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16-September-2008 20:42:47 - Folic acid Folic acid Folic acid IUPAC name S-2-4-2-amino-4-hydroxypteridin-6-ylmethylaminobenzamidopentanedioic acid Other names N-42-Amino-4-hydroxy pteridin-6-ylmethylamino benzoyl-L+-glutamic acid; pteroyl-L-glutamic acid; Vitamin B9; Vitamin M; Folacin Identifiers CAS number 59-30-3 RTECS number LP5425000 SMILES C1=CC=CC=C1C=ONC CCC=OOC=OO NCC2=CN=C3C=N2 C=ON=CN3N Properties Molecular formula C19H19N7O6 Molar mass 441.403 g/mol Appearance yellow-orange crystalline powder Melting point 250 °C 523 K, decomp. Solubility in water 0.0016 mg/ml 25 °C Acidity pKa 1st: 2.3, 2nd: 8.3 Hazards Main hazards non-toxic, non-flammable Except where noted otherwise, data are given for materials in their standard state at 25 °C, 100 kPa Infobox references Folic acid also known as Vitamin M and Folacin 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. Contents 1 Folate in foods and other sources 2 History 3 Biological roles of folate 3.1 DNA and cell division 3.2 Biochemistry of DNA base and amino acid production 3.2.1 Overview of drugs that interfere with folate reactions 3.3 Recommended Daily Allowance RDA 4 Folate deficiency 5 Human reproduction 6 Folic acid supplements and masking of B12 deficiency 7 Health risk of too much folic acid 8 Some current issues and controversies about folate 8.1 Dietary fortification of folic acid 8.2 Heart disease 8.3 Stroke 8.4 Cancer 8.5 Antifolates 8.6 Depression 8.7 Memory and mental agility 8.8 Fertility 9 Induction of acute renal failure 10 Bibliography 11 References 12 External links 12.1 Biochemistry links Folate in foods and other sources Leafy vegetables such as spinach, turnip greens, lettuces, dried beans and peas, fortified cereal products, sunflower seeds and certain other fruits and vegetables are rich sources of folate. Some breakfast cereals 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.Folate is also found in Vegemite, with an average serving 5g containing 100μg. Folate is also synthesized in bacteria. 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 synthesized in 1946 by Yellapragada Subbarao. Biological roles of folate A diagram of the chemical structure of folate. A diagram of the chemical structure of folate. DNA and cell division 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 synthesize DNA bases most notably thymine, but also purine bases needed for DNA replication. Thus folate deficiency hinders DNA synthesis and cell division, affecting most notably bone marrow and cancer, both of which participate in rapid cell division. RNA transcription, and subsequent protein synthesis, are less affected by folate deficiency as the mRNA can be recycled and used again as opposed to DNA synthesis where a new genomic copy must be created. Since folate deficiency limits cell division, erythropoiesis, production of red blood cells RBCs is hindered and leads to megaloblastic anemia which is characterized by large immature RBCs. This pathology results from persistently thwarted attempts at normal DNA replication, DNA repair, and cell division and produces abnormally large cells megaloblasts with abundant cytoplasm capable of RNA and protein synthesis but with clumping and fragmentation of nuclear chromatin. Some of these large cells, although immature, are released early from the marrow in an attempt to compensate for the anemia caused by lack of RBCs. 2 Both adults and children need folate to make normal RBCs and prevent anemia.3 Deficiency of folate in pregnant women has been implicated in neural tube defects and so many cereals sold in developed countries are enriched with folate to avoid such complications. Biochemistry of DNA base and amino acid production In the form of a series of tetrahydrofolate THF compounds, folate derivatives are substrates 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 is a substrate for an important reaction that involves vitamin B12 and it is necessary for the synthesis of DNA, required for all dividing cells. The pathway leading to the formation of tetrahydrofolate FH4 begins when folate F is reduced to dihydrofolate DHF FH2, which is then reduced to THF. Dihydrofolate reductase catalyses the last step.4 Vitamin B3 in the form of NADPH is a necessary cofactor for both steps of the synthesis. Methylene-THF CH2FH4 is formed from THF by the addition of methylene groups from one of three carbon donors: formaldehyde, serine, or glycine. Methyl tetrahydrofolate CH3-THF can be made from methylene-THF by reduction of the methylene group with NADPH. It is important to note that Vitamin B12 is the only acceptor of methyl-THF. There is also only one acceptor for methyl-B12 which is homocysteine in a reaction catalyzed by homocysteine methyltransferase. This is important because a defect in homocysteine methyltransferase or a defeciency of B12 can lead to a methyl-trap of THF and a subsequent deficiency. Thus, a deficiency in B12 can generate a large pool of methyl-THF that is unable to undergo reactions and will mimic folate deficiency. Another form of THF, formyl-THF or folinic acid results from oxidation of methylene-THF or is formed from formate donating formyl group to THF. Finally, histidine can donate a single carbon to THF to form methenyl-THF. In other words: F → DHF → THF → CH2-THF Formyl-THF ↔ Methynl-THF ↔ Methylene-THF → Methyl-THF Overview of drugs that interfere with folate reactions A number of drugs interfere with the biosynthesis of folic acid and THF. Among them are the dihydrofolate reductase inhibitors such as trimethoprim, pyrimethamine and methotrexate; the sulfonamides competitive inhibitors of para-aminobenzoic acid in the reactions of dihydropteroate synthetase. Recommended Daily Allowance RDA 1998 RDAs for Folate Men Women 19+ 19+ Pregnancy Breast feeding 400 µg 400 µg 600 µg 500 µg 1 µg of food folate = 0.6 µg folic acid from supplements and fortified foods 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 See Folate deficiency Human reproduction There are several important nutrients that serve as building blocks of a healthy pregnancy. Two of the more well-known nutrients for women during child bearing years are folic acid and calcium with Vitamin D. One nutrient that women are not as familiar with is DHA docosahexaenoic acid omega-3. DHA is important for optimal infant brain, eye and nervous system development, and has been shown to support a healthy 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 defects.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. The most notable birth defects that occur from folate deficiency are neural tube 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 600-800 micrograms, twice the normal RDA of 400 micrograms for women who are not pregnant.11 Recent research has shown that it is also very important for men who are planning on fathering children, reducing birth defect risks.12 Folic acid supplements and masking of B12 deficiency There has been concern about the interaction between vitamin B12 and folic acid.13Folic 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 µg 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.14 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.15 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, even though public health policies tend generally to support the developmental needs of infants and children over slight risks to other population groups. 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.16 Health risk of too much folic acid The risk of toxicity from folic acid is low.17 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.18 Research suggests high levels of folic acid can interfere with some antimalarial treatments.19 A 10000-patient study at Tufts University in 2007 concluded that excess folic acid worsens the effects of B12 deficiency and in fact may affect the absorption of B12. 20 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 organizations 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 controversial, with issues having been raised concerning individual liberty, and the masking effect of folate fortification on pernicious anaemia vitamin B12 deficiency. However, almost all American countries now fortify their flour, along with a number of Middle Eastern countries and Indonesia. Mongolia and a number of ex-Soviet republics are amongst those having widespread voluntary fortification; about five more countries including Morocco, the first African country have agreed but not yet implemented fortification. In the UK the Food Standards Agency has recommended fortification.212223 To date, no EU country has yet mandated fortification.24 Australia and New Zealand have jointly agreed to fortification. Australia will fortify all flour, whereas New Zealand will fortify bread excluding organic and unleavened varieties from 18 September 2009.25 The requirement is 0.135mg of folate per 100g of bread. There has been previous debate in the United Kingdom26 and Australia27 regarding the inclusion of folic acid in products such as bread and flour. In the USA many grain products are fortified with folic acid. In the USA many grain products are fortified with folic acid. 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.2829 This ruling took effect 1998-01-01, and was specifically targeted to reduce the risk of neural tube birth defects in newborns.30 There are concerns that the amount of folate added is insufficient3. In October 2006, the Australian press claimed that U.S. regulations requiring fortification of grain products were being interpreted as disallowing fortification in non-grain products, specifically Vegemite 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.4 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.31 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. 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.32 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.33 However, there is currently no evidence available to suggest that lowering homocysteine with vitamins will reduce risk of heart disease. Clinical intervention trials are needed to determine whether supplementation with folic acid, vitamin B12 or vitamin B6 can lower the risk of developing coronary heart disease. The NORVIT trial suggests that folic acid supplementation may do more harm than good.34 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.353637 However a 2005 study found that 5 mg. of folate daily over a three-week period reduced pulse pressure by 4.7 mmHg. compared with a placebo, and concluded that38 Folic acid is a safe and effective supplement that targets large artery stiffness and may prevent isolated systolic hypertension. Also, as a result of new research, heart experts at Johns Hopkins Medical Center reported in March 2008 39 in favour of therapeutic folate, although they cautioned that it is premature for people to begin to self-medicate by taking high doses of folic acid. Stroke Folic acid appears to reduce the risk of stroke. The reviews indicate only that in some individuals the risk of stroke appears to be reduced, but a definite recommendation regarding supplementation beyond the current recommended daily allowance has not been established for stroke prevention.40 Observed stroke reduction is consistent with the reduction in pulse pressure produced by folate supplementation of 5 mg per day, since hypertension is a key risk factor for stroke. Cancer The association between folate and cancer appears to be complex.41 It has been suggested that folate may help prevent cancer, as it is involved in the synthesis, repair, and functioning of DNA, and a deficiency of folate may result in damage to DNA that may lead to cancer.42 Some investigations have proposed that good levels of folic acid may be related to lower risk of esophagus, stomach and ovarian cancer, but benefices of folic acid against cancer may depend on when it is taken and on individual conditions. In addition folic acid may not be helpful, and could even be damaging, in people who already are suffering from cancer or from a precancerous condition. Conversely, it has been suggested that excess folate may promote tumor initiation.43 Diets high in folate are associated with decreased risk of colorectal cancer; some studies show an association which is stronger for folate from foods alone than for folate from foods and supplements,44 while other studies find that folate from supplements is more effective due to greater bioavailability45 and a 2007 randomized clinical trial found that folate supplements did not reduce the risk of colorectal adenomas.46 A 2006 prospective study of 81,922 Swedish adults found that diets high in folate from foods, but not from supplements, were associated with a reduced risk of pancreatic cancer.47 Most epidemiologic studies suggest that diets high in folate are associated with decreased risk of breast cancer, but results are not uniformly consistent: one large cancer screening trial reported a potential harmful effect of high folate intake on breast cancer risk, suggesting that routine folate supplementation should not be recommended as a breast cancer preventive,48 but a 2007 Swedish prospective study found that a high folate intake was associated with a lower incidence of postmenopausal breast cancer.49 It is very difficult to affirm how each nutrient or nutrient combination affects a person's risk of cancer. People whose diets are rich in vegetables and low in animal fat and meat have lower risks for some of the most frequent types of cancer. Taking a variety of healthful foods, with most of them coming from plant sources, is a better solution than taking vitaminic supplements. So the authorities are not really sure if this will work for cancer or not, or the age at which it is safe to start taking folate supplements but hopefully this will all become clear in the light of research now underway. Antifolates Folate is important for cells and tissues that rapidly divide.1 Cancer cells divide rapidly, and drugs that interfere with folate metabolism are used to treat cancer. The antifolate methotrexate is a drug often used to treat cancer because it inhibits the production of the active form of THF from the inactive dihydrofolate DHF. Unfortunately, methotrexate can be toxic,505152 producing side effects such as inflammation in the digestive tract that make it difficult to eat normally. Folinic acid, under the drug name leucovorin, is a form of folate formyl-THF that can help rescue or reverse the toxic effects of methotrexate.53 Folinic acid is not the same as folic acid. Folic acid supplements have little established role in cancer chemotherapy.5455 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. The supplement of folinic acid in patients undergoing methotrexate treatment is to give non rapidly dividing cells enough folate to maintain normal cell functions. The amount of folate given will be depleted by rapidly dividing cells cancer very fast and so will not negate the effects of methotrexate. Low dose methotrexate is used to treat a wide variety of non-cancerous diseases such as rheumatoid arthritis, lupus, scleroderma, psoriasis, asthma, sarcoidoisis, primary biliary cirrhosis, and inflammatory bowel disease.56 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.5758 Anyone taking low dose methotrexate for the health problems listed above should consult with a physician about the need for a folic acid supplement. While the role in folate as a cancer treatment is well established its long term effectiveness is diminished by cellular response. In response to decreased THF the cell begins to transcribe more DHF reductase, the enzyme that reduces DHF to THF. Because methotrexate is a competitive inhibitor of DHF reductase increased concentrations of DHF reductase can overcome the drugs inhibition. Depression Some evidence links low levels of folate with depression.59 There is some limited evidence from randomised controlled trials that using folic acid in addition to antidepressant medication may have benefits.60 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 .61 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 2007.62 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 to receive sufficient amounts through the diet, in order to avoid subfertility.63 Induction of acute renal failure Folic acid is used in extremely high doses to induce Acute renal failure in murine models. 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-approximately 120 times the FDA's daily recommended intake of 0.4mg. The folic acid is usually administered in a vehicle of 0.3mmol/L of sodium bicarbonate.64 Bibliography This article contains information from the public domain resource at http://www.cc.nih.gov/ccc/supplements/folate.html Herbert V. 1999. Folic Acid. Shils M, Olson J, Shike M, Ross AC, Eds.. Nutrition in Health and Disease. Baltimore: Williams Wilkins. Food and Nutrition Board, Institute of Medicine 1998. Dietary reference intakes for thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12, pantothenic acid, biotin, and choline / a report of the Standing Committee on the Scientific Evaluation of Dietary Reference Intakes and its Panel on Folate, Other B Vitamins, and Choline and Subcommittee on Upper Reference Levels of Nutrients. Washington, D.C.: National Academy Press. ISBN 0-309-06554-2. Dietary Guidelines Advisory Committee, Agricultural Research Service, United States Department of Agriculture USDA. Report of the Dietary Guidelines Advisory Committee on the Dietary Guidelines for Americans, 2000. http://www.ars.usda.gov/dgac References ^ a b Kamen B 1997. Folate and antifolate pharmacology. Seminars in oncology 24 5 Suppl 18: S18-30-S18-39. PMID 9420019. ^ Lieberman, et al. Marks' Essentials of Biochemistry, A Clinical Approach. Lippincott Wiliams and Wilkins. 2007. ISBN 0 7817 9340 8 ^ Zittoun J 1993. Anemias due to disorder of folate, vitamin B12 and transcobalamin metabolism. La Revue du praticien 43 11: 1358-63. PMID 8235383. French ^ EC 1.5.1.3 ^ Alaimo K, McDowell MA, Briefel RR, Bischof AM, Caughman CR, Loria CM, Johnson CL 1994. Dietary intake of vitamins, minerals, and fiber of persons ages 2 months and over in the United States: Third National Health and Nutrition Examination Survey, Phase 1, 1988-91. Advance Data 258: 1-28. PMID 10138938. ^ Raiten DJ, Fisher KD 1995. Assessment of folate methodology used in the Third National Health and Nutrition Examination Survey NHANES III, 1988-1994. The Journal of Nutrition 125 5: 1371S-1398S. PMID 7738698. ^ Lewis CJ, Crane NT, Wilson DB, Yetley EA 1999. Estimated folate intakes: data updated to reflect food fortification, increased bioavailability, and dietary supplement use. The American Journal of Clinical Nutrition 70 2: 198-207. PMID 10426695. ^ Shaw GM, Schaffer D, Velie EM, Morland K, Harris JA 1995. Periconceptional vitamin use, dietary folate, and the occurrence of neural tube defects. Epidemiology 6 3: 219-226. doi:10.1097/00001648-199505000-00005. PMID 7619926. ^ Mulinare J, Cordero JF, Erickson JD, Berry RJ 1988. Periconceptional use of multivitamins and the occurrence of neural tube defects. Journal of the American Medical Association 260 21: 3141-3145. doi:10.1001/jama.260.21.3141. PMID 3184392. ^ Milunsky A, Jick H, Jick SS, Bruell CL, MacLaughlin DS, Rothman KJ, Willett W 1989. Multivitamin/folic acid supplementation in early pregnancy reduces the prevalence of neural tube defects. Journal of the American Medical Association 262 20: 2847-2852. doi:10.1001/jama.262.20.2847. PMID 2478730. ^ Health Professionals Recommendations, Folic Acid, NCBDDD, CDC ^ Medical News: Extra Folate for Men May Reduce Birth Defects - in Primary Care, Diet Nutrition from MedPage Today ^ Scott JM 1999 May. Folate and vitamin B12. Proc Nutr Soc. 2 58: 441-8. PMID 10466189. ^ Mills JL, Von Kohorn I, Conley MR, Zeller JA, Cox C, Williamson RE, Dufour DR 2003 Jun. Low vitamin B-12 concentrations in patients without anemia: the effect of folic acid fortification of grain. Am J Clin Nutr. 6 77: 1474-7. PMID 12791626. ^ 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 ^ BBC News | HEALTH | Folic acid 'heart boost for elderly' ^ Hathcock JN. 1997. Vitamins and minerals: efficacy and safety. American Journal of Clinical Nutrition 66 2: 427-37. PMID 9250127. ^ Baggott JE, Morgan SL, HaT, Vaughn WH, Hine RJ 1992. Inhibition of folate-dependent enzymes by non-steroidal anti-inflammatory drugs. Biochemical Journal 282 Pt 1: 197-202. PMID 1540135. ^ BBC Folic acid 'hinders malaria drug' 21 October 2006 ^ Foodproductiondaily 1 ^ FSA 2007-05-17. Board recommends mandatory fortification. Retrieved on 2007-05-18. ^ Backing for folic acid in bread. Retrieved on 2007-05-18. ^ BBC Experts back folic acid in flour 11 May 2007 ^ Russell, Andrew. 2006. The UK campaign on folic acid and flour fortification. Cerebrospinal Fluid Research 2006; 3Suppl 1: S33, via PubMed Central website. Retrieved on 2007-09-27. ^ NZ Herald 2 2007-06-22 ^ BBC 'Put folic acid in bread' 2000-01-13 ^ The Sydney Morning Herald Bread fortification 'not justified' 2006-07-29 ^ Malinow MR, Duell PB, Hess DL, Anderson PH, Kruger WD, Phillipson BE, Gluckman RA, Block PC, Upson BM 1998. Reduction of plasma homocysteine levels by breakfast cereal fortified with folic acid in patients with coronary heart disease. New England Journal of Medicine 338 15: 1009-15. doi:10.1056/NEJM199804093381501. PMID 9535664. ^ Daly S, Mills JL, Molloy AM, Conley M, Lee YJ, Kirke PN, Weir DG, Scott JM 1997. Minimum effective dose of folic acid for food fortification to prevent neural-tube defects. Lancet 350 9092: 1666-9. doi:10.1016/S0140-67369707247-4. PMID 9400511. ^ Crandall BF, Corson VL, Evans MI, Goldberg JD, Knight G, Salafsky IS 1998. American College of Medical Genetics statement on folic acid: fortification and supplementation. American Journal of Medical Genetics 78 4: 381. doi:10.1002/SICI1096-86281998072478:4381::AID-AJMG163.0.CO;2-E. PMID 9714444. ^ Centers for Disease Control and Prevention CDC 2004. Spina bifida and anencephaly before and after folic acid mandate--United States, 1995-1996 and 1999-2000. Morbidity and Mortality Weekly Report 53 17: 362-5. PMID 15129193. ^ Refsum H, Ueland PM, Nygard O, Vollset SE 1998. Homocysteine and cardiovascular disease. Annual Review of Medicine 49 1: 31-62. doi:10.1146/annurev.med.49.1.31. PMID 9509248. ^ Malinow MR 1995. Plasma homocysteine and arterial occlusive diseases: A mini-review. Clinical Chemistry 41 1: 173-6. PMID 7813076. ^ NORVIT Trial- High dose B vitamins do not lower stroke or MI risk ^ Zoungas S, McGrath BP, Branley P, Kerr PG, Muske C, Wolfe R, Atkins RC, Nicholls K, Fraenkel M, Hutchison BG, Walker R, McNeil JJ 2006. Cardiovascular morbidity and mortality in the Atherosclerosis and Folic Acid Supplementation Trial ASFAST in chronic renal failure: a multicenter, randomized, controlled trial. J Am Coll Cardiol 47 6: 1108-16. doi:10.1016/j.jacc.2005.10.064. PMID 16545638. ^ Homocysteine Lowering with Folic Acid and B Vitamins in Vascular Disease 2006. N Engl J Med. PMID 16531613 Full text PDF. ^ Bonaa KH, Njolstad I, Ueland PM, Schirmer H, Tverdal A, Steigen T, Wang H, Nordrehaug JE, Arnesen E, Rasmussen K 2006. Homocysteine Lowering and Cardiovascular Events after Acute Myocardial Infarction. N Engl J Med: 1578. doi:10.1056/NEJMoa055227. PMID 16531614 Full text PDF. ^ Carolyn Williams, Bronwyn A Kingwell, Kevin Burke, Jane McPherson and Anthony M Dart Folic acid supplementation for 3 wk reduces pulse pressure and large artery stiffness independent of MTHFR genotype American Journal of Clinical Nutrition, Vol. 82, No. 1, 26-31, July 2005 http://www.ajcn.org/cgi/content/full/82/1/26 ^ Brief, high doses of folate blunt damage from heart attack ^ BBC Folic acid 'reduces stroke risks' 31 May 2007 ^ Van Guelpen B 2007. Folate in colorectal cancer, prostate cancer and cardiovascular disease. Scand J Clin Lab Invest 67 5: 459-73. doi:10.1080/00365510601161513. PMID 17763182. ^ Jennings E 1995. Folic acid as a cancer-preventing agent. Med Hypotheses 45 3: 297-303. doi:10.1016/0306-98779590121-3. PMID 8569555. ^ Kim YI 2004. Will mandatory folic acid fortification prevent or promote cancer?. Am J Clin Nutr 80 5: 1123-8. PMID 15531657. ^ Sanjoaquin MA, Allen N, Couto E, Roddam AW, Key TJ 2005. Folate intake and colorectal cancer risk: a meta-analytical approach. Int J Cancer 113 5: 825. doi:10.1002/ijc.20648. PMID 15499620. ^ Giovannucci E, Stampfer MJ, Colditz GA, et al 1998. Multivitamin use, folate, and colon cancer in women in the Nurses' Health Study. Ann. Intern. Med. 129 7: 517-24. PMID 9758570. ^ Cole BF, Baron JA, Sandler RS et al. 2007. Folic acid for the prevention of colorectal adenomas: a randomized clinical trial. JAMA 297 21: 2351-9. doi:10.1001/jama.297.21.2351. PMID 17551129. ^ Larsson SC, HÃ¥kansson N, Giovannucci E, Wolk A 2006. Folate intake and pancreatic cancer incidence: a prospective study of Swedish women and men. J Natl Cancer Inst 98 6: 407-13. doi:10.1093/jnci/djj094. PMID 16537833. ^ Kim YI 2006. Does a high folate intake increase the risk of breast cancer?. Nutr Rev 64 10 Pt 1: 468-75. doi:10.1301/nr.2006.oct.468-475. PMID 17063929. ^ Ericson U, Sonestedt E, Gullberg B, Olsson H, Wirfält E 2007. High folate intake is associated with lower breast cancer incidence in postmenopausal women in the Malmö Diet and Cancer cohort. Am J Clin Nutr 86 2: 434-43. PMID 17684216. ^ Rubio IT, Cao Y, Hutchins LF, Westbrook KC, Klimberg VS 1998. Effect of glutamine on methotrexate efficacy and toxicity. Annals of Surgery 227 5: 772-8. doi:10.1097/00000658-199805000-00018. PMID 9605669. ^ Wolff JE, Hauch H, Kuhl J, Egeler RM, Jurgens H 1998. Dexamethasone increases hepatotoxicity of MTX in children with brain tumors. Anticancer Research 18 4B: 2895-9. PMID 9713483. ^ Kepka L, De Lassence A, Ribrag V, Gachot B, Blot F, Theodore C, Bonnay M, Korenbaum C, Nitenberg G 1998. Successful rescue in a patient with high dose methotrexate-induced nephrotoxicity and acute renal failure. Leukemia Lymphoma 29 1-2: 205-9. doi:10.3109/10428199809058397. PMID 9638991. ^ Branda RF, Nigels E, Lafayette AR, Hacker M. 1998. Nutritional folate status influences the efficacy and toxicity of chemotherapy in rats. Blood 92 7: 2471-6. PMID 9746787. ^ Shiroky JB 1997. The use of folates concomitantly with low-dose pulse methotrexate. Rheumatic Diseases Clinics of North America 23 4: 969-80. doi:10.1016/S0889-857X0570369-0. PMID 9361164. ^ Keshava C, Keshava N, Whong WZ, Nath J, Ong TM 1998. Inhibition of methotrexate-induced chromosomal damage by folinic acid in V79 cells. Mutation Research 397 2: 221-8. PMID 9541646. ^ Morgan SL, Baggott JE 1995. Folate antagonists in nonneoplastic disease: proposed mechanisms of efficacy and toxicity. In Bailey LB, Folate in Health and Disease, 405-433. New York: Marcel Dekker. ISBN 0-8247-9280-7. ^ Morgan SL, Baggott JE, Alarcon GS 1997. Methotrexate in rheumatoid arthritis: folate supplementation should always be given. BioDrugs 8 1: 164-175. Click here to request reprint from publisher ^ Morgan SL, Baggott JE, Lee JY, Alarcon GS 1998. Folic acid supplementation prevents deficient blood folate levels and hyperhomocysteinemia during longterm, low dose methotrexate therapy for rheumatoid arthritis: Implications for cardiovascular disease prevention. Journal of Rheumatology 25 3: 441-6. PMID 9517760. ^ Coppen A, Bolander-Gouaille C. 2005. Treatment of depression: time to consider folic acid and vitamin B12. Journal of Psychopharmacology 19 1: 59-65. doi:10.1177/0269881105048899. PMID 15671130. ^ Taylor MJ, Carney SM, Goodwin GM, Geddes JR. 2004. Folate for depressive disorders: systematic review and meta-analysis of randomized controlled trials. Journal of Psychopharmacology 18 2: 251-6. doi:10.1177/0269881104042630. PMID 15260915. ^ ScientistLive Website dead link - Scholar search . American Journal of Epidemiology. ^ 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 ^ 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 ^ Bing Wan, Li Hao, Yuhua Qiu, Zhongwen Sun, Qi Cao, Yi Zhang, Tongyu Zhu, Hao Wang, Yanyun Zhang 2006. Blocking tumor necrosis factor-alpha inhibits folic acid-induced renal failure. Experimental and Molecular Pathology 81: 211-216. doi:10.1016/j.yexmp.2006.02.005. PMID 16595132. External links Jane Higdon, Folic Acid, Micronutrient Information Center, Linus Pauling Institute Health Canada article about folic acid US Public Health Service information page on folic acid BMJ orial - Delaying folic acid fortification of flour Folic Acid and Birth Defects Article from Journal of Postgraduate Medicine Folic Acid The Vitamin That Does Almost Everything-U.C Berkeley Wellness Letter April 2003 BMC Pregnancy and Childbirth 2004: no vitamin B12 problems in Canada after folic acid fortification The primary prevention of birth defects: Multivitamins or folic acid? Mills et al, Am J Clin Nutr 2003: no vitamin B12 problems in the US after folic acid fortification Folic acid may help prevent throat cancer Folic acid may help treat bipolar disorder Biochemistry links Folate biosynthesis early stages Folate biosynthesis later stages Folate coenzymes C1 metabolism with folate Formylation, hydroxymethylation and methylation using folate IUPAC nomenclature of folate related compounds v d e Dietary supplements Types Amino acids Bodybuilding supplement Energy drink Energy bar Fatty acids Herbal Supplements Minerals Prebiotics Probiotics Lactobacillus, Bifidobacterium Vitamins Whole food supplements Vitamins and minerals Retinol Vitamin A B vitamins: Thiamine B1 Riboflavin B2 Niacin B3 Pantothenic acid B5 Pyridoxine B6 Biotin B7 Folic acid B9 Cyanocobalamin B12 Ascorbic acid Vitamin C Ergocalciferol and Cholecalciferol Vitamin D Tocopherol Vitamin E Naphthoquinone Vitamin K Calcium Choline Chlorine Chromium Cobalt Copper Fluorine Iodine Iron Magnesium Manganese Molybdenum Phosphorus Potassium Selenium Sodium Sulfur Zinc Other common ingredients Carnitine Chondroitin sulfate Cod liver oil Copper gluconate Creatine/Creatine supplements Dietary fiber Elemental calcium Ephedra Fish oil Folic acid Ginseng Glucosamine Glutamine Iron supplements Japanese Honeysuckle Krill oil Lingzhi Linseed oil Melatonin Red yeast rice Royal jelly Saw palmetto Spirulina Taurine Wheatgrass Wolfberry Yohimbine Zinc gluconate Related articles Codex Alimentarius Enzyte Metabolife Hadacol Nutraceutical Multivitamin Nutrition v d e Vitamins A11 Fat soluble A: Retinol - Beta-carotene - Tretinoin - Alpha-carotene D3: 7-Dehydrocholesterol → Previtamin D3 → Cholecalciferol D3 → Calcidiol → Calcitriol active form → Calcitroic acid D2: Ergosterol → Ergocalciferol D2 D analogues: Dihydrotachysterol - Calcipotriol - Tacalcitol E: Tocopherol - Tocotrienol K: Naphthoquinone - Phylloquinone/K1 - Menatetrenone/K2 Water soluble: B vitamins B1 Thiamine - B2 Riboflavin - B3 Niacin, Nicotinamide - B5 Pantothenic acid, Dexpanthenol, Pantethine - B6 Pyridoxine, Pyridoxal phosphate, Pyridoxamine - B7 Biotin - B9 Folic acid, Folinic acid - B12 Cyanocobalamin, Hydroxocobalamin, Methylcobalamin, Cobamamide Water soluble: other C Ascorbic acid - Choline see also enzyme cofactors Retrieved from http://en..org/wiki/Folic_acid Categories: Dietary supplements | FolatesHidden categories: All articles with dead external links | Articles with dead external links since June 2008 Views Article Discussion this page History Personal tools Log in / create account Navigation Main page Contents Featured content Current events Random article Search Go Search Interaction Community portal Recent changes Contact Donate to Help Toolbox What links here Related changes Upload file Special pages Printable version Permanent link Cite this page Languages العربية БългарÑ?ки Català Česky Dansk Deutsch Eesti Español Esperanto Ù?ارسی Français í•œêµì–´ Hrvatski Bahasa Indonesia Ã?slenska Italiano עברית Lëtzebuergesch Lietuvių Nederlands 日本語 ‪Norsk bokmÃ¥l‬ Polski Português Română РуÑ?Ñ?кий Shqip SlovenÄ?ina SlovenÅ¡Ä?ina СрпÑ?ки / Srpski Suomi Svenska Tiếng Việt Türkçe ä¸æ–‡ This page was last modified on 15 August 2008, at 15:17
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