FOLATE

Folate is an essential vitamin that is also known as folic acid and folacin. The synthetic form of the vitamin (folic acid), pteroylglutamic acid, is seldom found naturally in food. The folates found in nature contain the core chemical structure of pteroylglutamic acid but vary in their state of reduction, the single carbon moiety they bear and/or the length of the glutamate chain attached. At least 50% of whole body folate is stored in the liver.

The metabolic role of folate is as an acceptor and donor of one-carbon units in a variety of reactions involved in amino acid and nucleotide metabolism. The carbon can be carried as a methyl, methylene, formyl, formimino or methenyl group. The coenzyme form of the vitamin is typically fully reduced and poly-glutamylated. In the adult, folate is absorbed primarily in the proximal one-third of the small intestine. It is also conceivable that a portion of the large depot of bacterially synthesized folate in the large intestine may be absorbed. A large portion of folate delivered to the liver is secreted into bile and redistributed to peripheral tissues. Polyglutamylation (addition of glutamic acids) of folate is believed necessary to concentrate and store folates in tissues.

Deficiencies: Given the role that folate coenzymes play in the synthesis of RNA, DNA and protein, it is not surprising that the folate requirement and, consequently, the risk of deficiency is elevated during periods of rapid growth and/or enhanced metabolic activity (e.g. pregnancy, lactation). Overt symptoms of severe folate deficiency such as depapillation of the tongue are uncommon. Megaloblastic anemia, indistinguishable from megaloblastic anemia secondary to vitamin B12 deficiency, is a more frequently cited functional outcome. Less than optimal maternal folate status has been implicated in a number of negative maternal and fetal outcomes, including low infant birthweight, abruptio placenta, cervical dysplasia and neural tube defects. Low folate intakes also are correlated with high levels of serum homocysteine which are associated with an increased risk of atherosclerosis and several forms of vascular disease. However, it is unclear currently whether supplemental folate lowers risk.

Clinical Uses: Recent public policy recommendations suggest that women of child-bearing potential consume 400 µg/d of folate to reduce the number of pregnancies affected by a neural tube defect. Consumption of large amounts of folate may interfere with the diagnosis of pernicious anemia, a condition not uncommon in the elderly which may produce neurologic defects. Very high doses of folic acid may counteract certain antiepileptic drugs. Because of the importance of folate in the synthesis of nucleotides, which are required for cell multiplication, antifolate drugs such as methotrexate are important in cancer therapy. When methotrexate is used in arthritis therapy, folate supplements often are used to lessen side effects.

Diet Recommendations: The Dietary Reference Intakes (DRIs) for folate each day are 400 µg Dietary Folate Equivalents (DFE) for adults and teenagers. Pregnant women need a greater amount, 600 µg DFE, for building red blood cells; lactating women require 500 µg. For children, DRIs are 65 µg for infants 0-0.5 yr. and 80 µg for infants 0.5-1 yr.; and 150 µg for ages 1-3 yr., 200 µg for ages 4-8 yr., and 300 µg for ages 9 - 13 yr.

Food Sources: The folate content of foods is inherently variable and a large fraction of the folate consumed each day comes from foods that are frequently ingested, but not particularly concentrated, sources of the vitamin. Excellent food sources of folate (>55 µg/d) include fortified cereals, citrus fruits and juices, asparagus, Brussels sprouts, spinach, baked beans, chickpeas, kidney beans or lentils.

Many cereal-grain foods (flour, rice, pasta, cornmeal) constitute important sources because they are fortified with folic acid. Folate bioavailability varies with food type and overall diet composition. In general, added folic acid in fortified foods is absorbed more efficiently than many forms of naturally-occurring folate.

Toxicity:Most reports of folate toxicity have involved massive (nonphysiological) doses given by injection. Such massive doses have produced evidence of neuro- and nephrotoxicity. The main concern of large doses of dietary folate intakes and commonly available supplements is that a large intake might mask a B12 deficiency by allowing some synthesis of blood cells by temporarily relieving the block of nucleotide synthesis. This possibility should be continually evaluated in populations at risk, including the elderly individuals. Under conditions of typical intake in the US population, the beneficial effects of improved folate status currently outweigh this small potential risk.

For Further Information:

Bailey, L. B. and Gregory, J. F. (1999) Folate metabolism and requirements. J. Nutr. 129: 779-782.

Bailey, L. B. and Gregory, J. F. (1999) Polymorphisms of methylenetetrahydrofolate reductase and other enzymes: metabolic significance, risks and impact on folate requirement. J. Nutr. 129: 919-922.

Committee on the Scientific Evaluation of Dietary Reference Intakes, Institute of Medicine (1998) Folate. In: Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic acid, Biotin, and Choline. pp. 8-1 - 8-68. National Academy Press, Washington, DC.

Selhub, J. & Rosenberg, J. H. (1996) Folic acid. In: Present Knowledge in Nutrition (Ziegler, E.E. and Filer, L. J., eds.), 7th ed., pp. 206-219. International Life Sciences Institute Press, Washington, DC.

Prepared By:

Susan Ettinger
Assistant Director
Clinical Nutrition
417 West 120th Street
Apt. #2A
New York, NY 10027-6041
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Jesse F. Gregory, Ph.D.
Professor
Dept of Food Science & Human Nutrition
University of Florida
P.O. Box 110370
Gainesville, FL 32611-0370
Phone: 904-392-1991
FAX: 904-392-9467
Email: jfgy@gnv.ifas.ufl.edu