folacin n : a B vitamin that is essential for cell growth and reproduction [syn: vitamin Bc, vitamin M, folate, folic acid, pteroylglutamic acid, pteroylmonoglutamic acid]
Folic acid and folate (the anion form) are forms of the water-soluble Vitamin B9. These occur naturally in food and can also be taken as supplements. Folate gets its name from the Latin word folium ("leaf").
Folate in foods and other sourcesLeafy vegetables such as spinach, turnip greens, lettuces, dried beans and peas, fortified cereal products, sunflower seeds and certain other fruits and vegetables are rich sources of folate. 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. Folate is also found in Vegemite, with an average serving (5gm) containing 100μg. Folate is also synthesized in bacteria.
HistoryA 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 extracted from spinach leaves in 1941. It was first synthesized in 1946 by Yellapragada Subbarao.
Biological roles of folate
- DNA and cell division
- Biochemistry of DNA base and amino acid production
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. 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. If 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 defeciency of B12 can lead to a methyl-trap of THF and a subsequent deficiency. 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: F → DHF2 → THF → CH2-THF Formyl-THF Methynl-THF 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).
- Recommended Daily Allowence (RDA)
Human reproductionFolic acid is very important for all women who may become pregnant. Adequate folate intake during the periconceptional period, the time just before and just after a woman becomes pregnant, helps protect against a number of congenital malformations including neural tube defects. Neural tube defects 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. 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. The most notable birth defects that occur from folate deficiency are neural tube defects. Taking 400 micrograms of synthetic folic acid daily from fortified foods and/or supplements has been suggested. The Recommended Dietary Allowance (RDA) for folate equivalents for pregnant women is 600-800 micrograms, twice the normal RDA of 400 micrograms for women who are not pregnant.
Recent research has shown that it is also very important for men who are planning on fathering children, reducing birth defect risks.
Folic acid supplements and masking of B12 deficiencyThere has been concern about the interaction between vitamin B12 and folic acid.Folic acid supplements can correct the anemia associated with vitamin B12 deficiency. 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 mcg 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 US has increased the prevalence of vitamin B12 deficiency or its consequences.
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. If the observed relationship for seniors between folic acid intake, B12 levels, and cognitive impairment is replicated and confirmed, this is likely to re-open the debate on folic acid fortification in food, even though public health policies tend generally to support the developmental needs of infants and children over slight risks to other population groups.
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. If you are 50 years of age or older, ask your physician to check your B12 status before you take a supplement that contains folic acid.
Health risk of too much folic acidThe risk of toxicity from folic acid is low. 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.
Research suggests high levels of folic acid can interfere with some antimalarial treatments.
A 10000-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.
Some current issues and controversies about folate
Dietary fortification of folic acidSince 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. For example, the United States Public Health Service (see External links) 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.
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, and the masking effect of folate fortification on pernicious anaemia (vitamin B12 deficiency). However, almost all American 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. In the UK the Food Standards Agency has recommended fortification. To date, no EU country has yet mandated fortification. Australia is considering fortification, but a period for comments ending 2006-07-31 attracted strong opposition from industry as well as academia.
Recent debate has emerged in the United Kingdom and Australia regarding the inclusion of folic acid in products such as bread and flour.
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. This ruling took effect 1998-01-01, and was specifically targeted to reduce the risk of neural tube birth defects in newborns. There are concerns that the amount of folate added is insufficienthttp://www.boston.com/yourlife/health/women/articles/2004/01/06/fda_muffed_chance_to_prevent_birth_defects/?page=full. 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.http://www.news.com.au/story/0,23599,20641599-1702,00.html
Since the folic acid fortification program took effect, 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. This data indicates that since the addition of folic acid in grain-based foods as mandated by the Food and Drug Administration, the rate of neural tube defects dropped by 25% in the United States.
Although folic acid does reduce the risk of birth defects, it is only one part of the picture and should not be considered a cure. Even women taking daily folic acid supplements have been known to have children with neural tube defects.
Heart diseaseAdequate 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. 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. However, there is currently no evidence available to suggest that lowering homocysteine with vitamins will reduce risk of heart disease. Clinical intervention trials are needed to determine whether supplementation with folic acid, vitamin B12 or vitamin B6 can lower the risk of developing coronary heart disease. The NORVIT trial suggests that folic acid supplementation may do more harm than good.
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.
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
- 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 in favour of therapeutic folate, although they cautioned that it was premature for those at risk of heart attack to self-medicate.
StrokeFolic 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. 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.
CancerThe association between folate and cancer appears to be complex. It has been suggested that folate may help prevent cancer, as it is involved in the synthesis, repair, and functioning of DNA, and a deficiency of folate may result in damage to DNA that may lead to cancer. Some investigations have proposed that good levels of folic acid may be related to lower risk of esophagus, 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. Diets high 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, while other studies find that folate from supplements is more effective due to greater bioavailability and a 2007 randomized clinical trial found that folate supplements did not reduce the risk of colorectal adenomas. A 2006 prospective study of 81,922 Swedish adults found that diets high in folate from foods, but not from supplements, were associated with a reduced risk of pancreatic cancer. Most epidemiologic studies suggest that diets high in folate are associated with decreased risk of breast cancer, but results are not uniformly consistent: one large cancer screening trial reported a potential harmful effect of high folate intake on breast cancer risk, suggesting that routine folate supplementation should not be recommended as a breast cancer preventive, but a 2007 Swedish prospective study found that a high folate intake was associated with a lower incidence of postmenopausal breast cancer. It is very difficult to affirm how each nutrient or nutrient combination affects a person’s risk of cancer. People whose diets are rich in vegetables and low in animal fat and meat have lower risks for some of the most frequent types of cancer. Taking a variety of healthful foods, with most of them coming from plant sources, is a better solution than taking vitaminic supplements. So the authorities are not really sure if this will work for cancer or not, (or the age at which it is safe to start taking folate supplements) but hopefully this will all become clear in the light of research now underway.
AntifolatesFolate is important for cells and tissues that rapidly divide. producing side effects such as inflammation in the digestive tract that make it difficult to eat normally.
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. Folinic acid is not the same as folic acid. Folic acid supplements have little established role in cancer chemotherapy. 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, psoriasis, asthma, sarcoidoisis, primary biliary cirrhosis, and inflammatory bowel disease. 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. 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.
DepressionSome evidence links low levels of folate with depression. There is some limited evidence from randomised controlled trials that using folic acid in addition to antidepressant medication may have benefits. Researchers at the University of York and Hull York Medical School have confirmed a link between depression and low levels of folate in a research study involving 15,315 . However, the evidence is probably too limited at present for this to be a routine treatment recommendation.
Memory and mental agilityIn 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 19 January 2007.
FertilityFolate 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.
Induction of acute renal failureFolic acid is used in extremely high doses to induce Acute renal failure in murine models. It should be noted that the dose reported below represents about 120 years of the recommended daily intake [0.4 mg for adults] in one application, an experiment irrelevant to human nutrition. The exact method through which folic acid induces kidney injury in such massive dose is unknown, however it is characterized by the appearance of folic acid crystals in renal tubules and acute tubular necrosis. This method of renal injury is also linked to increased expression of Tumor necrosis factor-alpha. The dose of folic acid used to induce renal injury is usually around 250mg of folic acid per kg of body weight. The folic acid is usually administered in a vehicle of 0.3mmol/L of sodium bicarbonate.
- This article contains information from the public domain resource at http://www.cc.nih.gov/ccc/supplements/folate.html
- Herbert V. (1999). Folic Acid. Shils M, Olson J, Shike M, Ross AC, (Eds.). Nutrition in Health and Disease. Baltimore: Williams & Wilkins.
- 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
- 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
- Health Canada article about folic acid
- US Public Health Service information page on folic acid
- BMJ Editorial – "Delaying folic acid fortification of flour"
- Folic Acid and Birth Defects Article from Journal of Postgraduate Medicine
- Folic Acid The Vitamin That Does Almost Everything-U.C Berkeley Wellness Letter April 2003
- BMC Pregnancy and Childbirth 2004: no vitamin B12 problems in Canada after folic acid fortification
- The primary prevention of birth defects: Multivitamins or folic acid?
- Mills et al, Am J Clin Nutr 2003: no vitamin B12 problems in the US after folic acid fortification
- Folic acid may help prevent throat cancer
- Folic acid may help treat bipolar disorder
folacin in Arabic: حمض فوليك
folacin in Bulgarian: Фолиева киселина
folacin in Catalan: Àcid fòlic
folacin in Czech: Kyselina listová
folacin in Danish: Folsyre
folacin in German: Folsäure
folacin in Spanish: Ácido fólico
folacin in Persian: ویتامین ب۹
folacin in French: Vitamine B9
folacin in Korean: 잎산
folacin in Croatian: Vitamin B9
folacin in Indonesian: Asam folik
folacin in Icelandic: Fólinsýra
folacin in Italian: Acido folico
folacin in Hebrew: חומצה פולית
folacin in Luxembourgish: Folsaier
folacin in Lithuanian: Folio rūgštis
folacin in Dutch: Foliumzuur
folacin in Japanese: 葉酸
folacin in Norwegian: folsyre
folacin in Polish: Kwas foliowy
folacin in Portuguese: Ácido fólico
folacin in Russian: Фолиевая кислота
folacin in Albanian: Acidi folik
folacin in Slovak: Kyselina listová
folacin in Slovenian: Folna kislina
folacin in Serbian: Folna kiselina
folacin in Finnish: Foolihappo
folacin in Swedish: Folsyra
folacin in Vietnamese: Axít folic
folacin in Turkish: Folik asit
folacin in Chinese: 叶酸