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Folic acid

2007 Schools Wikipedia Selection. Related subjects: Chemical compounds;
Health and medicine

                            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           C[19]H[19]N[7]O[6]
                            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 (pK[a])         1^st: 2.3, 2^nd: 8.3
            Chiral rotation [α][D]                       +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)
                             Infobox disclaimer and references

   Folic acid and folate (the anion form) are forms of a water-soluble B
   vitamin. 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, sun flower seeds and some other fruits
   and vegetables are rich sources of folate. Some breakfast cereals
   (ready-to-eat and others) are fortified with 25 percent or 100 percent
   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.

   Recently there have been debates in the United Kingdom and Australasia
   about including 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.

History

   A key observation of researcher Lucy Wills in 1931 led to the
   identification of folate as the nutrient needed to prevent the anaemia
   of pregnancy. Dr. Wills demonstrated that the anaemia could be
   corrected by 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 synthesised in 1946.

Biological roles

   Folate is necessary for the production and maintenance of new cells.
   This is especially important during periods of rapid cell division and
   growth such as infancy and pregnancy. Folate is needed to replicate
   DNA. It also helps prevent changes to DNA that may lead to cancer. 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 anaemia.
   Both adults and children need folate to make normal red blood cells and
   prevent anaemia.

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 in the formation of tetrahydrofolate (FH[4]) is the
   reduction of folate (F) to dihydrofolate (FH[2]) and then the
   subsequent reduction of dihydrofolate to tetrahydrofolate (FH[4]). Both
   these sequential reactions are carried out by dihydrofolate reductase
   EC 1.5.1.3.

   Methylene tetrahydrofolate (CH[2]FH[4]) is formed from tetrahydrofolate
   by the addition of methylene groups from one of three carbon donors:
   formaldehyde, serine, or glycine. Methyl tetrahydrofolate (CH[3]–FH[4])
   can be made from methylene tetrahydrofolate by reduction of the
   methylene group, and formyl tetrahydrofolate (CHO-FH[4], folinic acid)
   is made by oxidation of methylene tetrahydrofolate.

   In other words:

   F → FH[2] → FH[4] → CH[2]=FH[4] → 1-carbon chemistry

   A number of drugs interfere with the biosynthesis of folic acid and
   tetrahydrofolate. Among them are the dihydrofolate reductase inhibitors
   (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

Recommended Dietary Allowance for folate

   The Recommended Dietary Allowance (RDA) is the average daily dietary
   intake level that is sufficient to meet the nutrient requirements of
   nearly all (97 to 98 percent) healthy individuals in each life-stage
   and gender group. The 1998 RDAs 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. The 1998
   RDAs for folate expressed in micrograms (µg) of DFE for adults are:

   CAPTION: 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. 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.

Folate deficiency

   See 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. 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. 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.

Folic acid supplements and masking of B[12] deficiency

   There has been concern about the interaction between vitamin B[12] and
   folic acid. Folic acid supplements can correct the anaemia associated
   with vitamin B[12] deficiency. Unfortunately, folic acid will not
   correct changes in the nervous system that result from vitamin B[12]
   deficiency. Permanent nerve damage could theoretically occur if vitamin
   B[12] deficiency is not treated. Therefore, intake of supplemental
   folic acid should not exceed 1000 micrograms (1000 mcg or 1.000 mg) per
   day to prevent folic acid from masking symptoms of vitamin B[12]
   deficiency. In fact, 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[12]
   deficiency or its consequences.

   Still it is important for older adults to be aware of the relationship
   between folic acid and vitamin B[12] because they are at greater risk
   of having a vitamin B[12] deficiency. If you are 50 years of age or
   older, ask your physician to check your B[12] 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. The Institute of Medicine
   has established a tolerable upper intake level (UL) for folate of 1,000
   µg 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[12] deficiency.

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 not all pregnancies are planned 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 B[12] 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.
   Previously, the UK had decided not to fortify, mainly because of the
   vitamin B[12] concern. However, this decision is currently being
   reconsidered by the Food Standards Agency. Thus far, 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.

   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.
   This ruling took effect 1998- 01-01, and was specifically targeted to
   reduce the risk of neural tube birth defects in newborns. There are
   concerns that the amount of folate added is insufficient . 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.

   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 percent in the United States.

   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

   Low concentrations of folate, vitamin B[12], or vitamin B[6] may
   increase your level of homocysteine, an amino acid normally found in
   your blood. There is evidence that an elevated homocysteine level is an
   independent risk factor for heart disease and stroke. 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. 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
   B[12] or vitamin B[6] can lower your risk of developing coronary heart
   disease. The NORVIT trialsuggests that folic acid supplementation may
   do more harm than good.

   As of 2006, studies have shown that giving folic acid to reduce levels
   of homocysteine does not result in clinical benefit and suggests that
   in combination with B[12] may even increase some cardiovascular risks.

Folic acid and cancer

   Some evidence associates low blood levels of folate with a greater risk
   of cancer. 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. Several studies have associated
   diets low in folate with increased risk of breast, pancreatic, and
   colon cancer. 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.

   "Folate intake counteracts breast cancer risk associated with alcohol
   consumption" and "women who drink alcohol and have a high folate intake
   are not at increased risk of cancer" . 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 .

   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. Until results from such clinical trials are available, folic
   acid supplements should not be recommended to 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, 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. Folinic acid is not the same as folic
   acid. Folic acid supplements have little established role in cancer
   chemotherapy. 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. 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.
   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. There is some
   limited evidence from randomised controlled trials that using folic
   acid in addition to antidepressant medication may have benefits.
   However, the evidence is probably too limited at present for this to be
   a routine treatment recommendation.
   Retrieved from " http://en.wikipedia.org/wiki/Folic_acid"
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