Folic acid is a synthetic member of the folate (Vitamin B9) family, a group of chemically related compounds with shared biological activity. Naturally occurring folates exist primarily in reduced, methylated and/or polyglutamate-conjugated states and have relatively low oral bioavailability. Folic acid is oxidation-resistant and demonstrates increased bioavailability and stability. Dietary folates and orally administered folic acid are absorbed intestinally, reduced to dihydrofolate and tetrahydrofolate (THF) by dihydrofolate reductase (DHFR), and released into circulation. THF acts as a one-carbon acceptor, serving as a critical substrate in the biosynthesis of glycine from serine. Methylated forms of THF act as carbon donors in the synthesis of thymidine and purine nucleotides, and facilitate the conversion of homocysteine to methionine. Several commonly-used drugs impair folate metabolism, including methotrexate (DHFR antagonist), trimethoprim and pyrimethamine (bacterial DHFR antagonist), and sulfonamide antibiotics (bacterial folate synthesis).
Orally consumed folic acid and natural folates are deconjugated by the intestinal brush border and subsequently absorbed, modified, and released into circulation (primarily as 5-methyltetrahydrofolate) by intestinal mucosal cells. Folic acid delivered orally in large quantities or via parenteral routes of administration is thought to undergo conversion to biologically active forms in the plasma or peripheral tissues.
Lucy Wills (1888-1964), a pioneering British hemato-pathologist, first identified a component in marmite (a yeast extract) in the 1930’s that could reverse megaloblastic, “pernicious” anemia in pregnant women in Mumbai, India. This compound would eventually be identified as folate, or Vitamin B9. Folic acid, a synthetic form of folate, was first approved by the FDA as a pharmaceutical agent in 1947 as a treatment for megaloblastic anemia and anemias of pregnancy, nutritional, or pediatric origin. 40 years later the FDA would impose regulations that required folic acid fortification of enriched grain products as a preventative measure to reduce the incidence of fetal neural tube defects.
History and Foundational Studies
1930-31 – Yeast extract used to correct ‘pernicious anemia of pregnancy’ and ‘tropical anemia’
1932-33 – Marmite used to treat macrocytic anemia in celiac disease
1941 – Folate isolated from, and named after, spinach leaves (‘folium’)
1945 – Folic acid first synthesized in laboratory
1946 – Folic acid found to suppress anemia, but not neurological damage in pernicious anemia patients
1947 – Folic acid is approved by the United States FDA for the “treatment of megaloblastic anemias due to a deficiency of folic acid (as may be seen in tropical or nontropical sprue) and in anemias of nutritional origin, pregnancy, infancy, or childhood.”
1998 – FDA mandates enriched grain fortification with folic acid