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 B_c^[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 to 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]

Health benefits and risks

Reproduction

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]

Heart disease

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]

Stroke

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]

Cancer

A meta-analysis published in 2010 failed to find a statistically significant cancer risk due to folic acid treatments.^[31]

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.^[32] 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.^[33] Therefore, public health recommendations should be careful not to encourage too much folate intake.^[33]

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,^[34] 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.^[35]

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,^[36]but a 2007 Swedish prospective study found much folate intake was associated with a lower incidence of postmenopausal breast cancer.^[37] A 2008 study has shown no significant effect of folic acid on overall risk of total invasive cancer or breast cancer among women.^[38] 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.^[39] Folate intake of more than 300 µg/d may reduce the risk of breast cancer in women who consume alcohol.^[39]

Most research studies associate high dietary folate intake with a reduced risk of prostate cancer.^[35] 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.^[40] A Finnish study consisting of 29,133 older male smokers observed prostate cancer risk had no relationship with serum folate levels.^[7]

Antifolates

Folate is important for cells and tissues that rapidly divide.^[41] 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,^[42][43][44] 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.^[45] Folinic acid is not the same as folic acid. Folic acid supplements have little established role in cancer chemotherapy.^[46][47] 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.

Psychological

Some evidence links a shortage of folate with depression.^[48] Limited evidence from randomised controlled trials showed using folic acid in addition to antidepressants, to be specific SSRIs, may have benefits.^[49] Research at the University of York and Hull York Medical School has found a link between depression and low levels of folate.^[50] One study by the same team involved 15,315 subjects.^[51] 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.^[52]

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.^[53] 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.^[54]

Macular degeneration

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%.^[55]

B₁₂ deficiency

There has been concern about the interaction between vitamin B₁₂ and folic acid.^[56] 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".^[57] 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.^[58] 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."^[57]

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.^[59]However, one recent study has demonstrated high folic or folate levels, when combined with low B₁₂ levels, are associated with significant cognitive impairment among the elderly.^[60]

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.^[61]

Overdose risks

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.^[62] 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.^[63]

Folate deficiency

Folate deficiency may lead to glossitis, diarrhea, depression, confusion, anemia, and fetal neural tube defects and brain defects (during pregnancy).^[64] Folate deficiency is accelerated by alcohol consumption^[65] Folate deficiency is diagnosed by analyzing CBC and plasma vitamin B₁₂ and folate levels.^[64] CBC may indicate megaloblastic anemia but this could also be a sign of vitamin B₁₂ deficiency.^[64] A serum folate of 3 μg/L or lower indicates deficiency.^[64] Serum folate level reflects folate status but erythrocyte folate level better reflects tissue stores after intake.^[64] An erythrocyte folate level of 140 μg/L or lower indicates inadequate folate status.^[64] Increased homocysteine level suggests tissue folate deficiency but homocysteine is also affected by vitamin B₁₂ and vitamin B₆, renal function, and genetics.^[64] One way to differentiate between folate deficiency from vitamin B₁₂ deficiency is by testing for methylmalonic acid levels.^[64] Normal MMA levels indicate folate deficiency and elevated MMA levels indicate vitamin B₁₂ deficiency.^[64] Folate deficiency is treated with supplemental oral folate of 400 to 1000 μg per day.^[64] This treatment is very successful in replenishing tissues, even if deficiency was caused by malabsorption.^[64]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.^[64] Morbidly obese patients with BMIs of greater than 50 are more likely to develop folate deficiency.^[66] Patients with celiac disease have a higher chance of developing folate deficiency.^[66] 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.^[67]

Malaria

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.^[68]

Dietary reference intake

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.

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.^[69]

Sources

Certain foods are very high in folate:

• Leafy vegetables such as spinach, asparagus, turnip greens
• Legumes such as dried or fresh beans, peas and lentils
• Egg yolks.^[70]
• Baker's yeast
• Fortified grain products (pasta, cereal, bread); some breakfast cereals (ready-to-eat and others) are fortified with 25% to 100% of the recommended dietary allowance (RDA) for folic acid
• Sunflower seeds
• Liver and liver products contain high amounts of folate
• Kidney^[70]

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),^[71] beer.^[72]

A table of selected food sources of folate and folic acid can be found at the USDA National Nutrient Database for Standard Reference.^[73] 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.^[74] 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.^[75]

Folic acid naturally found in food is susceptible to high heat and ultraviolet light, and is soluble in water.^[76] It is heat-labile in acidic environments and may also be subject to oxidation.^[76]

Some meal replacement products do not meet the folate requirements as specified by the RDAs.^[77]

History

In the 1920s, scientists believed folate deficiency and anemia were the same condition.^[78] 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.^[79] 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.^[80] 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.^[81] 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.^[78] In 1960, experts first linked folate deficiency to neural tube defects.^[78] 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.^[78]

Biological roles

A diagram of the chemical structure of folate

DNA and cell division

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.^[41] 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).^[40] 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.^[82] Both adults and children need folate to make normal red and white blood cells and prevent anemia.^[83] 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.^[84]

Biochemistry of DNA base and amino acid production

Metabolism of folic acid to produce methyl-vitamin B₁₂

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.^[85]

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.^[86] 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.^[80] 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

Folate metabolism

Conversion to biologically active derivatives

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]

Overview of drugs that interfere with folate reactions

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.^[87][88] 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.^[89]

Dietary fortification

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.^[90]

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.^[91] These engineered folates can potentially help alleviate the effects of folate deficiency in the diet.^[91] 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.^[91]

Effects of fortification and plasma folate and homocysteine levels

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.^[92]

Australia

There has been previous debate in Australia regarding the inclusion of folic acid in products such as bread and flour.^[93]

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.^[94] 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.^[95]

The requirement is 0.135 mg of folate per 100g of bread.

Canada

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.^[96] In 2009, further evidence from McGill University showed a 6.2% decrease per year in the birth prevalence of severe congenital heart defects.^[97]

Folic acid used in fortified foods is a synthetic form called pteroylmonoglutamate.^[98] It is in its oxidized state and contains only one conjugated glutamate residue.^[98] 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.^[99] Folic acid has a higher bioavailability than natural folates and are rapidly absorbed across the intestine,^[98] 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.^[100] The purpose of fortification was to decrease the risk of neural tube defects in newborns.^[100] 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.^[101] 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.^[102] 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.^[101] This could be from the fact that many foods are over fortified by 160–175% the predicted value.^[101] 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.^[103] It is still unknown the amount of folic acid supplementation that might cause harm.^[100]

Supplementation promotion

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.^[102]

New Zealand

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.^[94]

The Association of Bakers ^[104] and the Green Party ^[105] 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 .^[106] The New Zealand Government is reviewing whether it will continue with the mandatory introduction of folic acid to bread.^[107]

United Kingdom

There has been previous debate in the United Kingdom regarding the inclusion of folic acid in products such as bread and flour.^[108]

The Food Standards Agency has recommended fortification.^{[109][110][111]}

United States

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.^[112] 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.^[112] Twenty nine percent of black women have inadequate intakes of folate.^[112] The age group consuming the most folate and folic acid is the >50 group.^[112] Only 5% of the population exceeds the Tolerable Upper Intake Level.^[112]

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.^[113][114] This ruling took effect on January 1, 1998, and was specifically targeted to reduce the risk of neural tube birth defects in newborns.^[115] There are concerns that the amount of folate added is insufficient .^[116] 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.^[117]

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.^[118] 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;^[119] 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.^[120] 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.^[120] 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.^[120] Taken together, folic acid fortification has led to a bigger increase in folic acid intake than first projected.^[120]

References

Bibliography

• 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

External links

• Jane Higdon, "Folic Acid", Micronutrient Information Center, Linus Pauling Institute, Oregon State University
• Health Canada article about folic acid
• US Public Health Service information page on folic acid
• The primary prevention of birth defects: Multivitamins or folic acid?

Biochemistry links

• Folate biosynthesis (early stages)
• Folate biosynthesis (later stages)
• Folate coenzymes
• C₁ metabolism with folate
• Formylation, hydroxymethylation and methylation using folate
• IUPAC nomenclature of folate related compounds