Dietary Supplement Fact Sheet
Folate is a water-soluble B vitamin that is naturally present in some foods, added to others, and available as a dietary supplement. Folate, formerly known as folacin, is the generic term for both naturally occurring food folate and folic acid, the fully oxidized monoglutamate form of the vitamin that is used in dietary supplements and fortified foods. Folic acid consists of a p-aminobenzoic molecule linked to a pteridine ring and one molecule of glutamic acid. Food folates, which exist in various forms, contain additional glutamate residues, making them polyglutamates [1 ].
Folate functions as a coenzyme or cosubstrate in single-carbon transfers in the synthesis of nucleic acids (DNA and RNA) and metabolism of amino acids [1-3 ]. One of the most important folate-dependent reactions is the conversion of homocysteine to methionine in the synthesis of S-adenosyl-methionine, an important methyl donor [1-3 ]. Another folate-dependent reaction, the methylation of deoxyuridylate to thymidylate in the formation of DNA, is required for proper cell division. An impairment of this reaction initiates a process that can lead to megaloblastic anemia, one of the hallmarks of folate deficiency [3 ].
When consumed, food folates are hydrolyzed to the monoglutamate form in the gut prior to absorption by active transport across the intestinal mucosa [2 ]. Passive diffusion also occurs when pharmacological doses of folic acid are consumed [2 ]. Before entering the bloodstream, the monoglutamate form is reduced to tetrahydrofolate (THF) and converted to either methyl or formyl forms [1 ]. The main form of folate in plasma is 5-methyl-THF. Folic acid can also be found in the blood unaltered (known as unmetabolized folic acid), but whether this form has any biological activity or can be used as a biomarker of status is not known [4 ].
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The total body content of folate is estimated to be 10 to 30 mg; about half of this amount is stored in the liver [1 ,3 ] and the remainder in blood and body tissues. A serum folate concentration is commonly used to assess folate status, with a value above 3 nanograms (ng)/mL indicating adequacy [1 ,2 ]. This indicator, however, is sensitive to recent dietary intake, so it might not reflect long-term status. Erythrocyte folate concentration provides a longer-term measure of folate intakes, so when day-to-day folate intakes are variable—such as in people who are ill and whose folate intake has recently declined—it might be a better indicator of tissue folate stores than serum folate concentration [2 ,4 ]. An erythrocyte folate concentration above 140 ng/mL indicates adequate folate status [2 ,4 ], although some researchers have suggested that higher values are optimal for preventing neural tube defects
A combination of serum or erythrocyte concentration and indicators of metabolic function can also be used to assess folate status. Plasma homocysteine concentration is a commonly used functional indicator of folate status because homocysteine levels rise when the body cannot convert homocysteine to methionine due to a 5-methyl-THF deficiency. Homocysteine levels, however, are not a highly specific indicator of folate status because they can be influenced by other factors, including kidney dysfunction and deficiencies of vitamin B12 and other micronutrients [1 ,3 ,6 ]. The most commonly used cutoff value for elevated homocysteine is 16 micromoles/L, although slightly lower values of 12 to 14 micromoles/L have also been used [2 ].
Intake recommendations for folate and other nutrients are provided in the Dietary Reference Intakes (DRIs) developed by the Food and Nutrition Board (FNB) at the Institute of Medicine (IOM) of the National Academies (formerly National Academy of Sciences) [2 ]. DRI is the general term for a set of reference values used for planning and assessing nutrient intakes of healthy people. These values, which vary by age and gender, include:
- Recommended Dietary Allowance (RDA): average daily level of intake sufficient to meet the nutrient requirements of nearly all (97%–98%) healthy individuals.
- Adequate Intake (AI): established when evidence is insufficient to develop an RDA and is set at a level assumed to ensure nutritional adequacy.
- Estimated Average Requirement (EAR): average daily level of intake estimated to meet the requirements of 50% of healthy individuals. It is usually used to assess the adequacy of nutrient intakes in populations but not individuals.
- Tolerable Upper Intake Level (UL): maximum daily intake unlikely to cause adverse health effects.
Table 1 lists the current RDAs for folate as micrograms (mcg) of dietary folate equivalents (DFEs). The FNB developed DFEs to reflect the higher bioavailability of folic acid than that of food folate. At least 85% of folic acid is estimated to be bioavailable when taken with food, whereas only about 50% of folate naturally present in food is bioavailable [2 ,3 ]. Based on these values, the FNB defined DFE as follows:
- 1 mcg DFE = 1 mcg food folate
- 1 mcg DFE = 0.6 mcg folic acid from fortified foods or dietary supplements consumed with foods
- 1 mcg DFE = 0.5 mcg folic acid from dietary supplements taken on an empty stomach
For infants from birth to 12 months, the FNB established an AI for folate that is equivalent to the mean intake of folate in healthy, breastfed infants in the United States.
Table 1: Recommended Dietary Allowances (RDAs) for Folate [2 ]