folate

Folic acid
IUPAC nameN-[4(2-Amino-4-hydroxy­pteridin-6-ylmethylamino)­benzoyl]-L(+)-glutamic acid.
Other namespteroyl-L-glutamic acid; Vitamin B9, Vitamin M; Folacin
Identifiers
CAS number59-30-3
RTECS numberLP5425000
SMILESC1=CC(=CC=C1C(=O)NC (CCC(=O)O)C(=O)O) NCC2=CN=C3C(=N2) C(=O)N=C(N3)N
Properties
Molecular formulaC19H19N7O6
Molar mass441.1396 g/mol
Appearanceyellow-orange crystalline powder
Melting point 250 °C (523 K), decomp.
Solubility in water8.5 g/100 ml (20 °C)
Acidity (pKa)1st: 2.3, 2nd: 8.3
Hazards
Main hazardsnon-toxic, non-flammable
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.

History

A key observation by researcher Lucy Wills in 1931 led to the identification of folate as the nutrient needed to prevent anemia during pregnancy. Dr. Wills demonstrated that anemia could be reversed with brewer's yeast. Folate was identified as the corrective substance in brewer's yeast in the late 1930s and was extracted from spinach leaves in 1941. It was first synthesised in 1946.

Biological roles

Folate is necessary for the production and maintenance of new cells.[1] This is especially important during periods of rapid cell division and growth such as infancy and pregnancy. Folate is needed to replicate DNA. Thus folate deficiency hinders DNA synthesis and cell division, affecting most clinically the bone marrow, a site of rapid cell turnover. Because RNA and protein synthesis are not hindered, large red blood cells called megaloblasts are produced, resulting in lots of POO megaloblastic anemia.[2] Both adults and children need folate to make normal red blood cells and prevent anemia.[3]

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.[4]

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).

1998 RDAs for Folate
Men Women
(19+) (19+) Pregnancy Breast feeding
400 µg400 µg600 µg500 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.[5][6] However, the folic acid fortification program in the United States has increased folic acid content of commonly eaten foods such as cereals and grains, and as a result diets of most adults now provide recommended amounts of folate equivalents.[7]

Folate deficiency

Folic acid and pregnancy

Folic acid is very important for all women who may become pregnant. Adequate folate intake during the periconceptional period, the time just before and just after a woman becomes pregnant, helps protect against a number of congenital malformations including neural tube defects.[8] Neural tube defects result in malformations of the spine (spina bifida), skull, and brain (anencephaly). The risk of neural tube defects is significantly reduced when supplemental folic acid is consumed in addition to a healthy diet prior to and during the first month following conception.[9][10] 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.[11]

Folic acid supplements and masking of B12 deficiency

There has been concern about the interaction between vitamin B12 and folic acid.[12]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.[13]

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.[14] 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.[15] 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.[16]

Research suggests high levels of folic acid can interfere with some antimalarial treatments.[17]

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.[18][19][20] To date, no EU country has yet mandated fortification.[21] Australia is considering fortification, but a period for comments ending 2006-07-31 attracted strong opposition from industry as well as academia.[22]

Recent debate has emerged in the United Kingdom[23] and Australia[24] regarding the inclusion of folic acid in products such as bread and flour.

Enlarge picture
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][34]

Folic acid and 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.[35]

Folic acid and cancer

Some evidence associates low blood levels of folate with a greater risk of cancer.[36] 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.[37] Several studies have associated diets low in folate with increased risk of breast, pancreatic, and colon cancer.[38] 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.[39]

"Folate intake counteracts breast cancer risk associated with alcohol consumption"[40] and "women who drink alcohol and have a high folate intake are not at increased risk of cancer".[41] 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.[42] A prospective study of over 17,000 women for ten years found that among those who consumed 40 grams of alcohol (about 3-4 drinks) per day and took 200 migcrograms of folic acid per day, the risk of breast cancer fell to below that of alcohol abstainers.[43]

Folic acid and methotrexate for cancer

Folate is important for cells and tissues that rapidly divide.[1] Cancer cells divide rapidly, and drugs that interfere with folate metabolism are used to treat cancer. Methotrexate is a drug often used to treat cancer because it inhibits the production of the active form, tetrahydrofolate. Unfortunately, methotrexate can be toxic,[44][45][46] 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.[47] Folinic acid is not the same as folic acid. Folic acid supplements have little established role in cancer chemotherapy.[48][49] 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.[50] 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.[51][52] 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.[53] There is some limited evidence from randomised controlled trials that using folic acid in addition to antidepressant medication may have benefits.[54] 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 .[55] 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.[56]

Fertility

Folate is necessary for fertility in both men and women. In men, it contributes to spermatogenesis. In women, on the other hand, it contributes to oocyte maturation, implantation, placentation, in addition to the general effects of folic acid and pregnancy. Therefore, it is necessary to receive sufficient amounts through the diet, in order to avoid subfertility.[57]

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.[58]

Bibliography

  • This article contains information from the public domain resource at http://www.cc.nih.gov/ccc/supplements/folate.html
  • Herbert V. (1999). Folic Acid. Shils M, Olson J, Shike M, Ross AC, (Eds.). Nutrition in Health and Disease. Baltimore: Williams & Wilkins.
  • Food and Nutrition Board, Institute of Medicine (1998). Dietary reference intakes for thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12, pantothenic acid, biotin, and choline / a report of the Standing Committee on the Scientific Evaluation of Dietary Reference Intakes and its Panel on Folate, Other B Vitamins, and Choline and Subcommittee on Upper Reference Levels of Nutrients. Washington, D.C.: National Academy Press. ISBN 0-309-06554-2. 
  • Dietary Guidelines Advisory Committee, Agricultural Research Service, United States Department of Agriculture (USDA). Report of the Dietary Guidelines Advisory Committee on the Dietary Guidelines for Americans, 2000. http://www.ars.usda.gov/dgac

References

1. ^ Kamen B (1997). "Folate and antifolate pharmacology". Seminars in oncology 24 (5 Suppl 18): S18-30-S18-39. PMID 9420019. 
2. ^ Fenech M, Aitken C, Rinaldi J (1998). "Folate, vitamin B12, homocysteine status and DNA damage in young Australian adults". Carcinogenesis 19 (7): 1163-71. PMID 9683174. 
3. ^ Zittoun J (1993). "Anemias due to disorder of folate, vitamin B12 and transcobalamin metabolism". La Revue du praticien 43 (11): 1358-63. PMID 8235383.  (Article in French)
4. ^ EC 1.5.1.3
5. ^ Alaimo K, McDowell MA, Briefel RR, Bischof AM, Caughman CR, Loria CM, Johnson CL (1994). "Dietary intake of vitamins, minerals, and fiber of persons ages 2 months and over in the United States: Third National Health and Nutrition Examination Survey, Phase 1, 1988-91". Advance Data n° 258: 1-28. PMID 10138938. 
6. ^ Raiten DJ, Fisher KD (1995). "Assessment of folate methodology used in the Third National Health and Nutrition Examination Survey (NHANES III, 1988-1994)". The Journal of Nutrition 125 (5): 1371S-1398S. PMID 7738698. 
7. ^ Lewis CJ, Crane NT, Wilson DB, Yetley EA (1999). "Estimated folate intakes: data updated to reflect food fortification, increased bioavailability, and dietary supplement use". The American Journal of Clinical Nutrition 70 (2): 198-207. PMID 10426695. 
8. ^ Shaw GM, Schaffer D, Velie EM, Morland K, Harris JA (1995). "Periconceptional vitamin use, dietary folate, and the occurrence of neural tube defects". Epidemiology 6 (3): 219-226. PMID 7619926. 
9. ^ Mulinare J, Cordero JF, Erickson JD, Berry RJ (1988). "Periconceptional use of multivitamins and the occurrence of neural tube defects". Journal of the American Medical Association 260 (21): 3141-3145. PMID 3184392. 
10. ^ Milunsky A, Jick H, Jick SS, Bruell CL, MacLaughlin DS, Rothman KJ, Willett W (1989). "Multivitamin/folic acid supplementation in early pregnancy reduces the prevalence of neural tube defects". Journal of the American Medical Association 262 (20): 2847-2852. PMID 2478730. 
11. ^ Swedish Nutrition Recommendations 2005
12. ^ Scott JM (1999 May). "Folate and vitamin B12". Proc Nutr Soc. 2 (58): 441-8. PMID 10466189. 
13. ^ Mills JL, Von Kohorn I, Conley MR, Zeller JA, Cox C, Williamson RE, Dufour DR (2003 Jun). "Low vitamin B-12 concentrations in patients without anemia: the effect of folic acid fortification of grain.". Am J Clin Nutr. 6 (77): 1474-7. PMID 12791626. 
14. ^ 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
15. ^ Hathcock JN. (1997). "Vitamins and minerals: efficacy and safety". American Journal of Clinical Nutrition 66 (2): 427-37. PMID 9250127. 
16. ^ Baggott JE, Morgan SL, HaT, Vaughn WH, Hine RJ (1992). "Inhibition of folate-dependent enzymes by non-steroidal anti-inflammatory drugs". Biochemical Journal 282 (Pt 1): 197-202. PMID 1540135. 
17. ^ BBC Folic acid 'hinders malaria drug' 21 October 2006
18. ^ FSA (17 May 2007). Board recommends mandatory fortification. Retrieved on 2007-05-18.
19. ^ Backing for folic acid in bread. Retrieved on 2007-05-18.
20. ^ BBC Experts back folic acid in flour 11 May 2007
21. ^ Russell, Andrew. (2006.) "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.
22. ^ The Sydney Morning Herald Bread fortification 'not justified' 2006-07-29
23. ^ BBC 'Put folic acid in bread' 2000-01-13
24. ^ The Sydney Morning Herald Bread fortification 'not justified' 2006-07-29
25. ^ Malinow MR, Duell PB, Hess DL, Anderson PH, Kruger WD, Phillipson BE, Gluckman RA, Block PC, Upson BM (1998). "Reduction of plasma homocyst(e)ine levels by breakfast cereal fortified with folic acid in patients with coronary heart disease". New England Journal of Medicine 338 (15): 1009-15. PMID 9535664. 
26. ^ Daly S, Mills JL, Molloy AM, Conley M, Lee YJ, Kirke PN, Weir DG, Scott JM (1997). "Minimum effective dose of folic acid for food fortification to prevent neural-tube defects". Lancet 350 (9092): 1666-9. PMID 9400511. 
27. ^ Crandall BF, Corson VL, Evans MI, Goldberg JD, Knight G, Salafsky IS (1998). "American College of Medical Genetics statement on folic acid: fortification and supplementation". American Journal of Medical Genetics 78 (4): 381. PMID 9714444. 
28. ^ Centers for Disease Control and Prevention (CDC) (2004). "Spina bifida and anencephaly before and after folic acid mandate--United States, 1995-1996 and 1999-2000". Morbidity and Mortality Weekly Report 53 (17): 362-5. PMID 15129193. 
29. ^ Refsum H, Ueland PM, Nygard O, Vollset SE (1998). "Homocysteine and cardiovascular disease". Annual Review of Medicine 49 (1): 31-62. PMID 9509248. 
30. ^ Malinow MR (1995). "Plasma homocyst(e)ine and arterial occlusive diseases: A mini-review". Clinical Chemistry 41 (1): 173-6. PMID 7813076. 
31. ^ NORVIT Trial- High dose B vitamins do not lower stroke or MI risk
32. ^ Zoungas S, McGrath BP, Branley P, Kerr PG, Muske C, Wolfe R, Atkins RC, Nicholls K, Fraenkel M, Hutchison BG, Walker R, McNeil JJ (2006). "Cardiovascular morbidity and mortality in the Atherosclerosis and Folic Acid Supplementation Trial (ASFAST) in chronic renal failure: a multicenter, randomized, controlled trial". J Am Coll Cardiol 47 (6): 1108-16. PMID 16545638. 
33. ^ (2006) "Homocysteine Lowering with Folic Acid and B Vitamins in Vascular Disease". N Engl J Med. PMID 16531613 Full text PDF. 
34. ^ Bonaa KH, Njolstad I, Ueland PM, Schirmer H, Tverdal A, Steigen T, Wang H, Nordrehaug JE, Arnesen E, Rasmussen K (2006). "Homocysteine Lowering and Cardiovascular Events after Acute Myocardial Infarction". N Engl J Med. PMID 16531614 Full text PDF. 
35. ^ BBC Folic acid 'reduces stroke risks' 31 May 2007
36. ^ Freudenheim JL, Grahm S, Marshall JR, Haughey BP, Cholewinski S, Wilkinson G (1991). "Folate intake and carcinogenesis of the colon and rectum". International Journal of Epidemiology 20 (2): 368-374. PMID 1917236. 
37. ^ Jennings E. (1995). "Folic acid as a cancer preventing agent". Medical Hypotheses 45 (3): 297-303. PMID 8569555. 
38. ^ Giovannucci E, Stampfer MJ, Colditz GA, Hunter DJ, Fuchs C, Rosner BA, Speizer FE, Willett WC. (1998). "Multivitamin use, folate, and colon cancer in women in the Nurses' Health Study". Annals of Internal Medicine 129 (7): 517-524. PMID 9758570. 
39. ^ Christensen B. (1996). "Folate deficiency, cancer and congenital abnormalities Is there a connection?". Tidsskrift for den Norske Laegeforening 116 (2): 250-4. PMID 8633336. 
40. ^ Mayo Clinic news release 2001-06-26 "Folate Intake Counteracts Breast Cancer Risk Associated with Alcohol Consumption"
41. ^ Boston University "Folate, Alcohol, and Cancer Risk"
42. ^ "A prospective study of folate intake and the risk of breast cancer"
43. ^ Baglietto, Laura, et al. Does dietary folate intake modify effect of alcohol consumption on breast cancer risk? Prospective cohort study. British Medical Journal, August 8, 2005
44. ^ Rubio IT, Cao Y, Hutchins LF, Westbrook KC, Klimberg VS (1998). "Effect of glutamine on methotrexate efficacy and toxicity". Annals of Surgery 227 (5): 772-8. PMID 9605669. 
45. ^ Wolff JE, Hauch H, Kuhl J, Egeler RM, Jurgens H (1998). "Dexamethasone increases hepatotoxicity of MTX in children with brain tumors". Anticancer Research 18 (4B): 2895-9. PMID 9713483. 
46. ^ Kepka L, De Lassence A, Ribrag V, Gachot B, Blot F, Theodore C, Bonnay M, Korenbaum C, Nitenberg G (1998). "Successful rescue in a patient with high dose methotrexate-induced nephrotoxicity and acute renal failure". Leukemia & Lymphoma 29 (1-2): 205-9. PMID 9638991. 
47. ^ Branda RF, Nigels E, Lafayette AR, Hacker M. (1998). "Nutritional folate status influences the efficacy and toxicity of chemotherapy in rats". Blood 92 (7): 2471-6. PMID 9746787. 
48. ^ Shiroky JB (1997). "The use of folates concomitantly with low-dose pulse methotrexate". Rheumatic Diseases Clinics of North America 23 (4): 969-80. PMID 9361164. 
49. ^ Keshava C, Keshava N, Whong WZ, Nath J, Ong TM (1998). "Inhibition of methotrexate-induced chromosomal damage by folinic acid in V79 cells". Mutation Research 397 (2): 221-8. PMID 9541646. 
50. ^ Morgan SL, Baggott JE (1995). "Folate antagonists in nonneoplastic disease: proposed mechanisms of efficacy and toxicity". In Bailey LB, Folate in Health and Disease, 405-433. New York: Marcel Dekker. ISBN 0-8247-9280-7.
51. ^ Morgan SL, Baggott JE, Alarcon GS (1997). "Methotrexate in rheumatoid arthritis: folate supplementation should always be given.". BioDrugs 8 (1): 164-175.  Click here to request reprint from publisher
52. ^ Morgan SL, Baggott JE, Lee JY, Alarcon GS (1998). "Folic acid supplementation prevents deficient blood folate levels and hyperhomocysteinemia during longterm, low dose methotrexate therapy for rheumatoid arthritis: Implications for cardiovascular disease prevention". Journal of Rheumatology 25 (3): 441-6. PMID 9517760. 
53. ^ Coppen A, Bolander-Gouaille C. (2005). "Treatment of depression: time to consider folic acid and vitamin B12". Journal of Psychopharmacology 19 (1): 59-65. PMID 15671130. 
54. ^ Taylor MJ, Carney SM, Goodwin GM, Geddes JR. (2004). "Folate for depressive disorders: systematic review and meta-analysis of randomized controlled trials". Journal of Psychopharmacology 18 (2): 251-6. PMID 15260915. 
55. ^ "ScientistLive Website". American Journal of Epidemiology. 
56. ^ 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)
57. ^ 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
58. ^ Bing Wan, Li Hao, Yuhua Qiu, Zhongwen Sun, Qi Cao, Yi Zhang, Tongyu Zhu, Hao Wang, Yanyun Zhang (2006). "Blocking tumor necrosis factor-alpha inhibits folic acid-induced renal failure". Experimental and Molecular Pathology 81: 211-216. PMID 16595132. 


External links

Biochemistry links

IUPAC nomenclature is a system of naming chemical compounds and of describing the science of chemistry in general. It is developed and kept up to date under the auspices of the International Union of Pure and Applied Chemistry (IUPAC).
..... Click the link for more information.
CAS registry numbers are unique numerical identifiers for chemical compounds, polymers, biological sequences, mixtures and alloys. They are also referred to as CAS numbers, CAS RNs or CAS #s.
..... Click the link for more information.
smiles

File extension: .smi
Type of format: chemical file format

The simplified molecular input line entry specification or SMILES
..... Click the link for more information.
A chemical formula is a concise way of expressing information about the atoms that constitute a particular chemical compound. A chemical formula is also a short way of showing how a chemical reaction occurs.
..... Click the link for more information.
Molar mass, symbol M,[1] is the mass of one mole of a substance (chemical element or chemical compound).[2] It is a physical property which is characteristic of each pure substance.
..... Click the link for more information.
The melting point of a crystalline solid is the temperature range at which it changes state from solid to liquid. Although the phrase would suggest a specific temperature and is commonly and incorrectly used as such in most textbooks and literature, most crystalline compounds
..... Click the link for more information.
Chemical decomposition or analysis is the fragmentation of a chemical compound into elements or smaller compounds. It is sometimes defined as the opposite of a chemical synthesis. Chemical decomposition is often an undesired chemical reaction.
..... Click the link for more information.
Solubility is a physical property referring to the ability for a given substance, the solute, to dissolve in a solvent.[1] It is measured in terms of the maximum amount of solute dissolved in a solvent at equilibrium. The resulting solution is called a saturated solution.
..... Click the link for more information.
Water is a common chemical substance that is essential to all known forms of life.[1] In typical usage, water refers only to its liquid form or state, but the substance also has a solid state, ice, and a gaseous state, water vapor.
..... Click the link for more information.
An acid dissociation constant, denoted by Ka, is an equilibrium constant for the dissociation of a weak acid. According to the Brønsted-Lowry theory of acids and bases an acid is only recognised by its reaction with a base.
..... Click the link for more information.
Occupational safety and health (OSH) is a cross-disciplinary area concerned with protecting the safety, health and welfare of people engaged in work or employment. As a secondary effect, OSH may also protect co-workers, family members, employers, customers, suppliers, nearby
..... Click the link for more information.
standard state of a material is its state at 1 bar (100 kilopascals exactly). This pressure was changed from 1 atm (101.325 kilopascals) by IUPAC in 1990.[1] The standard state of a material can be defined at any given temperature, most commonly 25 degrees Celsius,
..... Click the link for more information.
The B vitamins are eight water-soluble vitamins that play important roles in cell metabolism. Historically, the B vitamins were once thought to be a single vitamin, referred to as Vitamin B (much like how people refer to Vitamin C or Vitamin D).
..... Click the link for more information.
Food is any substance, usually composed primarily of carbohydrates, fats, water and/or proteins, that can be eaten or drunk by an animal or human being for nutrition or pleasure.
..... Click the link for more information.
dietary supplement (also known as food supplement) is intended to supply nutrients, (vitamins, minerals, fatty acids or amino acids) that are missing or not consumed in sufficient quantity in a person's diet.
..... Click the link for more information.
Leaf vegetables, also called potherbs, greens, or leafy greens, are plant leaves eaten as a vegetable, sometimes accompanied by tender petioles and shoots.
..... Click the link for more information.
S. oleracea

Binomial name
Spinacia oleracea
L.

Spinach (Spinacia oleracea) is a flowering plant in the family of Amaranthaceae, native to central and southwestern Asia.
..... Click the link for more information.
B. r. rapa

Trinomial name
Brassica rapa rapa
L.

For similar vegetables also called "turnip", see Turnip (disambiguation).
The turnip (Brassica rapa var.
..... Click the link for more information.
Bean is a common name for large plant seeds of several genera of Fabaceae (formerly Leguminosae) used for food or feed. They are also known as legumes.

Name

The term Bean
..... Click the link for more information.
PEA can stand for:
  • Phenylethylamine
  • Pea plant
  • Phillips Exeter Academy
  • Pulseless electrical activity (a form of cardiac arrest)
  • Prenatal exposure to alcohol
  • Phenylethyl Alcohol Agar
  • Polyadic equality algebras (See also Cylindric algebras (CA))

..... Click the link for more information.
Cereal crops or grains are mostly grasses cultivated for their edible grains or seeds (i.e., botanically a type of fruit called a caryopsis). Cereal grains are grown in greater quantities and provide more energy worldwide than any other type of crop; they are therefore
..... Click the link for more information.
The sunflower seed is the fruit of the sunflower (Helianthus annuus). The term "sunflower seed" is actually a misnomer when applied to the seed in its pericarp (hull). Botanically speaking, it is more properly referred to as an achene.
..... Click the link for more information.
fruit has different meanings depending on context. In botany, a fruit is the ripened ovary—together with seeds—of a flowering plant. In many species, the fruit incorporates the ripened ovary and surrounding tissues.
..... Click the link for more information.
Vegetable is a term which generally refers to an edible part of a plant. The definition is traditional rather than scientific and is somewhat arbitrary and subjective. All parts of herbaceous plants eaten as food by humans, whole or in part, are normally considered vegetables.
..... Click the link for more information.
A breakfast cereal is a food product marketed to consumers as a breakfast food. Breakfast cereals may be eaten cold and mixed with milk or yoghurt and fruit, or boiled like oatmeal.
..... Click the link for more information.
The Dietary Reference Intake is a system of nutrition recommendations from the Institute of Medicine of the USA National Academy (IOM). The DRI system is used by both the United States and Canada. It is intended for the general public and health professionals.
..... Click the link for more information.
Dr.Lucy Wills 1888-1964

Lucy Wills' key observations 70 years ago in Bombay (Mumbai) led to the identification of folate as the nutrient needed to prevent anemia and other defects during pregnancy.

Dr.
..... Click the link for more information.
Anemia
Classification & external resources

ICD-10 D 50. -D 64.
ICD-9 280 - 285

DiseasesDB 663
MedlinePlus 000560
eMedicine med/132   emerg/808 emerg/734
MeSH D000740

Anemia (AmE) or anæmia/anaemia
..... Click the link for more information.
Ascomycota (sac fungi)
  • Saccharomycotina (true yeasts)
  • Taphrinomycotina
  • Schizosaccharomycetes (fission yeasts)
Basidiomycota (club fungi)
  • Urediniomycetes

..... Click the link for more information.
S. oleracea

Binomial name
Spinacia oleracea
L.

Spinach (Spinacia oleracea) is a flowering plant in the family of Amaranthaceae, native to central and southwestern Asia.
..... Click the link for more information.


This article is copied from an article on Wikipedia.org - the free encyclopedia created and edited by online user community. The text was not checked or edited by anyone on our staff. Although the vast majority of the wikipedia encyclopedia articles provide accurate and timely information please do not assume the accuracy of any particular article. This article is distributed under the terms of GNU Free Documentation License.