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More about Folic Acid: Purpose Preparations Precautions Side effects Interactions Resources

Definition

Folic acid is a water-soluable 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, and there is evidence that deficiency is a problem on a worldwide scale. 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 and to help prevent neural tube defects (NTD).

— Patience Paradox

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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 B_c.

[Latin folium, leaf; see folium + –IC.]

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:

• Pregnancy or breast-feeding.
• Pernicious anemia.
• Allergies to leucovorin or any other drugs.
• Vitamin B¹² deficiency. Folic acid may mask hematologic signs of B₁₂ deficiency while neurologic damage progresses.

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

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.

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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.

folacin; pteroyl-l-glutamic 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.

n

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.

Brand names: Folvite®

Drug Forms:
• Folic Acid, Vitamin B₉ tablets (below)
• Folic Acid, Vitamin B₉ injection

Español:
• Tabletas de ácido fólico, vitamina B₉
• Inyección de ácido fólico, vitamina B₉

Folic Acid, Vitamin B₉ tablets

What are folic acid tablets?

FOLIC ACID (Folate, Vitamin B₉) is a B-complex vitamin that occurs naturally in such foods as yeast, liver, kidneys, and leafy, green vegetables. Folic acid is essential to the development of healthy blood cells, nerve cells, and proteins in the body. As a nutritional supplement folic acid treats or prevents folic acid deficiency and certain types of anemia. It helps treat tropical sprue, a condition sometimes seen in people who travel to tropical climates, in which food nutrients are not properly absorbed. There is also increasing evidence that some birth defects (neural tube defects or spina bifida) are related to lack of folic acid. These may be prevented if the mother has enough folic acid before and during her pregnancy. Generic folic acid tablets are available. Some multivitamin products for use as dietary supplements contain small amounts of folic acid.

What should I tell my health care provider before I take this medicine?

They need to know if you have any of these conditions:
• pernicious anemia
• an unusual or allergic reaction to folic acid, other B vitamins, other medicines, foods, dyes, or preservatives

How should I take this medicine?

Take folic acid tablets by mouth. Follow the directions on the prescription label. Swallow the tablets whole with a glass of water. Take your doses at regular intervals. Do not take your medicine more often than directed.

What if I miss a dose?

If you miss a dose, and are taking folic acid as a dietary supplement, skip the missed dose. If you are being treated for anemia and miss a dose there is no cause for concern, take it as soon as you can. If it is almost time for your next dose, take only that dose. Do not take double or extra doses.

What drug(s) may interact with folic acid?

• chloramphenicol
• cholestyramine
• methotrexate
• phenytoin
• pyrimethamine
• triamterene
• trimethoprim

Tell your prescriber or health care professional about all other medicines you are taking, including non-prescription medicines, nutritional supplements, or herbal products. Also tell your prescriber or health care professional if you are a frequent user of drinks with caffeine or alcohol, if you smoke, or if you use illegal drugs. These may affect the way your medicine works. Check with your health care professional before stopping or starting any of your medicines.

What should I watch for while taking folic acid?

Make sure you have a proper diet. Taking vitamin supplements is not a substitute for a healthy diet. Foods that contain folic acid include: whole grains/cereals, fruits, beans, leafy green vegetables, organ meats (liver, kidney), and potatoes. Be sure to include some of these in your diet each day. Note that folic acid is destroyed by overcooking or canning.

There is no scientific evidence to support claims that large doses of B vitamins prevent certain mental disorders. Treating yourself with large doses of folic acid can be unsafe. Do not treat yourself without your prescriber's advice.

What side effects may I notice from taking folic acid?

Folic acid is a water-soluble vitamin and when taken at prescribed doses is unlikely to cause side effects in patients with healthy kidneys. Side effects may be caused by an allergy to folic acid.
Possible side effects with folic acid include:
• chest tightness or pain
• depression
• irritability
• loss of appetite
• nausea, vomiting
• skin rash, redness and itching
• wheezing or shortness of breath

Where can I keep my medicine?

Keep out of the reach of children in a container that small children cannot open.

Store at room temperature between 15 and 30 degrees C (59 and 86 degrees F). Protect from light. Folic acid 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.

Description

Folic acid is a water-soluable vitamin belonging to the B-complex group of vitamins. These vitamins help the body break down complex carbohydrates into simple sugars that can be readily 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.

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, and there is evidence that deficiency is a problem worldwide. Folic acid is found in leafy green vegetables, beans, peas and lentils, liver, beets, Brussels 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 and to help prevent neural tube defects (NTD) in the fetus during pregnancy.

General Use

Folic acid works together with vitamin B₁₂ and vitamin C to metabolize protein. It is important for the formation of red and white blood cells. Folic acid is necessary for the proper differentiation and growth of cells, and for the development of the fetus. It is also used to form the nucleic acid of DNA and RNA. It increases the appetite, stimulates the production of stomach acid for digestion, and aids in maintaining a healthy liver. A folic acid deficiency may lead to megaloblastic anemia, in which there is decreased production of red blood cells, and the cells that are produced are abnormally large. This reduces the amounts of oxygen and nutrients that are able to reach 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.

People who are at high risk for strokes and heart disease may benefit from folic acid supplements. An elevated blood level of the amino acid homocysteine has been identified as a risk factor for some of these diseases. High levels of homocysteine have also been found to contribute to problems with osteoporosis. Folic acid, together with vitamins B₆ and B₁₂, aids in the breakdown of homocysteine, and may help reverse the problems associated with elevated levels.

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 neural tube defects (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 such as spina bifida or anencephaly, may occur. 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 50–70%. It also helps prevent cleft lip and palate.

Research shows that folic acid can be used to successfully treat cervical dysplasia, a condition that is diagnosed by a Pap smear, and consists of abnormal cells in the cervix. This condition is considered to be a possible precursor to cervical cancer. Daily consumption of 1,000 micrograms (mcg) of folic acid for three or more months has resulted in improved cervical cells upon repeat Pap smears.

Studies suggest that long-term use of folic acid supplements may also help prevent lung and colon cancers. Researchers have also found that alcoholics who have low folic acid levels face a greatly increased chance of developing colon cancer.

Preparations

Supplements are taken to correct a folic acid deficiency. 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 Allowance (RDA) for folate is 400 mcg per day for adults, 600 mcg per day for pregnant women, and 500 mcg daily for nursing women. Medicinal dosages of up to 1,000 to 2,000 mcg per day may be prescribed.

Precautions

Folic acid is not stable. It is easily destroyed by exposure to light, air, water, and cooking. Therefore, the supplement should be stored inside a dark container in a cold, dry place, such as a refrigerator. Many medications interfere with the body's absorption and ability to use folic acid. These medications include sulfa drugs, sleeping pills, estrogen, anti-convulsants, birth control pills, antacids, quinine, and some antibiotics.

The anemia caused by folic acid deficiency is identical to that caused by lack of vitamin B₁₂. Using large amounts of folic acid (e.g., over 5,000 mcg per day) can mask a vitamin B₁₂ deficiency, since the anemia will improve but the other effects of vitamin B₁₂ deficiency will continue. This can lead to irreversible nerve damage. Therefore, people with megaloblastic anemia should be treated under medical supervision, since regular testing may be required.

Side Effects

Folic acid is generally considered safe at levels of 5,000 mcg or less. 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.

Interactions

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.

Resources

Books

Braverman, Eric R., M.D., Carl C. Pfeiffer, M.D., Ph.D., Ken Blum, Ph.D., and Richard Smayda, D.O. The Healing Nutrients Within. New Canaan, CT: Keats Publishing, 1997.

Periodicals

Fallest-Strobl, Patricia, Ph.D., David Koch, James Stein, and Patrick McBride. "Homocysteine: A New Risk Factor for Atherosclerosis." American Family Physician (October 15, 1997): 1607-14.

Organizations

Centers for Disease Control and Prevention. 4770 Buford Highway NE, MSF-45, Atlanta, GA 30341-3724. (888) 232-6789. Flo@cdc.gov. .

Other

Adams, Suzanne L. The Art of Cytology: Folic Acid/B-12 Deficiency [cited June 6, 2004]. .

"Folic Acid." Cybervitamins [cited June 6, 2004]. .

"Folic Acid: Coming to A Grocery Store Near You" [cited June 6, 2004]. .

"Folic acid (oral/injectible)." Dr. Koop.com. Inc. 700 N. Mopac, Suite 400, Austin, TX 78731. .

Pregnancy and Nutrition Update. MayoHealth [cited June 6, 2004]. .

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 (accessed November 18, 2004).

"Folic Acid." Centers for Disease Control and Prevention (CDC). Available online at (accessed November 18, 2004).

"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]

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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.

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For more information on folic acid, visit Britannica.com.

folate: pteroylglutamic 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.

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

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 B_c, pteroylmonoglutamic acid.

• f. a. antagonist — a compound such as trimethoprim or methotrexate which acts as an antimetabolite of folic acid, interfering with DNA replication and cell division by inhibiting the enzyme dihydrofolate reductase.