Folic acid (also known as vitamin B9[1] or folacin) and folate (the naturally occurring form), as well as pteroyl-L-glutamic acid and pteroyl-L-glutamate, are forms of the water-soluble vitamin B9. Folic acid is itself not biologically active with its biological importance being due to tetrahydrofolate and other derivatives after its conversion to dihydrofolic acid in the liver.[2]
Vitamin B9 (folic acid and folate inclusive) is essential to numerous bodily functions ranging from nucleotide biosynthesis to the remethylation of homocysteine. It is especially important during periods of rapid cell division and growth. Both children and adults require folic acid to produce healthy red blood cells and prevent anemia.[3] 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.
A lack of dietary folic acid leads to folate deficiency (FD). This can result in many health problems, most notably neural tube defects in developing embryos. Supplementation in the general population may however lead to increased rates of cancer and all-cause mortality.[4]
Folate in foods and other sources
Leafy vegetables such as spinach, asparagus, turnip greens, lettuces, dried or fresh beans and peas, fortified cereal products, sunflower seeds and certain other fruits and vegetables are rich sources of folate. Liver and liver products also contain high amounts of folate, as does baker's yeast. Some breakfast cereals (ready-to-eat and others) are fortified with 25% to 100% of the recommended dietary allowance (RDA) for folic acid. A table of selected food sources of folate and folic acid can be found at the USDA National Nutrient Database for Standard Reference.[5] Folic acid is added to grain products in many countries, and in these countries fortified products make up a significant source of folate [6]. 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.[7]
Conversion to biologically active derivatives
All the biological functions of folic acid are performed by tetrahydrofolate and other derivatives. Their biological availabllity 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 a 5-fold variation in the activity of this enzyme exists between humans.[2] Due to this low activity it has been suggested that 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)."[2]
History
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 that 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 spinach leaves by Mitchell and others in 1941 [8]. 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[9]. This historical research project, of obtaining folic acid in a pure crystalline form in 1945,was done under the supervision and guidance of Dr. Yellapragada Subbarao, the Director of Research in Lederley Lab, Pearl River, NY and other men famously called 'folic acid boys'[10].This research subsequently lead to synthesis of Aminopterin, the first ever anti-cancer drug, the clinical proof of its efficacy was proven by Dr. S. Farber in 1948.
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.[11] It is especially important during periods of rapid cell division and growth such as infancy and pregnancy. Folate is needed to synthesize nucleic acids (most notably thymine, but also purine bases). 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.[12] Both adults and children need folate to make normal red and white blood cells and prevent anemia.[13] 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 NTD's occur early in pregnancy (first month) therefore women must have abundant folate upon conception.
Biochemistry of DNA base and amino acid production
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.[14]
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.[15] 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[9]. 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. Finally, histidine can donate a single carbon to THF to form methenyl-THF.
In other words:
- folate → dihydrofolate → tetrahydrofolate ↔ methylene-THF → methyl-THF
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 para-aminobenzoic acid in the reactions of dihydropteroate synthetase).
The National Health and Nutrition Examination Survey (NHANES III 1988–91) and the Continuing Survey of Food Intakes by Individuals (1994–96 CSFII) indicated that most adults did not consume adequate folate.[16][17] 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.[18]
Human reproduction
Folic acid is an important nutrient for women who may become pregnant. Adequate folate intake during the periconceptional 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).[19] Neural tube defects (NTDs) result in malformations of the spine (spina bifida), skull, and brain (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.[20][21] The protective effect of folate during pregnancy goes beyond NTDs. Supplementation with folic acid has been shown to reduce the risk of congenital heart defects, cleft lip[22], limb defects, and urinary tract anomalies.[23] 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 some serious birth defects. 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.[24]
Folic acid may also reduce chromosomal defects in sperm to some extent, which may be relevant for men considering to father a child.[25] A benefit is indicated even for more than 700 mcg folate per day,[25] which though below the tolerable upper intake levels of 1,000 µg/day was 1.8 times the recommended dietary allowance.
Health issues
Heart disease
Adequate concentrations of folate, vitamin B12, or vitamin B6 may decrease the circulating level of homocysteine, an amino acid normally found in blood. There is evidence that an elevated homocysteine level is an independent risk factor for heart disease and stroke.[26] The evidence suggests that high levels of homocysteine may damage coronary arteries or make it easier for blood clotting cells called platelets to clump together and form a clot.[27] However, there is currently no evidence available to suggest that lowering homocysteine with vitamins will reduce risk of heart disease. The NORVIT trial suggests that folic acid supplementation may do more harm than good.[28]
As of 2006, studies have shown that giving folic acid to reduce levels of homocysteine does not result in clinical benefit. One of these studies suggests that folic acid in combination with B12 may even increase some cardiovascular risks.[29][30][31]
However a 2005 study found that 5 mg of folate daily over a three-week period reduced pulse pressure by 4.7 mmHg compared with a placebo, and concluded that[32]
- Folic acid is a safe and effective supplement that targets large artery stiffness and may prevent isolated systolic hypertension.
Also, as a result of new research, "heart experts" at Johns Hopkins Medical Center reported in March 2008 [33] in favour of therapeutic folate, although they cautioned that it is premature for people to begin to self-medicate by taking high doses of folic acid."
Stroke
Folic acid appears to reduce the risk of stroke. The reviews indicate only that in some individuals the risk of stroke appears to be reduced, but a definite recommendation regarding supplementation beyond the current recommended daily allowance has not been established for stroke prevention.[34] 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.
Cancer
The association between folate and cancer appears to be complex.[35] Even though theoretically it has been suggested that folate may help prevent cancer[36] actual trials have found that supplementation increases rates of cancer.[37]
Some investigations have proposed that good levels of folic acid may be related to lower risk of esophageal, stomach, and ovarian cancer, but benefices 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 who already are suffering from cancer or from a precancerous condition. Conversely, it has been suggested that excess folate may promote tumor initiation.[38] Diets great in folate are associated with decreased risk of colorectal cancer; some studies show an association which is stronger for folate from foods alone than for folate from foods and supplements,[39] while other studies find that folate from supplements is more effective due to greater bioavailability.[40] A 2007 randomized clinical trial found that folate supplements did not reduce the risk of colorectal adenomas, but do in fact increase the presence of advanced lesions and adenoma multiplicity.[41] A 2006 prospective study of 81,922 Swedish adults found that diets great in folate from foods, but not from supplements, were associated with a reduced risk of pancreatic cancer.[42]
Most epidemiologic studies suggest that 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 that routine folate supplementation should not be recommended as a breast cancer preventive,[43] but a 2007 Swedish prospective study found that much folate intake was associated with a lower incidence of postmenopausal breast cancer.[44] A 2008 study has shown no significant effect of folic acid on overall risk of total invasive cancer or breast cancer among women.[45]
In men, folic acid supplementation appears to double the risk of prostate cancer.[46]
The cancer drug methotrexate is designed to inhibit the metabolism of folic acid. Folic acid may interact unexpectedly with the cancer drug fluorouracil. The exact mechanism of interaction is unknown.[47]
The low dihydrofolate reductase activity in the liver of humans compared to other animals and so the low conversion of folic acid into its active derivatives might be due to the control of this enzyme by transcription factors such as E2F-1 involved in cell proliferation. It has been suggested that "the low level of DHFR, and the other proteins under the control of E2F-1, in humans may have evolved to hinder the development of cancer. If this is the case, other animals with slow tissue turnover rates, possibly related to long life span, might also have low DHFR activity.[2]
Antifolates
Folate is important for cells and tissues that rapidly divide.[11] 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). Unfortunately, methotrexate can be toxic,[48][49][50] 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), acute renal and hepatic failure have been reported.
Folinic acid, under the drug name leucovorin, is a form of folate (formyl-THF) that can help "rescue" or reverse the toxic effects of methotrexate.[51] Folinic acid is not the same as folic acid. Folic acid supplements have little established role in cancer chemotherapy.[52][53] 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 non rapidly dividing cells 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. Low dose methotrexate is used to treat a wide variety of non-cancerous diseases such as rheumatoid arthritis, lupus, scleroderma, psoriasis, asthma, sarcoidoisis, primary biliary cirrhosis, polymyositis, and inflammatory bowel disease.[54] Low doses of methotrexate can deplete folate stores and cause side effects that are similar to folate deficiency. Both high folate diets and supplemental folic acid may help reduce the toxic side effects of low dose methotrexate without decreasing its effectiveness.[55][56] Anyone taking low dose methotrexate for the health problems listed above should consult with a physician about the need for a folic acid supplement.
While the role in folate as a cancer treatment is well established its long term effectiveness is diminished by cellular response. In response to decreased THF the cell begins to transcribe more DHF reductase, the enzyme that reduces DHF to THF. Because methotrexate is a competitive inhibitor of DHF reductase increased concentrations of DHF reductase can overcome the drugs inhibition.
Depression
Some evidence links a shortage of folate with depression.[57] There is some limited evidence from randomised controlled trials that using folic acid in addition to antidepressants, specifically SSRIs, may have benefits.[58] Research at the University of York and Hull York Medical School has found a link between depression and low levels of folate.[59] One study by the same team involved 15,315 subjects.[60] However, the evidence is probably too limited at present for this to be a routine treatment recommendation.
Memory and mental agility
In a 3-year trial on 818 people over the age of 50, short-term memory, mental agility, and verbal fluency were all found to be better among people who took 800 micrograms of folic acid daily, twice the current RDA, than those who took placebo. The study was reported in The Lancet on 20 January 2007.[61]
Fertility
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, in order to avoid subfertility.[62]
Macular degeneration
A substudy of the Women's Antioxidant and Folic Acid Cardiovascular Study published in 2009 reports that use of a nutritional supplement that contains folic acid, pyridoxine, and cyanocobalamin decreased the risk of developing age-related macular degeneration by 34%.[63]
Folic acid supplements and masking of B12 deficiency
There has been concern about the interaction between vitamin B12 and folic acid.[64] Folic acid supplements can correct the anemia associated with vitamin B12 deficiency.[citation needed] Unfortunately, folic acid will not correct changes in the nervous system that result from vitamin B12 deficiency. Permanent nerve damage could theoretically occur if vitamin B12 deficiency is not treated. Therefore, intake of supplemental folic acid should not exceed 1000 micrograms (1000 µg or 1 mg) per day to prevent folic acid from masking symptoms of vitamin B12 deficiency. In fact, to date the evidence that such masking actually occurs is scarce, and there is no evidence that folic acid fortification in Canada or the U.S. has increased the prevalence of vitamin B12 deficiency or its consequences.[65]
However, one recent study has demonstrated that high folic or folate levels, when combined with low B12 levels, are associated with significant cognitive impairment among the elderly.[66]
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 vitamin B12 deficiency. Patients 50 years of age or older should ask their physicians to check their vitamin B12 status before taking a supplement that contains folic acid.[67]
Health risk of too much folic acid
The risk of toxicity from folic acid is low.[68] 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.[69]
Research suggests high levels of folic acid can interfere with some antimalarial treatments.[70]
A 10,000-patient study at Tufts University in 2007 concluded that excess folic acid worsens the effects of B12 deficiency and in fact may affect the absorption of B12.[71]
A study at the University of Adelaide concluded that the intake of folic acid supplements during late pregnancy increases the risk of babies developing childhood asthma by 30%, although researchers emphasized that their finding did not contradict recommendations to supplement folic acid in first trimester, when no additional risk was found.[72]
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 (NTDs), 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 everyone benefiting 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 ex-Soviet republics are amongst 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.[73]
Australia
There has been previous debate in Australia regarding the inclusion of folic acid in products such as bread and flour.[74]
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.[75] 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 in New Zealand, and they will watch with interest.[76].
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 that 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.[77] In 2009, further evidence from McGill University showed a 6.2% decrease per year in the birth prevalence of severe congenital heart defects.[78]
New Zealand
New Zealand was going to fortify bread (excluding organic and unleavened varieties) from 18 September 2009 but has opted to wait until more research is done.[75]
The Association of Bakers [79] and the Green Party [80] 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 [81]. The New Zealand Government is reviewing whether it will continue with the mandatory introduction of folic acid to bread.[82]
United Kingdom
There has been previous debate in the United Kingdom regarding the inclusion of folic acid in products such as bread and flour.[83]
The Food Standards Agency has recommended fortification.[84][85][86]
United States
The United States Public Health Service recommends an extra 0.4 mg/day, which can be taken as a pill. However, many researchers believe that 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.
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.[87][88] This ruling took effect on January 1, 1998, and was specifically targeted to reduce the risk of neural tube birth defects in newborns.[89] There are concerns that the amount of folate added is insufficient [90]. 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.[91]
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 that cover about half of United States births, and extrapolated their findings to the rest of the country. These data indicate that 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[92]. 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;[93] 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.
See also
References
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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
- Biochemistry links
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Vitamins (A11) |
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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 ( Dihydrotachysterol, Calcipotriol, Tacalcitol, Paricalcitol)
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| Water soluble |
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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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