
n.
A yellowish-orange compound, C19H19N7O6, of the vitamin B complex group, occurring in green plants, fresh fruit, liver, and yeast. Also called folacin, folate, Also called vitamin Bc.
[Latin folium, leaf; see folium + -IC.]
On this page
American Heritage Dictionary:
fo·lic acid |
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Britannica Concise Encyclopedia:
folic acid |
For more information on folic acid, visit Britannica.com.
Gale Encyclopedia of Cancer:
Folic Acid |
Key Terms: Folic acid antagonist, Neoplasm.
Definition
Folic acid is a water-soluble B vitamin essential in the human diet. It is an important cofactor in the synthesis of DNA and RNA of dividing cells, particularly during pregnancy and infancy when there is an increase in cell division and growth.
Purpose
Folic acid is important to the field of oncology in two ways. First, prior to neoplasm formation, folic acid is important in the synthesis of DNA and RNA and the repair of damaged DNA. Second, after a tumor develops, a form of folicacid is used to counter the side effects of methotrexate and 5-fluorouracil (also called fluorouracil or 5-FU).
Description
Prior to Tumor Formation
Since folic acid is a cofactor in DNA replication and biosynthesis of purines and also in DNA repair, there is an increasing amount of research (epidemiological, clinical, and experimental) that suggests a folic acid deficiency might be a factor that predisposes the formation of tumors in normal epithelial tissue. There is an inverse relationship associated with low folate diets and an increase in DNA breakage and mutation that is unable to be effectively repaired. The preventative influence of dietary folic acid on the formation of colon cancer is currently under heavy research. Although a correlation is observed, it has not yet been proven to show cause and effect. However, there is enough evidence to encourage consuming minimal daily dietary requirements of folic acid to potentially reduce the risk. When choosing supplements, other names for folic acid that may be encountered are folate and folacin.
After Tumors Form
Once a neoplasm forms, folic acid levels need to be decreased. In neoplasms, DNA replication and cell division are both occurring in an uncontrolled manner. Folate, which assists in this process, needs to be inhibited, causing an interruption in DNA synthesis and slowing the growth of the tumor. Chemotherapeutic agents called antimetabolites, or folic acid antagonists, such as methotrexate and 5-fluorouracil (5-FU), inhibit the enzymatic pathways for biosynthesis of nucleic acids by substituting for folic acid and sabotaging the reaction. Unfortunately, drugs that inhibit the biosynthesis of cancer cells also inhibit the biosynthesis of normal cells, resulting in extremely toxic side effects. To counter the side effects, a drug called leucovorin (a form of folate also known as Wellcovorin, Citrovorum and folinic acid) opposes the toxic effects of methotrexate on normal tissue. Leucovorin also increases the anticancer effect of 5-FU.
Recommended Dosage
Non-cancer individuals supplementing their diet with folic acid may reduce the risk of cancer. Supplemental folic acid can be purchased over the counter and is also fortified in breakfast cereals and whole grain products produced in the United States. The recommended intake for adults is 400 micrograms (mcg) each day. While the risk of upper limit toxicity is low, adult men and women should not exceed the advised upper limit of 1,000 mcg per day. It is especially important that individuals diagnosed with cancer seek the advice of medical professionals before commencing or continuing supplemental folic acid use because it may interact with chemotherapy.
Cancer patients treated with methotrexate may be given leucovorin as a "rescue" treatment approximately 24 hours later to counteract the toxic side effects on normal tissues of the gastrointestinal system and bone marrow. Leucovorin is only available by prescription. It is a systemic drug available in oral form (tablets) or via injections. The dosage varies from person to person and is based on body size.
Precautions
Patients should inform their physician of the following conditions before they begin to take leucovorin:
Side Effects
Folic acid in general and specifically leucovorin are usually well-tolerated. However, there are some uncommon side effects that include skin rashes, itching, vomiting, nausea, diarrhea, and difficulty breathing. Although extremely rare, seizures have occurred in some patients taking leucovorin. Since leucovorin is taken with chemotherapeutic drugs, some side effects may be due to drug interaction.
Interactions
Supplemental folic acid can interact with anti-convulsant medications such as dilantin, phenytoin, and primidone. It also complicates the effects of metformin (used in individuals with type 2 diabetes), sulfasalazine (used in individuals with Crohn's disease), and triamterene (a diuretic).
Leucovorin enhances the effects of 5-FU and antagonizes the effects of methotrexate. It additionally interacts with barbiturate medications that may be taken by people with sleep disorders.
—Sally C. McFarlane-Parrott
McGraw-Hill Science & Technology Encyclopedia:
Folic acid |
A yellow vitamin, slightly soluble in water, which is usually found in conjugates containing varying numbers of glutamic acid residues. It is also known as pteroylglutamic acid (PGA), and has the structural formula shown.

Folic acid is so widespread in nature and intestinal synthesis is so great that a folic acid deficiency in humans because of low dietary intake is probably not very common. Deficiencies of other nutrients (particularly iron, ascorbic acid, or vitamin B12) may lead to a number of clinical conditions in which folic acid deficiency is involved. These include various nutritional macrocytic anemias, sprue, idiopathic steatorrhea, and pernicious anemia. See also Vitamin.
Oxford Food & Nutrition Dictionary:
folic acid |
A vitamin that functions as a carrier of one-carbon units in a variety of metabolic reactions. Essential for the synthesis of purines and pyrimidines (and so for nucleic acid synthesis and hence cell division); the principal deficiency disease is megaloblastic anaemia, due to failure of the normal maturation of red blood cells, with release into the circulation of immature precursor cells. Occurs in foods in various forms, of which probably about half is nutritionally useful. Rich sources include liver, kidney, green leafy vegetables, and yeast.
The reference intake is 200 μg/day (UK and EU), 400 μg dietary folate equivalents (USA/Canada). Supplements of 400 μg free folic acid per day, beginning before conception, reduces the incidence of spina bifida and other neural tube defects in babies; it is unlikely that ordinary foods could provide this much folate. High intakes of folate also lower plasma homocysteine, and may be proective against heart disease. Since 1998 cereal products are, by law, fortified with folic acid in the USA and a number of other countries.
Oxford Food & Fitness Dictionary:
folic acid |
A member of the B complex of vitamins. Folic acid is a bright yellow, crystalline, water soluble substance that is stable to heat but easily oxidized. It acts as a co-enzyme in the synthesis of a number of important chemicals in the body, including some amino acids and DNA. Because of its involvement in DNA synthesis, it is also essential for the formation of cells, especially red blood cells and embryonic cells. Just before and during the early stages of pregnancy, greater amounts are required for the growth of embryonic and maternal tissues. The Medical Research Council Vitamin Study at St. Bartholomew's hospital in London demonstrated a direct link between taking folic acid before pregnancy and avoiding neural tube defects (NTDs) in the embryo. The defects occur when the embryonic neural tube that forms the brain and spinal cord fails to close properly. NTDs are the most common birth defects in the Western world and cause babies to be born with spina bifida or, worse still, without a brain. In the UK, the Department of Health recommend that all women eat foods rich in folates and take 400 micrograms of folic acid each day if they are planning a pregnancy and for the first 12 weeks of pregnancy. Research undertaken in Northern Ireland, suggests that synthetic forms of the vitamin are better assimilated by the body than folate from foods such as broccoli. Supplementation must begin before conception because the neural tube closes about day 21 of pregnancy, usually before the woman knows that she is pregnant. Women at greater risk of folic acid deficiency (e.g. those who are anaemic, have had multiple pregnancies, or have used oral contraceptives for a long period) are often prescribed greater amounts.
Folic acid deficiency causes anaemia, diarrhoea, gastrointestinal disturbances, and other disorders. The risk of cervical dysplasia increases as levels of folic acid in the blood or cervix decrease. Cervical dysplasia is an abnormal growth of tissue in the cervix, linked to a viral infection. It is thought that folic acid may increase resistance to the virus.
Little is known of the effects of folic acid on physical performance, but a deficiency is likely to affect endurance athletes adversely owing to anaemia.
Folic acid is supplied in the diet from foods such as leafy green vegetables, liver, pulses, eggs, and wholemeal cereal products. The richest source is dried brewer's yeast (2400 micrograms of folic acid per 100 grams of yeast). It is also made in the body by intestinal bacteria, but this folate is probably not absorbed. In the UK, the adult daily Reference Nutrient Intake is 200 micrograms; in the USA, Recommended Dietary Allowance (1989) is 180 micrograms for females and 200 micrograms for males.
Drug Info:
Folic Acid, Vitamin B9 |
Brand names: Deplin, FA-8®, Folacin®, Folicet
Chemical formula:

Folic Acid (Vitamin B9) Oral tablet
What is this medicine?
FOLIC ACID (FOE lik AS id) is a water-soluble, B complex vitamin. It is in many foods like liver, kidneys, yeast, and leafy, green vegetables. It is used to treat megaloblastic anemia and anemia from poor diet in pregnant women, babies, and children.
This medicine may be used for other purposes; ask your health care provider or pharmacist if you have questions.
What should I tell my health care provider before I take this medicine?
They need to know if you have any of these conditions:
•alcoholism or alcohol cirrhosis
•pernicious anemia
•vitamin B12 deficient anemia
•an unusual or allergic reaction to folic acid, other B vitamins, other medicines, foods, dyes, or preservatives
•pregnant or trying to get pregnant
•breast-feeding
How should I use this medicine?
Take this medicine by mouth with a glass of water. Follow the directions on your prescription label. Take your doses at regular intervals. Do not stop taking your medicine unless your doctor tells you to.
Talk to your pediatrician regarding the use of this medicine in children. While this drug may be prescribed for selected conditions, precautions do apply.
Overdosage: If you think you have taken too much of this medicine contact a poison control center or emergency room at once.
NOTE: This medicine is only for you. Do not share this medicine with others.
What if I miss a dose?
It is important not to miss a dose. Let your prescriber or health care professional know if you are unable to keep an appointment.What may interact with this medicine?
•chloramphenicol
•cholestyramine
•medicines for seizures
•methotrexate
•nitrofurantoin
•pyrimethamine
This list may not describe all possible interactions. Give your health care provider a list of all the medicines, herbs, non-prescription drugs, or dietary supplements you use. Also tell them if you smoke, drink alcohol, or use illegal drugs. Some items may interact with your medicine.
What should I watch for while using this medicine?
Visit your doctor or health care professional for regular check ups. Your doctor may order blood tests.
You need to eat a proper diet even while you are taking this vitamin. Taking vitamin supplements is not a substitute for a healthy diet. Ask your doctor or health care provider for good nutrition advice.
What side effects may I notice from receiving this medicine?
Side effects that you should report to your doctor or health care professional as soon as possible:
•allergic reactions such as skin rash or itching, hives, swelling of the lips, mouth, tongue, or throat
•chest tightness or pain
•wheezing or shortness of breath
Side effects that usually do not require medical attention (report to your doctor or health care professional if they continue or are bothersome):
•bitter or bad taste
•confusion
•irritable
•loss of appetite
•nausea
•stomach gas
This list may not describe all possible side effects. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
Where should I keep my medicine?
Keep out of the reach of children.
Store at room temperature between 15 and 30 degrees C (59 and 86 degrees F). Protect from light. This medicine is quickly broken down and made inactive when exposed to heat or light. Throw away any unused medicine after the expiration date.
Last updated: 7/1/2002
Important Disclaimer: The drug information provided here is for educational purposes only. It is intended to supplement, not substitute for, the diagnosis, treatment and advice of a medical professional. This drug information does not cover all possible uses, precautions, side effects and interactions. It should not be construed to indicate that this or any drug is safe for you. Consult your medical professional for guidance before using any prescription or over the counter drugs.
Oxford A-Z of Medicinal Drugs:
folic acid |
| fluvoxamine maleate, fluvastatin, fluticasone propionate | |
| folinic acid, follitropin, fondaparinux sodium |
Gale Encyclopedia of Children's Health:
Folic Acid |
Definition
Folic acid is a water-soluble vitamin belonging to the B-complex group of vitamins. These vitamins help the body break down complex carbohydrates into simple sugars to be used for energy. Excess B vitamins are excreted from the body rather than stored for later use. This is why sufficient daily intake of folic acid is necessary.
Description
Folic acid is also known as folate or folacin. It is one of the nutrients most often found to be deficient in the Western diet. There is evidence that folate deficiency is a worldwide problem. Folic acid is found in leafy green vegetables, beans, peas and lentils, liver, beets, brussel sprouts, poultry, nutritional yeast, tuna, wheat germ, mushrooms, oranges, asparagus, broccoli, spinach, bananas, strawberries, and cantaloupes. In 1998, the U.S. Food and Drug Administration (FDA) required food manufacturers to add folic acid to enriched bread and grain products to boost intake. Pregnant women whose diets are deficient in folic acid have a greater chance of having a baby with neural tube defects (NTD), such as spina bifida.
General Use
Folic acid works together with vitamin B12 and vitamin C to metabolize protein in the body. It is important for the formation of red and white blood cells. It is also necessary for the proper differentiation and growth of cells in fetal development. It is also used to form the nucleic acid of DNA and RNA. It increases the appetite and stimulates the production of stomach acid for digestion, and it aids in maintaining a healthy liver. A deficiency of folic acid may lead to anemia, in which there is decreased production of red blood cells. This situation reduces the amounts of oxygen and nutrients that are able to get to the tissues. Symptoms may include fatigue, reduced secretion of digestive acids, confusion, and forgetfulness. During pregnancy, a folic acid deficiency may lead to preeclampsia, premature birth, and increased bleeding after birth.
Pregnant women have an increased need for folic acid, both for themselves and their unborn child. Folic acid is necessary for the proper growth and development of the fetus. Adequate intake of folic acid is vital for the prevention of several types of birth defects, particularly NTDs. The neural tube of the embryo develops into the brain, spinal cord, spinal column, and the skull. If this tube forms incompletely during the first few months of pregnancy, a serious, and often fatal, defect results in spina bifida or anencephaly (formation of the head without the brain). Folic acid, taken from one year to one month before conception through the first four months of pregnancy, can reduce the risk of NTDs by 50 to 70 percent. It also helps prevent cleft lip and palate.
Research shows that folic acid can be used to successfully treat cervical dysplasia. This condition is considered to be a possible precursor to cervical cancer and is diagnosed as an abnormal Pap smear. Daily consumption of 1,000 mcg of folic acid for three or more months has resulted in improved cervical cells upon repeat Pap smears.
Precautions
Folic acid is not stable. It is easily destroyed by exposure to light, air, water, and cooking. Therefore, the supplement should be stored in a dark container in a cold, dry place, such as a refrigerator. Many medications interfere with the body's absorption and use of folic acid. This includes sulfa drugs, sleeping pills, estrogen, anticonvulsants, birth control pills, antacids, quinine, and some antibiotics. Using large amounts of folic acid (e.g., over 5,000 mcg per day) can mask a vitamin B 12 deficiency and thereby risk of irreversible nerve damage.
Side Effects
At levels of 5,000 mcg or less, folic acid is generally safe for use. Side effects are uncommon. However, large doses may cause nausea, decreased appetite, bloating, gas, decreased ability to concentrate, and insomnia. Large doses may also decrease the effects of phenytoin (Dilantin), a seizure medication.
Parental Concerns
Pregnant women or those thinking of becoming pregnant should ensure that that they get the recommended amount of folic acid daily. As with all B-complex vitamins, it is best to take folic acid with the other B vitamins. Vitamin C is important to the absorption and functioning of folic acid in the body.
To correct a folic acid deficiency, supplements are taken in addition to food. Since the functioning of the B vitamins is interrelated, it is generally recommended that the appropriate dose of B-complex vitamins be taken in place of single B vitamin supplements. The Recommended Dietary Allowances (RDA) for folate is 400 mcg per day for adults, 600 mcg per day for pregnant women, and 500 mcg for nursing women. Medicinal dosages of up to 1,000–2,000 mcg per day may be prescribed. Nearly all multivitamin formulations for women include the RDA for folic acid.
Resources
Books
Folic Acid: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References. San Diego, CA: ICON Health Publications, 2004.
Heird, William C. "Nutritional Requirements." In Nelson Textbook of Pediatrics, 17th ed. Edited by Richard E. Behrman, et al. Philadelphia: Saunders, 2003, pp. 153–56.
Rock, Cheryl L. "Nutrition in the Prevention and Treatment of Disease." In Cecil Textbook of Medicine, 22nd ed. Edited by Lee Goldman, et al. Philadelphia: Saunders, 2003, pp. 1308–11.
Russell, Robert M. "Vitamin and Trace Mineral Deficiency and Excess." In Harrison's Principles of Internal Medicine, 15th ed. Edited by Eugene Braunwald et al. New York: McGraw Hill, 2001, pp. 461–69.
Periodicals
Allen, L. H. "Folate and vitamin B12 status in the Americas." Nutrition Reviews 62, no. 6, Pt. 2 (2004): 29–33.
Bailey, L. B. "Folate and vitamin B12 recommended intakes and status in the United States." Nutrition Reviews 62, no. 6, Pt. 2 (2004): S14–20.
Baro, L., et al. "The administration of a multivitamin/mineral fortified dairy product improves folate status and reduces plasma homocysteine concentration in women of reproductive age." International Journal of Vitamin and Nutritional Research 74, no. 3 (2004): 234–40.
Rockel, J. E., et al. "Folic acid fortified milk increases red blood cell folate concentration in women of childbearing age." Asia Pacific Journal of Clinical Nutrition 13, supplement (2004): S84–7.
Organizations
American Academy of Family Physicians. 11400 Tomahawk Creek Parkway, Leawood, KS 66211–2672. Web site: www.aafp.org/.
American Academy of Pediatrics. 141 Northwest Point Boulevard, Elk Grove Village, IL 60007–1098. Web site: www.aap.org/default.htm.
American Association of Naturopathic Physicians. 8201 Greensboro Drive, Suite 300, McLean, VA 22102. Web site:
American Heart Association. National Center, 7272 Greenville Avenue, Dallas, Texas 75231. Web site: www.americanheart.org/Heart_and_Stroke_A_Z_Guide/heim.html.
American Medical Association. 515 N. State Street, Chicago, IL 60610. Web site: www.ama-assn.org/.
American Osteopathic Association. 142 East Ontario Street, Chicago, IL 60611. Web site: www.osteopathic.org/
Web Sites
"Folate (Folacin, Folic Acid)." Ohio State University Extension Fact Sheet. Available online at
"Folic Acid." Centers for Disease Control and Prevention (CDC). Available online at
"Folic Acid." March of Dimes. Available online at www.marchofdimes.com/pnhec/173_769.asp (accessed November 18, 2004).
[Article by: L. Fleming Fallon Jr., MD, DrPH]
Gale Encyclopedia of Public Health:
Folic Acid |
Folic acid, one of the B vitamins, is necessary to make DNA and is, thus, essential for cell division. Folate deficiency causes serious birth defects and anemia, and it increases the risk for heart attacks and strokes. The United States Public Health Service, in 1992, and the Institute of Medicine, in 1998, recommended that all women of reproductive age consume 400 micrograms of synthetic folic acid to prevent birth defects. Most people are folate-deficient unless they eat approximately 400 micrograms of synthetic folic acid per day, either from a vitamin pill or from foods sufficiently fortified with synthetic folic acid. Governments that require adding a sufficient amount of folic acid to centrally processed and commonly eaten foods, such as flour and cornmeal, can eliminate folate deficiency.
(SEE ALSO: Foods and Diets; Micronutrient Malnutrition; Nutrition; Prenatal Care;)
Bibliography
Johnston, R. B., Jr. (1997). "Folic Acid: New Dimensions of an Old Friendship." Advances in Pediatrics 44:231–261.
Oakley, G. P. (1997). "Let's Increase Folic Acid Fortification and Include Vitamin B-12." American Journal of Clinical Nutrition 65:1889–1890.
— GODFREY P. OAKLEY, JR.
Oxford Dictionary of Sports Science & Medicine:
folic acid |
A member of the B-complex of vitamins. Folic acid is a yellow crystalline substance that acts as a coenzyme in the synthesis of nucleic acids and is involved in haematopoiesis (formation of red blood cells). Deficiency causes macrocytic anaemia (enlarged red blood cells), diarrhoea, and other gastrointestinal disorders, and is been linked to brain and spinal cord defects in the embryo. Little is known about the importance of folic acid on physical performance, but deficiency is likely to hinder endurance athletes due to anaemia. Brewer's yeast is a rich source of folic acid.
Gale Encyclopedia of Food & Culture:
Folic Acid |
Folic acid is a water-soluble B-vitamin first identified in 1930 by Wills and Mehta as "Wills factor." Wills factor cured the anemias of pregnant women in India, a clinical condition that commonly results from undernutrition. This vitamin was later isolated from spinach leaves and named folic acid (Latin folium, leaf). Unlike most bacteria and yeast, mammals cannot synthesize folate and, therefore, require folate in the diet. This vitamin is present in the body as a family of at least nine structurally related chemical compounds that are collectively referred to as folate. The term folic acid refers to a synthetic form of the vitamin. Folic acid, which is biologically inactive, is found in foods that have been fortified with it. Folic acid is also the form that is present in nutritional supplements. Folic acid can be converted by living cells to a biologically active form called tetrahydrofolate. This active form serves the same biological function as natural folates. The terms "folic acid" and "folate" are therefore often used interchangeably.
Chemical Forms of Folate
The different forms of folate found in the body exist primarily as modified forms of tetrahydrofolate. Each tetrahydrofolate form differs by modification of the selected positions in the molecule that involve the placement of a single carbon unit. Additionally, folate derivatives found in cells contain a glutamate polypeptide tail that consists of two to eight glutamate residues in length. This polyglutamate chain is required for folates to perform their biochemical functions and also to retain folate in the cell. The glutamate chain prevents the molecule from crossing cell membranes.
Dietary Folate
Vegetables are good dietary sources of naturally occurring folate, especially dark green leafy vegetables. Citrus fruits and fresh juices, berries, legumes, liver, and whole grains are other good sources. Most naturally occurring folates are sensitive to degradation by air and heat but are stabilized when bound to proteins present in foods. For this reason, fresh fruits and vegetables are the best sources of dietary folates since many food folates are destroyed during food preparation. Dietary folates contain a polyglutamate chain that must be removed by digestive enzymes in the intestine. These enzymes leave a single glutamate residue on the folate, and the folate is then absorbed by the intestinal cell. Most folates are taken up by the liver, which is the primary storage site for folate. Folates can then be redistributed to other tissues from the liver. Glutamate chains are re-elongated by the body after the absorption of folates with single glutamates.
Overview of Folate Metabolism
Folate serves as a cofactor that delivers single carbon units to particular enzymes that catalyze biochemical reactions. These folate-dependent biochemical reactions are referred to collectively as one-carbon metabolism. Folate functions in both the cytoplasm and mitochondria, the energy-producing units, of mammalian cells. Folate metabolism in mitochondria is responsible for the generation of formate, a source of one-carbon unit. Formate escapes the mitochondria and is a primary source of the single carbon units for one-carbon metabolism in the cytoplasm. One-carbon metabolism in the cytoplasm is required for the synthesis of DNA precursors, and the amino acid methionine from its precursor, homocysteine. Methionine, in turn, is converted to the cofactor S-adenosylmethionine or SAM. SAM serves as an additional source of single carbon units in the form of methyl groups that are required for other metabolic reactions including the methylation of DNA, RNA, and proteins. SAM also is required for the synthesis of phospholipids, neurotransmitters, and many small metabolites.
Folate As a Therapeutic Target
Folate-dependent reactions are fundamental for DNA synthesis and maintenance of DNA integrity. Therefore, folate is required for cell growth and replication. It is not surprising that folate-dependent enzymes have proven to be effective targets for antitumor and antimicrobial drug therapies. These pharmaceutical agents are structurally similar to folate and are referred to as antifolates. Agents including 5-fluorouracil and methotrexate (and related antifolates) bind to folate-dependent enzymes by mimicking the structure of folate but do not serve the same biological function. These agents enter the cell and inhibit folate-dependent reactions associated with DNA synthesis and result in cell death. Antifolates are used in the treatment of many cancers, Crohn's disease, rheumatoid arthritis, lupus, and other autoimmune disorders.
Folate Deficiency and Disease
The most common impairments of folate metabolism result from inadequate folate intake, certain drug therapies, smoking, malabsorption disorders, alcoholism, genetic mutations, and subtle individual genetic variations that occur normally in populations. Additionally, certain dietary factors can interfere with folate absorption in the gut and result in malabsorption of the vitamin. Inadequate folate status has been reported in many population groups including pregnant and lactating women, women twenty to forty-four years of age, adolescents, and the elderly. Folate requirements are greatly increased during pregnancy due to the high demand for folate by the growing fetus and placenta. Folate deficiency can present itself clinically as megaloblastic anemia, a clinical condition associated with enlarged red blood cells due to decreased DNA synthesis. Other clinical symptoms include an inflamed, redlooking tongue, nausea, vomiting, diarrhea, anorexia, hyperpigmentation, and fever. Folate deficiency during pregnancy is highly associated with several congenital defects including spina bifida. Population studies implicate impaired folate metabolism in other pathologies including cardiovascular disease, colon cancer, cervical dysplasia, and pre-eclampsia.
Folate and Homocysteine
One of the first biochemical indicators associated with impaired folate metabolism is increased serum homocysteine (resulting from decreased methionine synthesis). Both folate and vitamin B12 are required for converting homocysteine to methionine. Plasma homocysteine level is a sensitive marker of folate status, but homocysteine can be influenced by other vitamins, including vitamin B6 and B12 status, as well as age. The relationship between folic acid and homocysteine levels in the body is important because of the association between homocysteine and vascular disease. Elevated plasma homocysteine is now considered an independent risk factor for atherosclerotic vascular disease. The risk of cardiovascular disease rises in proportion to an individual's serum homocysteine concentrations. Some studies also suggest an independent role of folate deficiency in cardiovascular disease. The relationship between homocysteine and disease is not understood, but two mechanisms are the focus of current research. Homocysteine contains a reactive thiol group that can modify proteins and affect their function. Alternatively, homocysteine can also be converted to S-adenosylhomocysteine, which is a potent inhibitor of many methylation reactions that modify DNA proteins and influences gene expression. Either or both of these mechanisms may account for pathologies that are associated with elevated homocysteine in humans.
Dietary Recommendations
In 1998, the National Academy of Sciences released the Dietary Reference Intake (DRI) values for folate that include a recommended dietary allowance (RDA) of 400 micrograms for males and females aged fourteen years and younger. For these individuals, the source of folate is not important. However, it is recommended that women of childbearing age consume an additional 400 micrograms of folic acid per day from fortified foods and/or supplements in addition to the intake of food folate from a varied diet. It is critical that women be folate-sufficient prior to pregnancy, since most birth defects that result from folate deficiency occur before the twenty-ninth day of pregnancy, often before the woman realizes she is pregnant. Maintaining adequate folate status is especially critical for women with a history of bearing children with neural tube defects, to prevent future incidence of birth defects. Pregnant women should consume an additional 600 micrograms of synthetic folate per day in addition to a naturally folate-rich diet. It is not normally recommended that anyone consume more than 1 milligram of folate per day.
The RDA is expressed as dietary folate equivalents (DFEs) because synthetic folic acid is more easily absorbed in the intestine than naturally occurring folate. One microgram of naturally occurring food folate is equivalent to 0.6 microgram of folic acid from fortified foods or supplements consumed with meals and to 0.5 microgram of supplements not consumed with meals. Because of recent federal regulations for food fortification, synthetic folic acid can now be found not only in dietary supplements, but also in enriched grain products (0.43 to 1.4 milligrams of folic acid per pound grain product) such as flour and pasta. Initial results from the fortification program indicate that plasma folate levels have more than doubled among adults who do not use folic acid supplements. The effect of this program on reducing spina bifida and other folate-associated birth defects and pathologies is yet to be determined.
Bibliography
Centers for Disease Control and Prevention. "Knowledge and Use of Folic Acid by Women of Childbearing Age—United States, 1997." Morbidity and Mortality Weekly Report 46, no. 31 (8 August 1997): 721–723.
Centers for Disease Control and Prevention. "Recommendations for the Use of Folic Acid to Reduce the Number of Cases of Spina Bifida and Other Neural Tube Defects." Morbidity and Mortality Weekly Report, 41 no RR–14 (11 September 1992).
Gregory, Jesse F. "The Bioavailability of Folate" In Folate inHealth and Disease. Edited by Lynn B. Bailey. New York: M. Dekker, 1995.
Lindenbaum, John, and Robert H. Allen. "Clinical Spectrum and Diagnosis of Folate Deficiency" In Folate in Health and Disease. Edited by Lynn B. Bailey. New York: Marcel Dekker, 1995.
Shane, Barry. "Folate Chemistry and Metabolism." In Folate inHealth and Disease. Edited by Lynn B. Bailey. New York: Marcel Dekker, 1995.
Standing Committee on the Scientific Evaluation of Dietary Reference Intakes, Food and Nutrition Board, Institute of Medicine. "Dietary Reference Intakes: Folate, Other B Vitamins, and Choline." Washington, D.C., National Academy Press (7 April 1998).
Wagner, Conrad. "Biochemical Role of Folate in Cellular Metabolism" In Folate in Health and Disease. Edited by Lynn B. Bailey. New York: M. Dekker, 1995.
—Patrick J. Stover
Wiley Dictionary of Flavors:
Folic Acid |
Oxford Dictionary of Biochemistry:
folic acid |
| folding unit, folding problem, foldback DNA | |
| folic acid conjugate, folic acid reductase, folinic acid |
Saunders Veterinary Dictionary:
folic acid |
One of the vitamins of the B complex. Folic acid is involved in the synthesis of amino acids and DNA; its deficiency causes megaloblastic anemia. Folic acid is supplied in adequate amounts by natural pasture plants and most diets for dogs and cats. Possibly required in greater amounts in racing horses confined to stables. Called also vitamin Bc, pteroylmonoglutamic acid.
Mosby's Dental Dictionary:
folic acid |
Vitamin B9, a water-soluble B vitamin needed for erythro-poiesis, increases red blood cell, white blood cell, and platelet formation in megaloblastic anemias. Folic acid functions as a coenzyme with vitamin B12 and C in the breakdown and utilization of proteins and in the formation of nucleic acids. It is prescribed for use during pregnancy, megaloblastic or macrocytic anemia caused by folic acid deficiency, liver disease, alcoholism, hemolysis, and intestinal obstruction.
Random House Word Menu:
categories related to 'folic acid' |

Wikipedia on Answers.com:
Folic acid |
| Folic acid | |
|---|---|
|
(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 |
| PubChem | 6037 |
| ChemSpider | 5815 |
| UNII | 935E97BOY8 |
| DrugBank | DB00158 |
| KEGG | C00504 |
| ChEBI | CHEBI:27470 |
| ChEMBL | CHEMBL1622 |
| RTECS number | LP5425000 |
| ATC code | B03 |
| Jmol-3D images | Image 1 |
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| Properties | |
| Molecular formula | C19H19N7O6 |
| Molar mass | 441.4 g mol−1 |
| Appearance | yellow-orange crystalline powder |
| Melting point | |
| Solubility in water | 1.6 mg/L (25 °C)[1] |
| Acidity (pKa) | 1st: 4.65, 2nd: 6.75, 3rd: 9.00[2] |
| Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa) |
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| 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 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]
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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]
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]
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.
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]
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]
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]
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 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]
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]
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.
| 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.[69]
Certain foods are very high in folate:
Moderate amounts:
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]
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]
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]
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:
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.[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]
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]
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]
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.
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]
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 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]
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]
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]
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| vitamin M | |
| rhizopterin | |
| vitamin Bc |
| Can you take folic acid if you have gout? Read answer... | |
| Usages of folic acid in men? Read answer... | |
| What is folic acid medication? Read answer... |
| Which is stronger folic acid or hydrofolic acid? | |
| Where can you get folic acid from? | |
| Is 1mg folic acid equal to 1000 mcg of folic acid? |
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