View source for Folic acid detailed information

{{Chembox new
|   Name = Folic acid
|   ImageFile = Folicacid2.png
|   ImageSize = 250px
|   ImageName = Folic acid
|   IUPACName = (''S'')-2-(4-((2-amino-4-hydroxypteridin-6-yl)methylamino)benzamido)pentanedioic acid 
|   OtherNames = ''N''-[4(2-Amino-4-hydroxy pteridin-6-ylmethylamino) benzoyl]-L(+)-glutamic acid; pteroyl-L-glutamic acid; Vitamin B<sub>9</sub>; Vitamin M; Folacin
| Section1 = {{Chembox Identifiers
|   SMILES = C1=CC(=CC=C1C(=O)NC<br>(CCC(=O)O)C(=O)O)<br>NCC2=CN=C3C(=N2)<br>C(=O)N=C(N3)N
|   CASNo = 59-30-3
|   RTECS = LP5425000
  }}
| Section2 = {{Chembox Properties
|   Formula = C<sub>19</sub>H<sub>19</sub>N<sub>7</sub>O<sub>6</sub>
|   MolarMass = 441.403 g/mol
|   Appearance = yellow-orange crystalline powder
|   Density = 
|   Solubility = 0.0016 mg/ml (25 °C)
|   MeltingPt = 250 °C (523 K), [[Chemical decomposition|decomp.]]
|   pKa = 1<sup>st</sup>: 2.3, 2<sup>nd</sup>: 8.3
  }}
| Section7 = {{Chembox Hazards
|   MainHazards = non-toxic, non-flammable}}
}}
{{SI}}


'''Folic acid''' and '''folate''' (the [[anion]] form) are forms of the water-soluble [[B vitamins|Vitamin B<sub>9</sub>]]. These occur naturally in [[food]] and can also be taken as [[Dietary supplement|supplements]]. Folate gets its name from the Latin word ''folium'' ("leaf").

==Folate in foods and other sources==
[[Leafy vegetable]]s such as [[spinach]], [[turnip|turnip greens]], [[lettuce]]s, 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. 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
[http://www.ars.usda.gov/Services/docs.htm?docid=9673 USDA National Nutrient Database for Standard Reference].
Folate is also found in [[Vegemite]], with an average serving (5gm) 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==
*'''DNA and cell division'''
Folate is necessary for the production and maintenance of new cells.<ref name="Oldref_2">{{cite journal | author=Kamen B | title=Folate and antifolate pharmacology | journal=Seminars in oncology | volume=24 | issue=5 Suppl 18 | year=1997 | pages=S18–30–S18–39 | pmid=9420019}}</ref> 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 cell]]s (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. <ref>Lieberman, et al. Marks' Essentials of Biochemistry, A Clinical Approach. Lippincott Wiliams and Wilkins. 2007. ISBN 0 7817 9340 8</ref> Both adults and children need folate to make normal RBCs and prevent [[anemia]].<ref name="Oldref_4">{{cite journal | author=Zittoun J | title=Anemias due to disorder of folate, vitamin B<sub><small>12</small></sub> and transcobalamin metabolism | journal=La Revue du praticien | volume=43 | issue=11 | year=1993 | pages=1358–63 | pmid=8235383}} (Article in French)</ref> 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 [[substrate (biochemistry)|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 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]] (FH<sub>4</sub>) begins when folate (F) is [[redox|reduced]] to [[dihydrofolate]] (DHF) (FH<sub>2</sub>), which is then reduced to THF. [[Dihydrofolate reductase]] catalyses the last step.<ref>[http://us.expasy.org/enzyme/1.5.1.3 EC 1.5.1.3]</ref> Vitamin B<sub>3</sub> in the form of [[NADPH]] is a necessary cofactor for both steps of the synthesis. 

[[Methylene-THF]] (CH<sub>2</sub>FH<sub>4</sub>) is formed from THF by the addition of [[methylene]] groups from one of three carbon donors: [[formaldehyde]], [[serine]], or [[glycine]]. [[Methyl tetrahydrofolate]] (CH<sub>3</sub>-THF) can be made from methylene-THF by reduction of the methylene group with NADPH. If is important to note that Vitamin B<sub>12</sub> is the only acceptor of methyl-THF. There is also only one acceptor for methyl-B<sub>12</sub> which is homocysteine in a reaction catalyzed by homocysteine methyltransferase. This is important because a defect in homocysteine methyltransferase or a defeciency of B<sub>12</sub> can lead to a methyl-trap of THF and a subsequent deficiency. Thus, a deficiency in B<sub>12</sub> can generate a large pool of methyl-THF that is unable to undergo reactions and will mimic folate deficiency. Another form of THF, [[folinic acid|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<sub>2</sub> → THF → CH<sub>2<sub>-THF 
Formyl-THF <--> Methynl-THF <--> Methylene-THF --> Methyl-THF</sub>

'''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 [[:Category:Dihydrofolate reductase inhibitors|dihydrofolate reductase inhibitors]] such as [[trimethoprim]], [[pyrimethamine]] and [[methotrexate]]; the [[Sulfonamide (medicine)|sulfonamide]]s (competitive inhibitors of [[para-aminobenzoic acid]] in the reactions of [[dihydropteroate synthetase]]).

*Recommended Daily Allowance (RDA)
{| border=1 cellpadding=2 style="text-align:center"
|+ '''1998 RDAs for Folate'''
|-
! align="center" | Men !! colspan=3 align="center" | Women  
|-
!  align="center" | (19+) !! align="center" | (19+) !! align="center" | Pregnancy !! align="center" | Breast feeding
|-
| align="center" | 400 µg || align="center" | 400 µg || align="center" | 600 µg || align="center" | 500 µg
|-
| colspan=4 align="center" | ''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.<!--
  --><ref name="Oldref_12">{{cite journal | author=Alaimo K, McDowell MA, Briefel RR, Bischof AM, Caughman CR, Loria CM, Johnson CL | title=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 | journal=Advance Data n° 258 | year=1994 | pages=1–28 | pmid=10138938}}</ref><!--
  --><ref name="Oldref_13">{{cite journal | author=Raiten DJ, Fisher KD | title=Assessment of folate methodology used in the Third National Health and Nutrition Examination Survey (NHANES III, 1988-1994) | journal=The Journal of Nutrition | volume=125 | issue=5 | year=1995 | pages=1371S–1398S | pmid=7738698}}</ref>
However, the folic acid fortification program in the United States has increased folic acid content of commonly eaten foods such as [[breakfast cereal|cereals]] and [[cereal|grains]], and as a result diets of most adults now provide recommended amounts of folate equivalents.<!--
  --><ref name="Oldref_14">{{cite journal | author=Lewis CJ, Crane NT, Wilson DB, Yetley EA| title=Estimated folate intakes: data updated to reflect food fortification, increased bioavailability, and dietary supplement use| journal=The American Journal of Clinical Nutrition| volume=70| issue=2 | year=1999| pages=198–207 | pmid=10426695}}</ref>

==Folate deficiency==
{{dablink|See [[Folate deficiency]]}}

==Human reproduction==<!--linked from "fertility"-section in this article-->
Folic acid is very important for all women who may become [[Pregnancy|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.<!--
  --><ref name="Oldref_21">{{cite journal | author=Shaw GM, Schaffer D, Velie EM, Morland K, Harris JA | title=Periconceptional vitamin use, dietary folate, and the occurrence of neural tube defects | journal=Epidemiology | volume=6 | issue=3 | year=1995 | pages=219–226 | pmid=7619926 | doi = 10.1097/00001648-199505000-00005 <!--Retrieved from CrossRef by DOI bot-->}}</ref>
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.<!--
  --><!--<ref name="Oldref_5a">[[#endnote_Oldref_5|''see'' USDA, 1999.]]</ref> this is orphaned as no ‘Oldref_5’--><!--
  --><ref name="Oldref_22">{{cite journal | author=Mulinare J, Cordero JF, Erickson JD, Berry RJ | title=Periconceptional use of multivitamins and the occurrence of neural tube defects | journal=Journal of the American Medical Association | volume=260 | issue=21 | year=1988 | pages=3141–3145 | pmid=3184392 | doi = 10.1001/jama.260.21.3141 <!--Retrieved from CrossRef by DOI bot-->}}</ref><ref name="Oldref_23">{{cite journal | author=Milunsky A, Jick H, Jick SS, Bruell CL, MacLaughlin DS, Rothman KJ, Willett W | title=Multivitamin/folic acid supplementation in early pregnancy reduces the prevalence of neural tube defects | journal=Journal of the American Medical Association | volume=262 | issue=20 | year=1989 | pages=2847–2852 | pmid=2478730 | doi = 10.1001/jama.262.20.2847 <!--Retrieved from CrossRef by DOI bot-->}}</ref>
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.<ref>[http://www.cdc.gov/ncbddd/folicacid/health_recomm.htm Health Professionals Recommendations, Folic Acid, NCBDDD, CDC<!-- Bot generated title -->]</ref>

Recent research has shown that it is also very important for men who are planning on fathering children, reducing birth defect risks.<ref>[http://www.medpagetoday.com/PrimaryCare/DietNutrition/tb/8825 Medical News: Extra Folate for Men May Reduce Birth Defects - in Primary Care, Diet & Nutrition from MedPage Today<!-- Bot generated title -->]</ref>

==Folic acid supplements and masking of B<sub>12</sub> deficiency==
There has been concern about the interaction between [[Vitamin B12|vitamin B<sub>12</sub>]] and folic acid.<!--
--><ref name="pmid_10466189">{{cite journal | author=Scott JM | title=Folate and vitamin B12 | journal=Proc Nutr Soc. | volume=2 | issue=58 | year=1999 May | pages=441–8 | pmid=10466189}}</ref><!--
-->Folic acid supplements can correct the anemia associated with vitamin B<sub>12</sub> deficiency. Unfortunately, folic acid will not correct changes in the nervous system that result from vitamin B<sub>12</sub> deficiency. Permanent nerve damage could theoretically occur if vitamin B<sub>12</sub> deficiency is not treated. Therefore, intake of supplemental folic acid should not exceed 1000 [[Kilogram|micrograms]] (1000 mcg or 1 mg) per day to prevent folic acid from masking symptoms of vitamin B<sub>12</sub> 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 B<sub>12</sub> deficiency or its consequences.<!--
--><ref name="pmid_12791626">{{cite journal | author=Mills JL, Von Kohorn I, Conley MR, Zeller JA, Cox C, Williamson RE, Dufour DR | title=Low vitamin B-12 concentrations in patients without anemia: the effect of folic acid fortification of grain. | journal=Am J Clin Nutr. | volume=6 | issue=77 | year=2003 Jun | pages=1474–7 | pmid=12791626}}</ref>

However one recent study has demonstrated that high folic or folate levels when combined with low B<sub>12</sub> levels are associated with significant cognitive impairment among the elderly.<ref>M.S. Morris et al, "Folate and vitamin B<sub>12</sub> 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</ref> If the observed relationship for seniors between folic acid intake, B<sub>12</sub> 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 B<sub>12</sub> because they are at greater risk of having a vitamin B<sub>12</sub> deficiency. If you are 50 years of age or older, ask your physician to check your B<sub>12</sub> 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.<!--
  --><ref name="Oldref_55">{{cite journal | author=Hathcock JN. | title=Vitamins and minerals: efficacy and safety | journal=American Journal of Clinical Nutrition | volume=66 | issue=2 | year=1997 | pages=427–37 | pmid=9250127}}</ref>
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 B<sub>12</sub> deficiency.<!--
  --><ref name="Oldref_29">{{cite journal | author=Baggott JE, Morgan SL, HaT, Vaughn WH, Hine RJ | title=Inhibition of folate-dependent enzymes by non-steroidal anti-inflammatory drugs | journal=Biochemical Journal | volume=282 | issue=Pt 1 | year=1992 | pages=197–202 | pmid=1540135}}</ref>

Research suggests high levels of folic acid can interfere with some [[malaria|antimalarial]] treatments.<ref name="malaria">BBC [http://news.bbc.co.uk/1/hi/health/6067450.stm Folic acid 'hinders malaria drug'] 21 October 2006</ref>

A 10000-patient study at Tufts University in 2007 concluded that excess folic acid worsens the effects of B<sub>12</sub> deficiency and in fact may affect the absorption of B<sub>12</sub>. <ref name="tufts">Foodproductiondaily [http://www.foodproductiondaily.com/news/ng.asp?n=82165-vitamin-b-folate-dementia]</ref>

==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 ''[[dietary supplement|supplementation]]'' for women intending to become [[Pregnancy|pregnant]]. For example, the [[United States Public Health Service]] (see [[#External links|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 B<sub>12</sub> 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 [[Soviet Union|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 [[United Kingdom|UK]] the [[Food Standards Agency]] has recommended fortification.<ref>{{cite web |url=http://www.food.gov.uk/news/newsarchive/2007/may/folatefort |title=Board recommends mandatory fortification |accessdate=2007-05-18 |author=FSA |date=2007-05-17 }}</ref><ref>{{cite web |url=http://news.bbc.co.uk/1/hi/health/6665109.stm |title=Backing for folic acid in bread |accessdate=2007-05-18}}</ref><ref>BBC [http://news.bbc.co.uk/1/hi/health/6648059.stm Experts back folic acid in flour] 11 May 2007</ref> To date, no [[European Union|EU]] country has yet mandated fortification.<ref>Russell, Andrew. (2006.) [http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1716791 "The UK campaign on folic acid and flour fortification."] ''Cerebrospinal Fluid Research'' 2006; 3(Suppl 1): S33, via PubMed Central website. Retrieved on [[2007]]-[[09-27]].</ref> [[Australia]] is considering fortification, but a period for comments ending [[2006-07-31]] attracted strong opposition from industry as well as academia.<ref>''The Sydney Morning Herald'' [http://www.smh.com.au/news/National/Bread-fortification-not-justified/2006/07/29/1153816426688.html Bread fortification 'not justified'] [[2006-07-29]]</ref>

Recent debate has emerged in the [[United Kingdom]]<ref>BBC [http://news.bbc.co.uk/1/hi/health/601909.stm 'Put folic acid in bread'] [[2000-01-13]]</ref> and [[Australia]]<ref>''The Sydney Morning Herald'' [http://www.smh.com.au/news/National/Bread-fortification-not-justified/2006/07/29/1153816426688.html Bread fortification 'not justified'] [[2006-07-29]]</ref> regarding the inclusion of folic acid in products such as [[bread]] and [[flour]].

[[Image:GrainProducts.jpg|right|thumb|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.<ref name="Oldref_7">{{cite journal | author=Malinow MR, Duell PB, Hess DL, Anderson PH, Kruger WD, Phillipson BE, Gluckman RA, Block PC, Upson BM | title=Reduction of plasma homocyst(e)ine levels by breakfast cereal fortified with folic acid in patients with coronary heart disease | journal= New England Journal of Medicine | volume=338 | issue=15 | year=1998 | pages=1009–15 | pmid=9535664 | doi = 10.1056/NEJM199804093381501 <!--Retrieved from CrossRef by DOI bot-->}}</ref><!--
  --><ref name="Oldref_8">{{cite journal | author=Daly S, Mills JL, Molloy AM, Conley M, Lee YJ, Kirke PN, Weir DG, Scott JM | title=Minimum effective dose of folic acid for food fortification to prevent neural-tube defects | journal=Lancet | volume=350 | issue=9092 | year=1997 | pages=1666–9 | pmid=9400511 | doi = 10.1016/S0140-6736(97)07247-4 <!--Retrieved from CrossRef by DOI bot-->}}</ref>
This ruling took effect [[1998-01-01]], and was specifically targeted to reduce the risk of neural tube birth defects in newborns.<!--
  --><ref name="Oldref_9">{{cite journal | author=Crandall BF, Corson VL, Evans MI, Goldberg JD, Knight G, Salafsky IS | title=American College of Medical Genetics statement on folic acid: fortification and supplementation | journal=American Journal of Medical Genetics| volume=78 | issue=4 | year=1998 | pages=381 | pmid=9714444 | doi = 10.1002/(SICI)1096-8628(19980724)78:4<381::AID-AJMG16>3.0.CO;2-E}}</ref> There are concerns that the amount of [[folate]] added is insufficient[http://www.boston.com/yourlife/health/women/articles/2004/01/06/fda_muffed_chance_to_prevent_birth_defects/?page=full]. 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.[http://www.news.com.au/story/0,23599,20641599-1702,00.html]

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.<ref name="Oldref_57">{{cite journal | author=Centers for Disease Control and Prevention (CDC) | title=Spina bifida and anencephaly before and after folic acid mandate--United States, 1995-1996 and 1999-2000 | journal=Morbidity and Mortality Weekly Report | volume=53 | issue=17 | year=2004 | pages=362–5 | pmid=15129193}}</ref>

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 B<sub>12</sub>, or vitamin B<sub>6</sub> 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.<!--
  --><ref name="Oldref_30">{{cite journal | author=Refsum H, Ueland PM, Nygard O, Vollset SE | title=Homocysteine and cardiovascular disease | journal=Annual Review of Medicine | volume=49 | issue=1 | year=1998 | pages=31–62 | pmid=9509248 | doi = 10.1146/annurev.med.49.1.31 <!--Retrieved from CrossRef by DOI bot-->}}</ref>
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.<!--
  --><ref name="Oldref_36">{{cite journal | author=Malinow MR | title=Plasma homocyst(e)ine and arterial occlusive diseases: A mini-review | journal=Clinical Chemistry | volume=41 | issue=1 | year=1995 | pages=173–6  | pmid=7813076}}</ref>
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 B<sub>12</sub> or vitamin B<sub>6</sub> can lower the risk of developing coronary heart disease. The NORVIT trial suggests that folic acid supplementation may do more harm than good.<ref>[http://www.rxpgnews.com/research/cardiology/myocardialinfarction/article_2298.shtml NORVIT Trial- High dose B vitamins do not lower stroke or MI risk]</ref>

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 B<sub>12</sub> may even increase some cardiovascular risks.<!--
  --><ref name="JAmCollCardiol2006-Zoungas">{{cite journal | author=Zoungas S, McGrath BP, Branley P, Kerr PG, Muske C, Wolfe R, Atkins RC, Nicholls K, Fraenkel M, Hutchison BG, Walker R, McNeil JJ | title=Cardiovascular morbidity and mortality in the Atherosclerosis and Folic Acid Supplementation Trial (ASFAST) in chronic renal failure: a multicenter, randomized, controlled trial | journal=J Am Coll Cardiol | year=2006 | pages=1108–16 | volume=47 | issue=6 | pmid=16545638 | doi = 10.1016/j.jacc.2005.10.064 <!--Retrieved from CrossRef by DOI bot-->}}</ref><!--
  --><ref name="NEJM2006a">{{cite journal | author= | title=Homocysteine Lowering with Folic Acid and B Vitamins in Vascular Disease | journal=N Engl J Med | year=2006 | pages= | volume= | pmid=16531613 [http://content.nejm.org/cgi/reprint/NEJMoa060900v1.pdf Full text PDF]}}</ref><!--
  --><ref name="NEJM2006-Bonna>{{cite journal | author=Bonaa KH, Njolstad I, Ueland PM, Schirmer H, Tverdal A, Steigen T, Wang H, Nordrehaug JE, Arnesen E, Rasmussen K | title=Homocysteine Lowering and Cardiovascular Events after Acute Myocardial Infarction | journal=N Engl J Med | year=2006 | pages = 1578| volume= | pmid=16531614 [http://content.nejm.org/cgi/reprint/NEJMoa055227v1.pdf Full text PDF] | doi = 10.1056/NEJMoa055227 <!--Retrieved from CrossRef by DOI bot-->}}</ref>

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 that<ref>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
</ref> 

: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 <ref>[http://www.sciencedaily.com/releases/2008/03/080327092140.htm Brief, high doses of folate blunt damage from heart attack]</ref> in favour of therapeutic folate, although they cautioned that it was premature for those at risk of heart attack to self-medicate.

===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.<ref>BBC [http://news.bbc.co.uk/1/hi/health/6709101.stm Folic acid 'reduces stroke risks'] 31 May 2007</ref> 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.<ref>{{cite journal |journal= Scand J Clin Lab Invest |date=2007 |volume=67 |issue=5 |pages=459–73 |title=Folate in colorectal cancer, prostate cancer and cardiovascular disease |author= Van Guelpen B |pmid=17763182 |doi=10.1080/00365510601161513}}</ref> 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.<ref>{{cite journal |journal= Med Hypotheses |date=1995 |volume=45 |issue=3 |pages=297–303 |title= Folic acid as a cancer-preventing agent |author= Jennings E |doi=10.1016/0306-9877(95)90121-3 |pmid=8569555}}</ref> 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.<ref>{{cite journal |journal= Am J Clin Nutr |year=2004 |volume=80 |issue=5 |pages=1123–8 |title= Will mandatory folic acid fortification prevent or promote cancer? |author= Kim YI |pmid=15531657 |url=http://www.ajcn.org/cgi/content/full/80/5/1123}}</ref>
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,<ref>{{cite journal |journal= Int J Cancer |date=2005 |volume=113 |issue=5 |page=825–8 |title=Folate intake and colorectal cancer risk: a meta-analytical approach |author= Sanjoaquin MA, Allen N, Couto E, Roddam AW, Key TJ |doi=10.1002/ijc.20648 |pmid=15499620 | pages = 825}}</ref> while other studies find that folate from supplements is more effective due to greater bioavailability<ref name="folatecancer98">{{cite journal |author=Giovannucci E, Stampfer MJ, Colditz GA, ''et al'' |title=Multivitamin use, folate, and colon cancer in women in the Nurses' Health Study |journal=Ann. Intern. Med. |volume=129 |issue=7 |pages=517–24 |year=1998 |pmid=9758570 |doi=}}</ref> and a 2007 randomized clinical trial found that folate supplements did not reduce the risk of colorectal [[adenoma]]s.<ref>{{cite journal |journal=JAMA |date=2007 |volume=297 |issue=21 |pages=2351–9 |title= Folic acid for the prevention of colorectal adenomas: a randomized clinical trial |author= Cole BF, Baron JA, Sandler RS ''et al.'' |pmid=17551129 | doi = 10.1001/jama.297.21.2351 <!--Retrieved from CrossRef by DOI bot-->}}</ref> 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.<ref>{{cite journal |journal= J Natl Cancer Inst |date=2006 |volume=98 |issue=6 |pages=407–13 |title= Folate intake and pancreatic cancer incidence: a prospective study of Swedish women and men |author= Larsson SC, Håkansson N, Giovannucci E, Wolk A |doi=10.1093/jnci/djj094 |pmid=16537833 |url=http://jnci.oxfordjournals.org/cgi/content/full/98/6/407}}</ref> 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,<ref>{{cite journal |journal=Nutr Rev |date=2006 |volume=64 |issue= 10 Pt 1 |pages=468–75 |title= Does a high folate intake increase the risk of breast cancer? |author= Kim YI |doi=10.1301/nr.2006.oct.468-475 |pmid=17063929}}</ref> but a 2007 Swedish prospective study found that a high folate intake was associated with a lower incidence of postmenopausal breast cancer.<ref>{{cite journal |journal= Am J Clin Nutr |date=2007 |volume=86 |issue=2 |pages=434–43 |title= High folate intake is associated with lower breast cancer incidence in postmenopausal women in the Malmö Diet and Cancer cohort |author= Ericson U, Sonestedt E, Gullberg B, Olsson H, Wirfält E |pmid=17684216}}</ref> 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.<!--
  --><ref name="Oldref_2"/>
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,<!--
  --><ref name="Oldref_46">{{cite journal | author=Rubio IT, Cao Y, Hutchins LF, Westbrook KC, Klimberg VS | title=Effect of glutamine on methotrexate efficacy and toxicity | journal=Annals of Surgery | volume=227 | issue=5 | year=1998 | pages=772–8 | pmid=9605669 | doi = 10.1097/00000658-199805000-00018 <!--Retrieved from CrossRef by DOI bot-->}}</ref><!--
  --><ref name="Oldref_47">{{cite journal | author=Wolff JE, Hauch H, Kuhl J, Egeler RM, Jurgens H | title=Dexamethasone increases hepatotoxicity of MTX in children with brain tumors | journal=Anticancer Research | volume=18 | issue=4B | year=1998 | pages=2895–9 | pmid=9713483}}</ref><!--
  --><ref name="Oldref_48">{{cite journal | author=Kepka L, De Lassence A, Ribrag V, Gachot B, Blot F, Theodore C, Bonnay M, Korenbaum C, Nitenberg G | title=Successful rescue in a patient with high dose methotrexate-induced nephrotoxicity and acute renal failure | journal=Leukemia & Lymphoma | volume=29 | issue=1-2 | year=1998 | pages=205–9 | pmid=9638991 | doi = 10.3109/10428199809058397 <!--Retrieved from CrossRef by DOI bot-->}}</ref>
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.<!--
  --><ref name="Oldref_49">{{cite journal | author=Branda RF, Nigels E, Lafayette AR, Hacker M. | title=Nutritional folate status influences the efficacy and toxicity of chemotherapy in rats | journal=Blood | volume=92 | issue=7 | year=1998 | pages=2471–6 | pmid=9746787}}</ref>
Folinic acid is ''not'' the same as folic acid. Folic acid supplements have little established role in cancer chemotherapy.<!--
  --><ref name="Oldref_50">{{cite journal | author=Shiroky JB | title=The use of folates concomitantly with low-dose pulse methotrexate | journal=Rheumatic Diseases Clinics of North America | volume=23 | issue=4 | year=1997 | pages=969–80 | pmid=9361164 | doi=10.1016/S0889-857X(05)70369-0}}</ref><!--
  --><ref name="Oldref_51">{{cite journal | author=Keshava C, Keshava N, Whong WZ, Nath J, Ong TM | title=Inhibition of methotrexate-induced chromosomal damage by folinic acid in V79 cells | journal=Mutation Research | volume=397 | issue=2 | year=1998 | pages=221–8 | pmid=9541646}}</ref>
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 erythematosus|lupus]], [[scleroderma]], [[psoriasis]], [[asthma]], [[sarcoidoisis]], [[primary biliary cirrhosis]], and [[inflammatory bowel disease]].<!--
  --><ref name="Oldref_52">Morgan SL, Baggott JE {{Section:Chapter reference after author|Year=1995|Title=Folate antagonists in nonneoplastic disease: proposed mechanisms of efficacy and toxicity|Editor=Bailey LB| Book=Folate in Health and Disease|Pages=405-433|Publisher=New York: Marcel Dekker|ID=ISBN 0-8247-9280-7}}</ref>
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.<!--
  --><ref name="Oldref_53">{{cite journal | author=Morgan SL, Baggott JE, Alarcon GS | title=Methotrexate in rheumatoid arthritis: folate supplementation should always be given. | journal=BioDrugs | volume=8 | issue=1 | year=1997 | pages=164–175}} [http://www.adisonline.info/reprints.asp Click here to request reprint from publisher]</ref><!--
  --><ref name="Oldref_54">{{cite journal | author=Morgan SL, Baggott JE, Lee JY, Alarcon GS | title=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=Journal of Rheumatology | volume=25 | issue=3 | year=1998 | pages=441–6 | pmid=9517760}}</ref>
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 [[Clinical depression|depression]].<!--
  --><ref name="dep_coppen">{{cite journal | author=Coppen A, Bolander-Gouaille C.  | title= Treatment of depression: time to consider folic acid and vitamin B12 | journal= Journal of Psychopharmacology | volume=19 | issue=1 | year=2005 | pages=59–65  | pmid=15671130 | doi = 10.1177/0269881105048899 <!--Retrieved from CrossRef by DOI bot-->}}</ref>
There is some limited evidence from [[Randomized controlled trials|randomised controlled trials]] that using folic acid in addition to [[antidepressant|antidepressant medication]] may have benefits.<!--
  --><ref name="dep_taylor">{{cite journal | author=Taylor MJ, Carney SM, Goodwin GM, Geddes JR. | title= Folate for depressive disorders: systematic review and meta-analysis of randomized controlled trials | journal= Journal of Psychopharmacology | volume=18 | issue=2 | year=2004 | pages=251–6 | pmid=15260915 | doi = 10.1177/0269881104042630 <!--Retrieved from CrossRef by DOI bot-->}}</ref> 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 .<!--
  --><ref name="Journal_of_Epidemiology">{{cite journal | title=ScientistLive Website | journal= American Journal of Epidemiology | url=http://www.scientistlive.com/18059/depression-tied-to-folate-levels.thtml | format={{dead link|date=June 2008}} &ndash; <sup>[http://scholar.google.co.uk/scholar?hl=en&lr=&q=intitle%3AScientistLive+Website&as_publication=American+Journal+of+Epidemiology&as_ylo=&as_yhi=&btnG=Search Scholar search]</sup> }}</ref>
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&mdash;twice the current RDA&mdash;than those who took placebo. The study was reported in ''[[The Lancet]]'' on [[19 January]] 2007.<ref>Dr Jane Durga, Martin PJ van Boxtel, Prof Evert G Schouten, Prof Frans J Kok, Prof Jelle Jolles, Martijn B Katan, and Petra Verhoef [http://www.thelancet.com/journals/lancet/article/PIIS0140673607601093/abstract 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)</ref>

===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 [[#Human reproduction|folic acid and pregnancy]]. Therefore, it is necessary  to receive sufficient amounts through the diet, in order to avoid [[subfertility]].<ref>[http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=17099205&ordinalpos=3&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum 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]</ref>

==Induction of acute renal failure==
Folic acid is used in extremely high doses to induce [[Acute renal failure]] in [[murine]] [[Model organism|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]].<ref>{{cite journal | author=Bing Wan, Li Hao, Yuhua Qiu, Zhongwen Sun, Qi Cao,  Yi Zhang, Tongyu Zhu, Hao Wang, Yanyun Zhang | title=Blocking tumor necrosis factor-alpha inhibits folic acid-induced renal failure | journal=Experimental and Molecular Pathology | volume=81 | year=2006 | pages=211–216 | pmid=16595132 | doi=10.1016/j.yexmp.2006.02.005 }}</ref>

==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.<!-- old reference 1 -->
* {{cite book | author=Food and Nutrition Board, Institute of Medicine | title=Dietary reference intakes for thiamin, riboflavin, niacin, vitamin B<sub><small>6</small></sub>, folate, vitamin B<sub><small>12</small></sub>, 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 | location=Washington, D.C.  | publisher=National Academy Press | year=1998 | id=ISBN 0-309-06554-2}}
<!-- old reference 10 -->
* 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<!-- old reference 56 -->

==References==
{{Reflist|2}}

==External links==
* {{pauling|id=vitamins/fa|title=Folic Acid|author=Jane Higdon}}
* [http://www.hc-sc.gc.ca/english/iyh/medical/folic_acid.html Health Canada article about folic acid]
* [http://www.cdc.gov/ncbddd/folicacid/ US Public Health Service information page on folic acid]
* [http://bmj.com/cgi/content/full/324/7350/1348 BMJ Editorial – "Delaying folic acid fortification of flour"]
*[http://www.jpgmonline.com/article.asp?issn=0022-3859;year=2003;volume=49;issue=3;spage=195;epage=196;aulast=Salvi Folic Acid and Birth Defects] Article from Journal of Postgraduate Medicine
* [http://www.berkeleywellness.com/html/ds/dsFolicAcid.php Folic Acid The Vitamin That Does Almost Everything]-U.C Berkeley Wellness Letter April 2003
* [http://www.biomedcentral.com/1471-2393/4/20 BMC Pregnancy and Childbirth 2004: no vitamin B<sub><small>12</small></sub> problems in Canada after folic acid fortification]
*[http://www.medsci.org/v01p0050.htm The primary prevention of birth defects: Multivitamins or folic acid?]
* [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12791626&query_hl=7 Mills et al, Am J Clin Nutr 2003: no vitamin B<sub><small>12</small></sub> problems in the US after folic acid fortification]
*[http://www.newscientist.com/article.ns?id=dn9314&feedId=online-news_rss20 Folic acid may help prevent throat cancer]
*[http://www.bipolar-lives.com/benefits-of-folic-acid.html Folic acid may help treat bipolar disorder]

===Biochemistry links===
*[http://www.chem.qmul.ac.uk/iubmb/enzyme/reaction/misc/folate1.html Folate biosynthesis (early stages)]
*[http://www.chem.qmul.ac.uk/iubmb/enzyme/reaction/misc/folate2.html Folate biosynthesis (later stages)]
*[http://www.chem.qmul.ac.uk/iubmb/enzyme/reaction/misc/folate3.html Folate coenzymes]
*[http://www.chem.qmul.ac.uk/iubmb/enzyme/reaction/misc/folate5.html C<sub>1</sub> metabolism with folate]
*[http://www.chem.qmul.ac.uk/iubmb/enzyme/reaction/misc/folate4.html Formylation, hydroxymethylation and methylation using folate]
*[http://www.chem.qmul.ac.uk/iupac/misc/folic.html IUPAC nomenclature of folate related compounds]

{{Dietary supplement}}
{{Vitamin}}

[[Category:Dietary supplements]]
[[Category:Folates]]

[[ar:حمض فوليك]]
[[bg:Фолиева киселина]]
[[ca:Àcid fòlic]]
[[cs:Kyselina listová]]
[[da:Folsyre]]
[[de:Folsäure]]
[[et:Foolhape]]
[[es:Ácido fólico]]
[[fa:ویتامین ب۹]]
[[fr:Vitamine B9]]
[[ko:잎산]]
[[hr:Vitamin B9]]
[[id:Asam folik]]
[[is:Fólinsýra]]
[[it:Acido folico]]
[[he:חומצה פולית]]
[[lb:Folsaier]]
[[lt:Folio rūgštis]]
[[nl:Foliumzuur]]
[[ja:葉酸]]
[[no:folsyre]]
[[pl:Kwas foliowy]]
[[pt:Ácido fólico]]
[[ru:Фолиевая кислота]]
[[sq:Acidi folik]]
[[sk:Kyselina listová]]
[[sl:Folna kislina]]
[[sr:Folna kiselina]]
[[fi:Foolihappo]]
[[sv:Folsyra]]
[[vi:Axít folic]]
[[tr:Folik asit]]
[[zh:叶酸]]
{{WH}}
{{WS}}