Introduction
Folic Acid is a water-soluble B-vitamin that is comprised of pteridine, para-aminobenzoic acid (PABA) conjugated with one, three or seven molecules of glutamic acid. Some of the glutamic acid molecules must be split off to form an unconjugated Folic Acid molecule, pteroylmonoglutamic acid (PGA), which is the active form referred to as Folic Acid. Vitamin B12 is required to convert Folic Acid into its active form. Because Folic Acid was first discovered in spinach leaves, it was called Folic Acid from the Latin “folium” leaf.
Absorption and Metabolism
Folic Acid is well absorbed from the intestinal tract. In the presence of Nicotinamide Adenine Dinucleotide (NAD), Folic Acid is reduced to tetrahydrofolic acid in the body. The liver contains half the body stores of Folic Acid.
Functions
In conjunction with Vitamin B12, Folic Acid enables each cell in the body to recycle homocysteine back to methionine by providing an all-important methyl group. From methionine the body easily makes S-adenosyl methionine by adding an adenosyl ring from Adenosine Triphosphate (ATP). Once formed, S-adenosyl methionine can transfer its methyl group to permit the synthesis of thymine nucleotides of DNA, neurotransmitters in the brain, creatine in the liver and other crucial functions, including a direct effect on detoxification reactions in the liver. A deficiency of either Folic Acid or Vitamin B12 results in megaloblastosis, or the development of red blood cells that are enlarged because normal cell division has not taken place.1
As a major dietary source of a transferable methyl group, Folic Acid is a vital nutrient for DNA synthesis and hence, the prevention of neural tube defects (e.g., spina bifida, anencephaly) and hypomethylation of DNA, which is linked to increased cancer risk.2,3
Because it helps to recycle homocysteine to methionine it is also important in the prevention of atherosclerosis, due to its ability to contain the build up on homocysteine. When elevated levels of homocysteine occur in body cells, it diffuses out of the cells to enter the bloodstream. In the bloodstream homocysteine oxidizes LDL-cholesterol, promotes vasoconstriction, coagulation of platelets, thereby accelerating the atherosclerotic process leading to heart attack, stroke and peripheral vascular disease.4,5
Folic Acid is vital for the synthesis of red blood cells, hence the onset of megaloblastic anemia in folate deficiency.
Recommended Dietary Allowance (Folic Acid)
Supplementation Studies
Prevention of Neural Tube Defects
If all women of childbearing age ingested a minimum of 400 mcgs of Folic Acid from a combination of food and supplementation, there would be a 48 percent reduction in the incidence of neural tube defects. Presently, the average ingestion of Folic Acid is only 180 mcg per day from food.2
Heart Disease
Elevated homocysteine is considered to account for approximately 10 percent of the risk for coronary artery disease.4 Supplementation studies with Folic Acid have been shown to reduce elevated homocysteine levels into a safer range (<10 micromoles per litre, or μmol/L). Folic Acid supplementation of 200 mcg reduces homocysteine by approximately 4 μmol/L. A 5 μmol/L homocysteine increment elevates coronary artery disease risk by as much as a cholesterol elevation of 0.5 μmol/L (20 mg/dL). Supplementation studies to lower homocysteine have used 1 to 2.5 mg of Folic Acid daily. Note that Vitamin B6 and Vitamin B12 are also important to homocysteine metabolism. These vitamins work synergistically with Folic Acid to lower and regulate homocysteine levels.4-8
Cervical Dysplasia
In clinical studies Folic Acid supplementation (10 mg per day) has been shown to reverse early and moderate stage cervical dysplasia as demonstrated by pap smear testing. Success rates vary from 20 to 100 percent. Folic Acid appears to improve the integrity (chromosomal linkages) of cervical DNA, making it less resistant to the effect of the human papilloma virus (HPV). The HPV is known to cause cervical dysplasia.9,10,11
The B-vitamin Folic Acid is critical to synthesis of normal DNA as cells divide from one generation to the next. Cells that line the cervix replace themselves every 7-14 days and, therefore, the cells must continuously form DNA as part of their genetic structure. Previous studies have demonstrated that poor Folic Acid status can lead to DNA abnormalities with subsequent development of cervical dysplasia or megaloblastic features of cervical cells (large abnormal cell appearance).
Oral contraceptives are known to increase the rate of cell division of cervical cells, hence, escalating the need for adequate Folic Acid intake. Studies by Whitehead et al. and Butterworth et al. demonstrated that Folic Acid supplementation could reverse cervical megaloblastic charges and cervical dysplasia, respectively, in patients using oral contraceptives. In fact, oral contraceptive use is a known risk factor for cervical dysplasia, primarily due to its effect on speeding up cell division rates.
In the study by Butterworth et al., patients with mild and moderate degrees of cervical dysplasia showed reversal of their condition over a 3-month trial period with Folic Acid supplementation.
In both studies the authors noted a statistically lower mean red blood cell Folic Acid concentration in oral contraceptive users compared with non-users, which was particularly marked in patients with cervical dysplasia. Red blood cell Folic Acid levels are considered a good indicator of Folic Acid status.
Other population studies (epidemiologic) consistently support the hypothesis that Folic Acid plays a protective role in the prevention of cervical dysplasia.
Unfortunately, up to 88 percent of the population consumes less than 400 mcg per day of Folic Acid. This is the level that women should ingest to reduce the risk of spinal birth defects in their offspring, and may help defend against cervical dysplasia.12
Depression in the Elderly
Correction of an underlying Folic Acid deficiency has demonstrated significant reversal of mental and psychological symptoms in some patients, especially elderly patients suffering from impaired mental function. Folic Acid is required to synthesize S-adenosyl-methionine and tetrahydrobioptein (BH4). These substances participate as coenzymes in the production of serotonin, thus exerting a mild antidepressant effect. To correct a folate deficiency where psychological symptoms are present, a daily dose of 10 mg is used until the deficiency state is corrected (see Vitamin B12 for more details).13-18
Interactions
Folic Acid supplementation should always include Vitamin B12 supplementation (400-1,000 mcg Folic Acid) because Folic Acid supplementation can mask an underlying Vitamin B12 deficiency, until serious neurological signs and symptoms of B12 deficiency manifest themselves.1
Folic AcicToxicity
Folic Acid is well tolerated, even at high daily dosages used to treat cervical dysplasia (e.g. 5-10 mg). However, high dosages can cause nausea, loss of appetite and gastro-intestinal-upset. It may also increase seizure activity in epileptics.
Drug-Nutrient Interactions
Antacids (containing aluminum/magnesium): These drugs reduce stomach acid and consequently impair Folic Acid absorption19
Bile Acid Sequestrants (cholestyramine, colestipol): These drugs decrease Folic Acid absorption.20
H2 Receptor Antagonists (cimetidine, famotidine, nizatidine, ranitidine): These drugs decrease stomach acid and thereby also decrease Folic Acid absorption21
Potassium Sparing Diuretics (triamterene, HCT21 triamterine): These drugs inhibit Folic Acid absorption in animal studies.22,23
Alcohol: Excessive alcohol intake depletes Folic Acid status.24
Anticonvulsants (barbituates, fosphenytoin, phenytoin, carbamazepine, primidone): These drugs are reported to deplete Folic Acid levels. However, high dose Folic Acid supplementation may counteract the drugs’ effectiveness.25-29
Salicytates: These drugs increase urinary loss of Folic Acid (eg. Aspirin, diflunisal, salsalate).30,31
Corticosteroid Drugs (prednisone): These drugs are reported to decrease blood levels Folic Acid.32
Non Steroidal Anti-inflammatory Drugs (NSAIDs): Animal studies reveal that these drugs interrupt the use of Folic Acid in the body.33
Oral Contraceptives: These drugs promote Folic Acid depletion.34,35
Metformin: This drug is reported to cause depletion of Folic Acid.36
Methotrexate: This cancer drug is designed to interrupt the use of Folic Acid by cancer cells to block their DNA syntheses. Do not supplement with Folic Acid if patient is taking methotrexate for cancer treatment.37,38 Conversely,
patients taking methotrexate to treat rheumatoid diseases are usually instructed to take Folic Acid.
Trimethoprim Containing antibiotics: These drugs promote Folic Acid depletion.39
Sulfasalazine: Animal studies suggest that this drug interrupts the use of Folic Acid.40
Standard Textbooks of Nutritional Science:
- Shils M, Shike M, Olson J, Ross C. Modern Nutrition in Health and Disease. 9th ed. Baltimore, MD: Lippincott Williams & Wilkins; 1993.
- Escott-Stump S, Mahan LK, editors. Food, Nutrition and Diet Therapy. 10th ed. Philadelphia, PA: W.B. Saunders Company; 2000.
- Bowman B, Russell RM, editors. Present Knowledge in Nutrition, 8th ed. Washington, DC:.ILSI Press; 2001.
- Kreutler PA, Czajka-Narins DM, editors. Nutrition in Perspective. 2nd ed. Upper Saddle River, NJ: Prentice Hall Inc.; 1987.
Daly LE. Folate levels and neural tube defects. JAMA 1997;274(21):1698-703.
Kim YI, Pogribny IP, Basnakian AG, Miller JW, Selhub J, James SJ, et al. Folate deficiency in rats induces DNA strand breaks and hypomethylation within the p53 tumor suppressor gene. Am J Clin Nutr 1997;65:46-52.
Boushey C, Beresford SAA, Omenn GS, Motulsky A. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease: probable benefits of increasing folic acid intakes. JAMA 1995;274(13):1049-57.
Rimm EB, Willett WC, Hu FB, Sampson L, Colditz GA, Manson JE, et al. Folate and Vitamin B6 from diet and supplements in relation to risk of coronary heart disease among women. JAMA 1998;279(5):359-66.
Landgren F, Israelsson B, Lindgren A, Hultberg B, Andersson A, Brattstrom L. Plasma homocysteine in acute myocardial infarction: homocysteine lowering effect Folic acid. J Int Med 1995;237:381-8.
Ubbink JB, Vermaak WJ, Van der Merwe A, Becker PJ. Vitamin B12, Vitamin B6, and folate nutritional status in men with hyper-homocysteinemia. Am J Clin Nutr 1998;57:47-53.
Ubbink JB, vander Merwe WJ, Delport R. Hyperhomocysteinimia and the response to vitamin supplementation. Clin Invest 1993;71,993-8.
Streiff R. Folate deficiency and oral contraceptives. JAMA 1970;214:105-8.
Whitehead N, Reyner Fand Lindenbaum J. Megaloblastic changes in the cervical epithelium association with oral contraceptive therapy and reversal with Folic Acid. JAMA 1973;226:1421-4.
Butterworth CE Jr., Hatch KD, Gore H, Mueller H, Krumdieck CL. Improvement in cervical dysplasia associated with Folic Acid therapy in users of oral contraceptives. Am J Clin Nutr 1982;35:73-82.
Meyskens FL, Manetta A. Prevention of cervical intraepithelial neoplasia and cervical cancer. Am J Clin Nutr 1995;62(Suppl):1417S-9S.
Crellin R, Bottiglieri T, Reynolds EH. Folates and psychiatric disorders. Clinical potential. Drugs 1993;45:623-36.
Godfrey PSA, Toone BK, Carney MWP, Flynn TG, Bottiglieri T, Laundy M, et al. Enhancement of recovery from psychiatric illness by methyl folate. Lancet 1990;336;392-5.
Thornton WE, Thornton BP. Geriatric mental function and Folic Acid, a review and survey. Southern Med J 1977;70:919-22.
Wesson VA, Levitt AJ, Joffe RT. Change in folate status with antidepressant treatment. Psychiatry Res 1994;53:313-22.
Zucker DK, Livingston RL, Nakra R, Clayton PJ. B12 deficiency and psychiatric disorders: a case report and literature review. Biol Psychiatry 1989;16:197-205.
Kivela SL, Pahkala K, Eronen A. Depression in the aged: Relation to folate and Vitamins C and B12. Biol Psychiatry 1989;26:209-13.
MacKenzie JF, Russell, RI. The effect of pH on Folic Acid absorption in Man. Clin Sci Mol Med 1976;51 (4):3363-8.
Leonard JP, Desager JP, Beckers C, Harvengt C. In vitro binding of various biological substances by two hypocholesterolaemic resins. Cholestyramine and colestipol. Arzneimettelforschung 1979;29(7):979-81.
Russell RM, Golner BB, Krasinski SD, Sadowski JA, Suter PM, Braun CL. Effect of antacid and H2 receptor antagonists on the intestinal absorption of Folic Acid. J Lab Clin Med 1988;112(4):458-63.
Lambie DG, Johnson RH. Drugs and folate metabolism. Drugs 1985;30(2):145-55.
Lieberman Fl, Bateman JR. Megaloblastic anemia possibly induced by triamterene in patients with alcoholic cirrhosis. Two case reports. Ann Intern Med 1968;68(1):168-73.
Lambie, Johnson RH. Drugs and folate metabolism. Drugs 1985;30(2):145-55.
Kishi T, Fujita N, Eguchi T, Ueda K. Mechanism for reduction of Serum folate by antiepileptic drugs during prolonged therapy. J Neurol Sci 1997;145(1):109-12
Carl GF, Smith ML. Phenytoin-folate interactions: differing effects of the sodium salt and the Free Acid of phenytoin. Epilepsia 1992;33(2):327-75.
Carl GF, Gill MW, Schatz RA. Effect of chronic primidone treatment of folate-dependent one-carbon metabolism in the Rat. Biochem Pharmacol 1987;36(13):2139-44.
Hendel J, Dam M, Gram L, Winkel P, Jørgensen I. The effect of carbamazepine and valproate on folate metabolism in Man. Acta Neurol Scand 1984;69(4):226-31.
Seligmann H, Potasman I, Weller B, Schwartz M, Prokocimer M. Phenytoin-Folic Acid interaction: a lesson to be learned. Clin Neuropharmacol 1999;22(5):268-72.
Lawrence VA, et al. Aspirin and folate binding: in vivo and in vitro studies of serum binding and urinary excretion of endogenous folate. J Lab Clin Med 1984;103(6):944-8.
Baggott JE, Morgan SL, Ha T, Vaughn WH, Hine RJ. Inhibition of folate-dependent enzymes by nonsteroidal anti-inflammatory drugs. Biochem J 1992;282(Pt 1):197-202.
Roe DA. Handbook Interactions of Selected Drugs and Nutrients in Patients. 3rd edition. Chicago: The American Dietetic Association; 1984. p. 89.
Baggott JE, Morgan SL, Ha T, Vaughn WH, Hine RJ. Inhibition of folate-dependent enzymes by nonsteroidal anti-inflammatory drugs. Biochem J 1992;282(Pt 1):197-202.
Webb JL. Nutritional effects of oral contraceptive use: a review. J Reprod Med 1980;25(4):150-6.
Shojania AM. Oral contraceptives: effect of folate and Vitamin B12 metabolism. Can Med Assoc J. 1982;126(3):244-7.
Carlsen SM, Folling I, Grill V, Bjerve KS, Schneede J, Refsum H. Metformin increases total serum homocyteine levels in non-diabetic male patients with coronary heart disease. Scand J Clin Invest 1997;57(6):521-7.
Dijkmans BA. Folate supplementation and methotrexate. Br J Rheumatol 1995;34(12):1172-4.
Leeb BF, Witzmann G, Ogris E, Studnicka-Benke A, Andel I, Schweitzer H et al. Folic acid and cyanocobalamin levels in serum and erythrocytes during low-dose methotrexate therapy of rheumatoid arthritis and psoriatic arthritis patients. Clin Exp Rheumatol 1995;13(4):459-63.
Kahn SB, Fein SA, Brodsky I. Effects of trimethoprim on folate metabolism in Man. Clin Pharmacol Ther 1996;9(5):550-60.
Baggott JE, Morgan SL, Ha T, Vaughn WH, Hine RJ. Inhibition of folate-dependent enzymes by nonsteroidal anti-inflammatory drugs. Biochem J 1992;282(Pt 1):197-202.