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| Folic acid | |
|---|---|
 Folic acid  Folic acid | |
| General | |
| Systematic name | N-[4(2-Amino-4-hydroxy- pteridin-6-ylmethylamino)- benzoyl]-L(+)-glutamic acid. |
| Other names | pteroyl-L-glutamic acid, Vitamin B9, Vitamin M, Folacin |
| Molecular formula | C19H19N7O6 |
| SMILES | C1=CC(=CC=C1C(=O)NC (CCC(=O)O)C(=O)O)NCC2=CN=C3C(=N2)C(=O)N=C(N3)N |
| Molar mass | 441.1396 g/mol |
| Appearance | yellow-orange crystalline powder |
| CAS number | [59-30-3] |
| Properties | |
| Density and phase | ? g/cm³, solid |
| Solubility in water | 8.5 g/100 ml (20 °C) |
| In ethanol, ether, acetone | insoluble |
| Melting point | 250 °C (523 K), decomp. |
| Acidity (p''K''a) | 1st: 2.3, 2nd: 8.3 |
| Chiral rotation | +23° 0.5% in 0.1 M NaOH |
| Hazards | |
| Main hazards | non-toxic, non-flammable |
| R/S statement | R: – S: 24/25 |
| RTECS number | LP5425000 |
| UV-Vis | |
| Lambda-max (pH 13) | 259 nm 368 nm |
| Extinction coefficient (pH 13) | 32340 (259 nm) 7410 (368 nm) |
| Related compounds | |
| Salts | sodium folate |
| Except where noted otherwise, data are given for materials in their standard state (at 25°C, 100 kPa) | |
'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 vegetables such as spinach and turnip greens, dried beans and peas, fortified cereal products, sunflower seeds and certain other fruits and vegetables are rich sources of folate, as is liver. 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.
Recent debate has emerged in the United Kingdom[1] and Australia[2]regarding the inclusion of folic acid in products such as bread and flour. Experts claim that this will decrease the number of babies with disabilities such as spina bifida. Research suggests high levels of folic acid can interfere with some antimalarial treatments.[3] Folic acid might have a preventative effect on a number of other diseases such as heart diseases or stroke, 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.[4]
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.[5]
Both adults and children need folate to make normal red blood cells and prevent anemia.[6]
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 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 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.[7]
Methylene tetrahydrofolate (CH2FH4) is formed from tetrahydrofolate by the addition of methylene groups from one of three carbon donors: formaldehyde, 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 sulfonamides (competitive inhibitors of para-aminobenzoic acid in the reactions of dihydropteroate synthetase), and the anticancer drug methotrexate (inhibits both folate reductase and dihydrofolate reductase).
Schematic structure of tetrahydrofolate
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.[8] The 1998 RDAs for folate expressed in micrograms (µg) of DFE for adults are:
| 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.[9][10]
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.[11]
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 defects.[12]
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.[13][14]
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. [15].
Folic acid supplements and masking of B12 deficiency
There has been concern about the interaction between vitamin B12 and folic acid. [16]Folic 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.[17]
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, [18]. 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.[19]
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.[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 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 pernicious anaemia (vitamin B12 deficiency). However, most North and South 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.[21][22][23] To date, no EU country has yet fortified. Australia is considering fortification, but a period for comments ending 2006-07-31 attracted strong opposition from industry as well as academia.[2]
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.[25][26]
This ruling took effect 1998-01-01, and was specifically targeted to reduce the risk of neural tube birth defects in newborns.[27] There are concerns that the amount of folate added is insufficient[1]. 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.[2]
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.[28]
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.[29]
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.[30]
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.[31]
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.[32][33]stroke===
Folic acid appears to reduce the risk of stroke.[34]
Folic acid and cancer
Some evidence associates low blood levels of folate with a greater risk of cancer.[35]
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.[36]
Several studies have associated diets low in folate with increased risk of breast, pancreatic, and colon cancer.[37]
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.[38]
"Folate intake counteracts breast cancer risk associated with alcohol consumption"[39] and "women who drink alcohol and have a high folate intake are not at increased risk of cancer".[40] Those who have a high (200 micrograms or more per day) level of folate (folic acid or Vitamin B9) in their diet are not at increased risk of breast cancer compared to those who abstain from alcohol.[41]
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,[42][43][44]
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.[45]
Folinic acid is ''not'' the same as folic acid. Folic acid supplements have little established role in cancer chemotherapy.[46][47]
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.[48]
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.[49][50]
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.[51]
There is some limited evidence from randomised controlled trials that using folic acid in addition to antidepressant medication may have benefits.[52] 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 . [53]
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. [54]
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 [55].
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 [0.4 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.[56]
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.
★ 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, Food and Nutrition Board, Institute of Medicine, , , National Academy Press, 1998, 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
1. BBC 'Put folic acid in bread' 2000-01-13
2. ''The Sydney Morning Herald'' Bread fortification 'not justified' 2006-07-29
3. BBC Folic acid 'hinders malaria drug' 21 October 2006
4. Folate and antifolate pharmacology, Kamen B, , , Seminars in oncology, 1997
5. Folate, vitamin B12, homocysteine status and DNA damage in young Australian adults, Fenech M, Aitken C, Rinaldi J, , , Carcinogenesis, 1998
6. Anemias due to disorder of folate, vitamin B12 and transcobalamin metabolism, Zittoun J, , , La Revue du praticien, 1993 (Article in French)
7. EC 1.5.1.3
8. Dietary folate equivalents: interpretation and application, Suitor CW, Bailey LB, , , Journal of the American Dietetic Association, 2000
9. 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, Alaimo K, McDowell MA, Briefel RR, Bischof AM, Caughman CR, Loria CM, Johnson CL, , , Advance Data n° 258, 1994
10. Assessment of folate methodology used in the Third National Health and Nutrition Examination Survey (NHANES III, 1988-1994), Raiten DJ, Fisher KD, , , The Journal of Nutrition, 1995
11. Estimated folate intakes: data updated to reflect food fortification, increased bioavailability, and dietary supplement use, Lewis CJ, Crane NT, Wilson DB, Yetley EA, , , The American Journal of Clinical Nutrition, 1999
12. Periconceptional vitamin use, dietary folate, and the occurrence of neural tube defects, Shaw GM, Schaffer D, Velie EM, Morland K, Harris JA, , , Epidemiology, 1995
13. Periconceptional use of multivitamins and the occurrence of neural tube defects, Mulinare J, Cordero JF, Erickson JD, Berry RJ, , , Journal of the American Medical Association, 1988
14. Multivitamin/folic acid supplementation in early pregnancy reduces the prevalence of neural tube defects, Milunsky A, Jick H, Jick SS, Bruell CL, MacLaughlin DS, Rothman KJ, Willett W, , , Journal of the American Medical Association, 1989
15. Swedish Nutrition Recommendations 2005
16. Folate and vitamin B12, Scott JM, , , Proc Nutr Soc., 1999 May
17. Low vitamin B-12 concentrations in patients without anemia: the effect of folic acid fortification of grain., Mills JL, Von Kohorn I, Conley MR, Zeller JA, Cox C, Williamson RE, Dufour DR, , , Am J Clin Nutr., 2003 Jun
18. 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
19. Vitamins and minerals: efficacy and safety, Hathcock JN., , , American Journal of Clinical Nutrition, 1997
20. Inhibition of folate-dependent enzymes by non-steroidal anti-inflammatory drugs, Baggott JE, Morgan SL, HaT, Vaughn WH, Hine RJ, , , Biochemical Journal, 1992
21. Board recommends mandatory fortification FSA
22. Backing for folic acid in bread
23. BBC Experts back folic acid in flour 11 May 2007
24. ''The Sydney Morning Herald'' Bread fortification 'not justified' 2006-07-29
25. Reduction of plasma homocyst(e)ine levels by breakfast cereal fortified with folic acid in patients with coronary heart disease, Malinow MR, Duell PB, Hess DL, Anderson PH, Kruger WD, Phillipson BE, Gluckman RA, Block PC, Upson BM, , , New England Journal of Medicine, 1998
26. Minimum effective dose of folic acid for food fortification to prevent neural-tube defects, Daly S, Mills JL, Molloy AM, Conley M, Lee YJ, Kirke PN, Weir DG, Scott JM, , , Lancet, 1997
27. American College of Medical Genetics statement on folic acid: fortification and supplementation, Crandall BF, Corson VL, Evans MI, Goldberg JD, Knight G, Salafsky IS, , , American Journal of Medical Genetics, 1998
28. Spina bifida and anencephaly before and after folic acid mandate--United States, 1995-1996 and 1999-2000, Centers for Disease Control and Prevention (CDC), , , Morbidity and Mortality Weekly Report, 2004
29. Homocysteine and cardiovascular disease, Refsum H, Ueland PM, Nygard O, Vollset SE, , , Annual Review of Medicine, 1998
30. Plasma homocyst(e)ine and arterial occlusive diseases: A mini-review, Malinow MR, , , Clinical Chemistry, 1995
31. NORVIT Trial- High dose B vitamins do not lower stroke or MI risk
32. Cardiovascular morbidity and mortality in the Atherosclerosis and Folic Acid Supplementation Trial (ASFAST) in chronic renal failure: a multicenter, randomized, controlled trial, Zoungas S, McGrath BP, Branley P, Kerr PG, Muske C, Wolfe R, Atkins RC, Nicholls K, Fraenkel M, Hutchison BG, Walker R, McNeil JJ, , , J Am Coll Cardiol, 2006
33. Homocysteine Lowering with Folic Acid and B Vitamins in Vascular Disease, , , , N Engl J Med, 2006
34. BBC Folic acid 'reduces stroke risks' 31 May 2007
35. Folate intake and carcinogenesis of the colon and rectum, Freudenheim JL, Grahm S, Marshall JR, Haughey BP, Cholewinski S, Wilkinson G, , , International Journal of Epidemiology, 1991
36. Folic acid as a cancer preventing agent, Jennings E., , , Medical Hypotheses, 1995
37. Multivitamin use, folate, and colon cancer in women in the Nurses' Health Study, Giovannucci E, Stampfer MJ, Colditz GA, Hunter DJ, Fuchs C, Rosner BA, Speizer FE, Willett WC., , , Annals of Internal Medicine, 1998
38. Folate deficiency, cancer and congenital abnormalities Is there a connection?, Christensen B., , , Tidsskrift for den Norske Laegeforening, 1996
39. Mayo Clinic news release 2001-06-26 "Folate Intake Counteracts Breast Cancer Risk Associated with Alcohol Consumption"
40. Boston University "Folate, Alcohol, and Cancer Risk"
41. "A prospective study of folate intake and the risk of breast cancer"
42. Effect of glutamine on methotrexate efficacy and toxicity, Rubio IT, Cao Y, Hutchins LF, Westbrook KC, Klimberg VS, , , Annals of Surgery, 1998
43. Dexamethasone increases hepatotoxicity of MTX in children with brain tumors, Wolff JE, Hauch H, Kuhl J, Egeler RM, Jurgens H, , , Anticancer Research, 1998
44. Successful rescue in a patient with high dose methotrexate-induced nephrotoxicity and acute renal failure, Kepka L, De Lassence A, Ribrag V, Gachot B, Blot F, Theodore C, Bonnay M, Korenbaum C, Nitenberg G, , , Leukemia & Lymphoma, 1998
45. Nutritional folate status influences the efficacy and toxicity of chemotherapy in rats, Branda RF, Nigels E, Lafayette AR, Hacker M., , , Blood, 1998
46. The use of folates concomitantly with low-dose pulse methotrexate, Shiroky JB, , , Rheumatic Diseases Clinics of North America, 1997
47. Inhibition of methotrexate-induced chromosomal damage by folinic acid in V79 cells, Keshava C, Keshava N, Whong WZ, Nath J, Ong TM, , , Mutation Research, 1998
48. Morgan SL, Baggott JE
49. Methotrexate in rheumatoid arthritis: folate supplementation should always be given., Morgan SL, Baggott JE, Alarcon GS, , , BioDrugs, 1997 Click here to request reprint from publisher
50. Folic acid supplementation prevents deficient blood folate levels and hyperhomocysteinemia during longterm, low dose methotrexate therapy for rheumatoid arthritis: Implications for cardiovascular disease prevention, Morgan SL, Baggott JE, Lee JY, Alarcon GS, , , Journal of Rheumatology, 1998
51. Treatment of depression: time to consider folic acid and vitamin B12, Coppen A, Bolander-Gouaille C., , , Journal of Psychopharmacology, 2005
52. Folate for depressive disorders: systematic review and meta-analysis of randomized controlled trials, Taylor MJ, Carney SM, Goodwin GM, Geddes JR., , , Journal of Psychopharmacology, 2004
53. ScientistLive Website, , , , American Journal of Epidemiology,
54. 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)
55. 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
56. Blocking tumor necrosis factor-alpha inhibits folic acid-induced renal failure, Bing Wan, Li Hao, Yuhua Qiu, Zhongwen Sun, Qi Cao, Yi Zhang, Tongyu Zhu, Hao Wang, Yanyun Zhang, , , Experimental and Molecular Pathology, 2006
External links
★
★ Health Canada article about folic acid
★ US Public Health Service information page on folic acid
★ BMJ Editorial – "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
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
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