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Folic acid and '''folate''' (the Anion form) are forms of the water-soluble Vitamin B9 . These occur naturally in Food and can also be taken as Supplements . Folate gets its name from the Latin word ''folium'' ("leaf"). FOLATE IN FOODS Leaf Vegetable s such as Spinach and Turnip Greens , dried Bean s and Pea s, fortified Cereal products, Sunflower Seed s and certain other Fruit s and Vegetable s are rich sources of folate, as is liver. Some Breakfast Cereal s (ready-to-eat and others) are fortified with 25% to 100% of the Recommended Dietary Allowance (RDA) for folic acid. A table of selected food sources of folate and folic acid can be found at the USDA National Nutrient Database for Standard Reference . Recent debate has emerged in the , but this positive effect is not yet proven. HISTORY A key observation by researcher Lucy Wills in 1931 led to the identification of folate as the nutrient needed to prevent Anemia during pregnancy. Dr. Wills demonstrated that anemia could be reversed with Brewer's Yeast . Folate was identified as the corrective substance in brewer's yeast in the late 1930s and was extracted from Spinach leaves in 1941. It was first synthesised in 1946. BIOLOGICAL ROLES Folate is necessary for the production and maintenance of new cells.1 This is especially important during periods of rapid cell division and growth such as infancy and pregnancy. Folate is needed to replicate DNA . Thus folate deficiency hinders DNA synthesis and cell division, affecting most clinically the bone marrow, a site of rapid cell turnover. Because RNA and protein synthesis are not hindered, large red blood cells called megaloblasts are produced, resulting in Megaloblastic Anemia .2 Both adults and children need folate to make normal Red Blood Cell s and prevent Anemia .3 (Article in French) Folate also helps prevent changes to DNA that may lead to cancer. BIOCHEMISTRY In the form of a series of tetrahydrofolate compounds, folate derivatives are Substrate s in a number of single-carbon-transfer reactions, and also are involved in the synthesis of DTMP (2'-deoxythymidine-5'-phosphate) from DUMP (2'-deoxyuridine-5'-phosphate). It helps convert vitamin B12 to one of its Coenzyme forms and helps synthesize the DNA required for all rapidly growing cells. The pathway leading to the formation of Tetrahydrofolate (FH4) begins when folate (F) is Reduced to Dihydrofolate (FH2), which is then reduced to tetrahydrofolate (FH4). Dihydrofolate Reductase catalyses both steps. EC 1.5.1.3 , Serine , or Glycine . Methyl Tetrahydrofolate (CH3–FH4) can be made from methylene tetrahydrofolate by reduction of the methylene group; Formyl Tetrahydrofolate (CHO-FH4, Folinic Acid ) results from Oxidation of methylene tetrahydrofolate. In other words: F → FH2 → FH4 → CH2=FH4 → 1-carbon chemistry A number of drugs interfere with the biosynthesis of folic acid and tetrahydrofolate. Among them are the (such as Trimethoprim and Pyrimethamine ), the Sulfonamide s (competitive inhibitors of Para-aminobenzoic Acid in the reactions of Dihydropteroate Synthetase ), and the anticancer drug Methotrexate (inhibits both folate reductase and dihydrofolate reductase). ]] RDI The Reference Daily Intake (RDI) is the average daily dietary intake level that is sufficient to meet the nutrient requirements of nearly all (97% to 98% of) healthy individuals in each life-stage and gender group. The 1998 RDIs for folate are expressed in a term called the "dietary folate equivalent" (DFE). This was developed to help account for the differences in absorption of naturally-occurring dietary folate and the more bioavailable synthetic folic acid.4 The 1998 RDAs for folate expressed in Microgram s (µg) of DFE for adults are: The National Health and Nutrition Examination Survey (NHANES III 1988-91) and the Continuing Survey of Food Intakes by Individuals (1994-96 CSFII) indicated that most adults did not consume adequate folate.56 However, the folic acid fortification program in the United States has increased folic acid content of commonly eaten foods such as Cereals and Grains , and as a result diets of most adults now provide recommended amounts of folate equivalents.7 FOLATE DEFICIENCY FOLIC ACID AND PREGNANCY Folic acid is very important for all women who may become Pregnant . Adequate folate intake during the periconceptional period, the time just before and just after a woman becomes pregnant, helps protect against a number of congenital malformations including Neural Tube Defect s.8 Neural tube defects result in malformations of the spine ( Spina Bifida ), skull, and brain ( Anencephaly ). The risk of neural tube defects is significantly reduced when supplemental folic acid is consumed in addition to a healthy diet prior to and during the first month following conception.910 Women who could become pregnant are advised to eat foods fortified with folic acid or take supplements in addition to eating folate-rich foods to reduce the risk of some serious birth defects. Taking 400 micrograms of synthetic folic acid daily from fortified foods and/or supplements has been suggested. The Recommended Dietary Allowance (RDA) for folate equivalents for pregnant women is 600 micrograms, twice the normal RDA of 300 micrograms for unpregnant women. Swedish Nutrition Recommendations 2005 . FOLIC ACID SUPPLEMENTS AND MASKING OF B<SUB>12</SUB> DEFICIENCY There has been concern about the interaction between Vitamin B12 and folic acid. 11Folic acid supplements can correct the anemia associated with vitamin B12 deficiency. Unfortunately, folic acid will not correct changes in the nervous system that result from vitamin B12 deficiency. Permanent nerve damage could theoretically occur if vitamin B12 deficiency is not treated. Therefore, intake of supplemental folic acid should not exceed 1000 Micrograms (1000 mcg or 1 mg) per day to prevent folic acid from masking symptoms of vitamin B12 deficiency. In fact, to date the evidence that such masking actually occurs is scarce, and there is no evidence that folic acid fortification in Canada or the US has increased the prevalence of vitamin B12 deficiency or its consequences.12 However one recent study has demonstrated that high folic or folate levels when combined with low B12 levels are associated with significant cognitive impairment among the elderly, M.S. Morris et al, "Folate and vitamin B12 status in relation to anemia, macrocytosis, and cognitive impairment in older Americans in the age of folic acid fortification”, American Journal of Clinical Nutrition, Jan 2007. If the observed relationship for seniors between folic acid intake, B12 levels, and cognitive impairment is replicated and confirmed, this is likely to re-open the debate on folic acid fortification in food. While public health policies tend generally to support the developmental needs of infants and children over slight risks to other population groups, the ratio of benefit in this case is likely to be on the scale of one child's life saved versus impairment of hundreds or thousands of seniors. In any case, it is important for older adults to be aware of the relationship between folic acid and vitamin B12 because they are at greater risk of having a vitamin B12 deficiency. If you are 50 years of age or older, ask your physician to check your B12 status before you take a supplement that contains folic acid. HEALTH RISK OF TOO MUCH FOLIC ACID The risk of toxicity from folic acid is low.13 The Institute Of Medicine has established a tolerable upper intake level (UL) for folate of 1 mg for adult men and women, and a UL of 800 µg for pregnant and lactating (breast-feeding) women less than 18 years of age. Supplemental folic acid should not exceed the UL to prevent folic acid from masking symptoms of vitamin B12 deficiency.14 SOME CURRENT ISSUES AND CONTROVERSIES ABOUT FOLATE Dietary fortification of folic acid Since the discovery of the link between insufficient folic acid and Neural Tube Defects (NTDs), governments and health organisations worldwide have made recommendations concerning folic acid '' Supplementation '' for women intending to become Pregnant . For example, the United States Public Health Service (see External Links ) recommends an extra 0.4 mg/day, which can be taken as a pill. However, many researchers believe that supplementation in this way can never work effectively enough since about half of all pregnancies in the U.S. are unplanned and not all women will comply with the recommendation. This has led to the introduction in many countries of ''fortification'', where folic acid is added to flour with the intention of everyone benefiting from the associated rise in blood folate levels. This is not uncontroversial, with issues having been raised concerning individual liberty, and the masking effect of folate fortification on In 1996, the United States Food And Drug Administration (FDA) published regulations requiring the addition of folic acid to enriched breads, cereals, flours, corn meals, pastas, rice, and other grain products.1718 This ruling took effect 1998-01-01 , and was specifically targeted to reduce the risk of neural tube birth defects in newborns.19 There are concerns that the amount of (an Australian Yeast Extract containing folate). The FDA later said the report was inaccurate, and no ban or other action was being taken against Vegemite. {Link without Title} Since the folic acid fortification program took effect, fortified foods have become a major source of folic acid in the American diet. The Centers For Disease Control And Prevention in Atlanta, Georgia used data from 23 birth defect registries that cover about half of United States births and extrapolated their findings to the rest of the country. This data indicates that since the addition of folic acid in grain-based foods as mandated by the Food And Drug Administration , the rate of neural tube defects dropped by 25% in the United States.20 Although folic acid does reduce the risk of birth defects, it is only one part of the picture and should not be considered a cure. Even women taking daily folic acid supplements have been known to have children with neural tube defects. Folic acid and heart disease Adequate concentrations of folate, vitamin B12, or vitamin B6 may decrease the circulating level of Homocysteine , an Amino Acid normally found in blood. There is evidence that an elevated homocysteine level is an independent risk factor for heart disease and stroke.21 The evidence suggests that high levels of homocysteine may damage coronary arteries or make it easier for blood clotting cells called platelets to clump together and form a clot.22 However, there is currently no evidence available to suggest that lowering homocysteine with vitamins will reduce your risk of heart disease. Clinical intervention trials are needed to determine whether supplementation with folic acid, vitamin B12 or vitamin B6 can lower your risk of developing coronary heart disease. The NORVIT trial suggests that folic acid supplementation may do more harm than good. NORVIT Trial- High dose B vitamins do not lower stroke or MI risk As of 2006 , studies have shown that giving folic acid to reduce levels of homocysteine does not result in clinical benefit. One of these studies suggests that folic acid in combination with B12 may even increase some cardiovascular risks.232425 Folic acid and Stroke Folic acid appears to reduce the risk of Stroke .BBC Folic acid 'reduces stroke risks' 31 May 2007 Folic acid and cancer Some evidence associates low blood levels of folate with a greater risk of Cancer .26 Folate is involved in the synthesis, repair, and functioning of DNA , our genetic map, and a deficiency of folate may result in damage to DNA that may lead to cancer.27 Several studies have associated diets low in folate with increased risk of Breast , Pancreatic , and Colon Cancer .28 Findings from a study of over 121,000 nurses suggested that long-term folic acid supplementation (for 15 years) was associated with a decreased risk of colon cancer in women 55 to 69 years of age.29 "Folate intake counteracts breast cancer risk associated with alcohol consumption"Mayo Clinic news release (folic acid or Vitamin B9) in their diet are not at increased risk of breast cancer compared to those who abstain from alcohol. "A prospective study of folate intake and the risk of breast cancer" However, associations between diet and disease do not indicate a direct cause. Researchers are continuing to investigate whether enhanced folate intake from foods or folic acid supplements may reduce the risk of cancer. Folic acid and methotrexate for cancer Folate is important for cells and tissues that rapidly divide. Cancer cells divide rapidly, and drugs that interfere with folate metabolism are used to treat cancer. Methotrexate is a drug often used to treat cancer because it inhibits the production of the active form, Tetrahydrofolate . Unfortunately, methotrexate can be toxic,303132 producing side effects such as inflammation in the digestive tract that make it difficult to eat normally. Folinic Acid is a form of folate that can help "rescue" or reverse the toxic effects of methotrexate.33 Folinic acid is ''not'' the same as folic acid. Folic acid supplements have little established role in cancer chemotherapy.3435 There have been cases of severe adverse effects of accidental substitution of folic acid for folinic acid in patients receiving methotrexate cancer chemotherapy. It is important for anyone receiving methotrexate to follow medical advice on the use of folic or folinic acid supplements. Folic acid and methotrexate for non-cancerous diseases Low dose Methotrexate is used to treat a wide variety of non-cancerous diseases such as Rheumatoid Arthritis , Lupus , Psoriasis , Asthma , Sarcoidoisis , Primary Biliary Cirrhosis , and Inflammatory Bowel Disease .Morgan SL, Baggott JE Low doses of methotrexate can deplete folate stores and cause side effects that are similar to folate deficiency. Both high folate diets and supplemental folic acid may help reduce the toxic side effects of low dose methotrexate without decreasing its effectiveness.36 Click here to request reprint from publisher 37 Anyone taking low dose methotrexate for the health problems listed above should consult with a physician about the need for a folic acid supplement. Folic acid and depression Some evidence links low levels of folate with Depression .38 There is some limited evidence from Randomised Controlled Trials that using folic acid in addition to Antidepressant Medication may have benefits.39 Researchers at the University of York and Hull York Medical School have confirmed a link between depression and low levels of folate in a research study involving 15,315 . 40 However, the evidence is probably too limited at present for this to be a routine treatment recommendation. Memory and mental agility In a 3-year trial on 818 people over the age of 50, short-term memory, mental agility and verbal fluency were all found to be better among people who took 800 micrograms of folic acid daily—twice the current RDA —than those who took placebo. The study was reported in '' The Lancet '' on 19 January 2007. Dr Jane Durga, Martin PJ van Boxtel, Prof Evert G Schouten, Prof Frans J Kok, Prof Jelle Jolles, Martijn B Katan, and Petra Verhoef Effect of 3-year folic acid supplementation on cognitive function in older adults in the FACIT trial: a randomised, double blind, controlled trial ''The Lancet'' 2007; 369:208-216 (free registration required) Fertility Folate is necessary for Fertility in both men and women. In men, it contributes to Spermatogenesis . In women, on the other hand, it contributes to Oocyte Maturation , Implantation , Placentation , in addition to the general effects of Folic Acid And Pregnancy . Therefore, it is necessary not to receive insufficient amounts through the diet, in order to avoid Subfertility The importance of folate, zinc and antioxidants in the pathogenesis and prevention of subfertility. Ebisch IM, Thomas CM, Peters WH, Braat DD, Steegers-Theunissen RP . INDUCTION OF ACUTE RENAL FAILURE Folic acid is used in extremely high doses to induce Acute Renal Failure in Murine Models . It should be noted that the dose reported below represents about 120 years of the recommended daily intake mg for adults in one application, an experiment irrelevant to human nutrition. The exact method through which folic acid induces kidney injury in such massive dose is unknown, however it is characterized by the appearance of folic acid crystals in Renal Tubules and Acute Tubular Necrosis . This method of renal injury is also linked to increased expression of Tumor Necrosis Factor-alpha . The dose of folic acid used to induce renal injury is usually around 250mg of folic acid per kg of body weight. The folic acid is usually administered in a vehicle of 0.3mmol/L of Sodium Bicarbonate .41 BIBLIOGRAPHY
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