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| Folate, also known as vitamin B9 and folacin, is one of the B vitamins. Manufactured folic acid, which is converted into folate by the body, is used as a dietary supplement and in food fortification as it is more stable during processing and storage. Folate is required for the body to make DNA and RNA and metabolise amino acids necessary for cell division and maturation of blood cells. As the human body cannot make folate, it is required in the diet, making it an essential nutrient. It occurs naturally in many foods. The recommended adult daily intake of folate in the U.S. is 400 micrograms from foods or dietary supplements.
Folate in the form of folic acid is used to treat anemia caused by folate deficiency. Folic acid is also used as a supplement by women during pregnancy to reduce the risk of neural tube defects (NTDs) in the baby. NTDs include anencephaly and spina bifida, among other defects. Low levels in early pregnancy are believed to be the cause of more than half of babies born with NTDs. More than 80 countries use either mandatory or voluntary fortification of certain foods with folic acid as a measure to decrease the rate of NTDs. Long-term supplementation with relatively large amounts of folic acid is associated with a small reduction in the risk of stroke and an increased risk of prostate cancer. There are concerns that large amounts of supplemental folic acid can hide vitamin B12 deficiency.
Not consuming enough folate can lead to folate deficiency. This may result in a type of anemia in which red blood cells become abnormally large. Symptoms may include feeling tired, heart palpitations, shortness of breath, open sores on the tongue, and changes in the color of the skin or hair. Folate deficiency in children may develop within a month of poor dietary intake. In adults, normal total body folate is between 10 and 30 mg with about half of this amount stored in the liver and the remainder in blood and body tissues. In plasma, the natural folate range is 150 to 450 nM.
Folate was discovered between 1931 and 1943. It is on the World Health Organization's List of Essential Medicines. In 2022, it was the 65th most commonly prescribed medication in the United States, with more than 10 million prescriptions. The term "folic" is from the Latin word folium (which means leaf) because it was found in dark-green leafy vegetables.
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Read full article at Wikipedia
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InChI=1S/C19H19N7O6/c20- 19-25-15-14(17(30)26-19)23-11(8-22-15)7-21-10-3-1-9(2-4-10)16(29)24-12(18(31)32)5-6-13(27)28/h1-4,8,12,21H,5-7H2,(H,24,29)(H,27,28)(H,31,32)(H3,20,22,25,26,30)/t12-/m0/s1 |
| OVBPIULPVIDEAO-LBPRGKRZSA-N |
| Nc1nc2ncc(CNc3ccc(cc3)C(=O)N[C@@H](CCC(O)=O)C(O)=O)nc2c(=O)[nH]1 |
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Mus musculus
(NCBI:txid10090)
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Source: BioModels - MODEL1507180067
See:
PubMed
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Mus musculus
(NCBI:txid10090)
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From MetaboLights
See:
MetaboLights Study
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Arabidopsis thaliana
(NCBI:txid3702)
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Found in
cell suspension culture
(BTO:0000221).
From MetaboLights
See:
MetaboLights Study
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Brassica napus
(NCBI:txid3708)
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Found in
leaf lamina
(BTO:0000719).
From MetaboLights
See:
MetaboLights Study
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Brassica napus
(NCBI:txid3708)
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From MetaboLights
See:
MetaboLights Study
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Brassica napus
(NCBI:txid3708)
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From MetaboLights
See:
MetaboLights Study
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Micromonas pusilla
(NCBI:txid38833)
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From MetaboLights
See:
MetaboLights Study
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Trypanosoma brucei
(NCBI:txid5691)
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From MetaboLights
See:
MetaboLights Study
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Ruegeria pomeroyi
(NCBI:txid89184)
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Found in
endometabolome
From MetaboLights
See:
MetaboLights Study
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Homo sapiens
(NCBI:txid9606)
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See:
DOI
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Homo sapiens
(NCBI:txid9606)
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Found in
cytoplasm
(GO:0005737).
See:
Geigy Scientific Tables, 8th Rev edition, pp. 131. Edited by C. Lentner, West Cadwell, N.J.: Medical education Div., Ciba-Geigy Corp. Basel, Switzerland c1981-1992.
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Homo sapiens
(NCBI:txid9606)
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Found in
blood
(UBERON:0000178).
See:
PubMed
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Homo sapiens
(NCBI:txid9606)
|
Found in
urine
(BTO:0001419).
See:
Geigy Scientific Tables, 8th Rev edition, pp. 130. Edited by C. Lentner, West Cadwell, N.J.: Medical education Div., Ciba-Geigy Corp. Basel, Switzerland c1981-1992.
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Homo sapiens
(NCBI:txid9606)
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Found in
cerebrospinal fluid
(UBERON:0001359).
See:
PubMed
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Bronsted acid
A molecular entity capable of donating a hydron to an acceptor (Bronsted base).
(via oxoacid )
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human metabolite
Any mammalian metabolite produced during a metabolic reaction in humans (Homo sapiens).
mouse metabolite
Any mammalian metabolite produced during a metabolic reaction in a mouse (Mus musculus).
nutrient
A nutrient is a food component that an organism uses to survive and grow.
water-soluble vitamin (role)
Any vitamin that dissolves in water and readily absorbed into tissues for immediate use. Unlike the fat-soluble vitamins, they are not stored in the body and need to be replenished regularly in the diet and will rarely accumulate to toxic levels since they are quickly excreted from the body via urine.
(via B vitamin )
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nutraceutical
A product in capsule, tablet or liquid form that provide essential nutrients, such as a vitamin, an essential mineral, a protein, an herb, or similar nutritional substance.
(via B vitamin )
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View more via ChEBI Ontology
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N-(4-{[(2-amino-4-oxo-3,4-dihydropteridin-6-yl)methyl]amino}benzoyl)-L-glutamic acid
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acide folique
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WHO MedNet
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ácido fólico
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WHO MedNet
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acidum folicum
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WHO MedNet
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folic acid
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WHO MedNet
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(2S)-2-(4-{[(2-amino-4-oxo-3,4-dihydropteridin-6-yl)methyl]amino}benzamido)pentanedioic acid
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IUPAC
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Folate
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KEGG COMPOUND
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Folsäure
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ChEBI
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N-[(4-{[(2-amino-4-oxo-1,4-dihydropteridin-6-yl)methyl]amino}phenyl)carbonyl]-L-glutamic acid
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PDBeChem
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N-pteroyl-L-glutamic acid
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ChEBI
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PGA
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NIST Chemistry WebBook
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PteGlu
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NIST Chemistry WebBook
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pteroyl-L-glutamic acid
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ChemIDplus
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pteroyl-L-monoglutamic acid
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ChemIDplus
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pteroylglutamic acid
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KEGG COMPOUND
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pteroylmonoglutamic acid
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ChemIDplus
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vitamin B11
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ChemIDplus
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vitamin B9
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ChemIDplus
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vitamin Bc
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ChemIDplus
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vitamin Be
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ChemIDplus
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vitamin M
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ChemIDplus
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Acfol
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ChemIDplus
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Folicet
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KEGG DRUG
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1231
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DrugCentral
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5815
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ChemSpider
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C00001539
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KNApSAcK
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C00504
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KEGG COMPOUND
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CPD-12826
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MetaCyc
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D00070
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KEGG DRUG
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DB00158
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DrugBank
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FDB014504
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FooDB
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FOL
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PDBeChem
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Folic_Acid
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Wikipedia
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HMDB0000121
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HMDB
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LSM-5355
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LINCS
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| View more database links |
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100781
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Reaxys Registry Number
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Reaxys
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59-30-3
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CAS Registry Number
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NIST Chemistry WebBook
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59-30-3
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CAS Registry Number
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ChemIDplus
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Goossens JF, Thuru X, Bailly C (2021)
Properties and reactivity of the folic acid and folate photoproduct 6-formylpterin.
Free radical biology & medicine 171, 1-10 [PubMed:33965562]
[show Abstract]
Folates (vitamin B9) are essential components of our diet and our gut microbiota. They are omnipresent in our cells and blood. Folates are necessary for DNA synthesis, methylation, and other vital bioprocesses. Folic acid (FA), as the synthetic form of folates, is largely found in supplements and fortified foods. FA and folate drugs are also extensively used as therapeutics. Therefore, we are continuously exposed to the pterin derivatives, and their photo-degradation products, such as 6-formylpterin (6-FPT) and pterin-6-carboxylic acid. During ultraviolet radiation, these two photolytic products generate reactive oxygen species (ROS) responsible for the cellular oxidative stress. 6-FPT can exhibit variable pro/anti-oxidative roles depending on the cell type and its environment (acting as a cell protector in normal cells, or as an enhancer of drug-induced cell death in cancer cells). The ROS-modulating capacity of 6-FPT is well-known, whereas its intrinsic reactivity has been much less investigated. Here, we have reviewed the properties of 6-FPT and highlighted its capacity to form covalent adducts with the ROS-scavenging drug edaravone (used to treat stroke and amyotrophic lateral sclerosis) as well as its implication in immune surveillance. 6-FPT and its analogue acetyl-6-FPT function as small molecule antigens, recognized by the major histocompatibility complex-related class I-like molecule, MR1, for presentation to mucosal-associated invariant T (MAIT) cells. As modulators of the MR1/MAIT machinery, 6-FPT derivatives could play a significant immuno-regulatory role in different diseases. This brief review shed light on the multiple properties and cellular activities of 6-FPT, well beyond its primary ROS-generating activity. | Williams BA, Mayer C, McCartney H, Devlin AM, Lamers Y, Vercauteren SM, Wu JK, Karakochuk CD (2021)
Detectable Unmetabolized Folic Acid and Elevated Folate Concentrations in Folic Acid-Supplemented Canadian Children With Sickle Cell Disease.
Frontiers in nutrition 8, 642306 [PubMed:33968971]
[show Abstract]
Sickle cell disease (SCD) is an inherited hemoglobinopathy caused by a variant (rs344) in the HBB gene encoding the β-globin subunit of hemoglobin. Chronic hemolytic anemia and increased erythropoiesis and RBC turnover in individuals with SCD can result in increased needs for folate and other B-vitamins. We assessed B-vitamin status, and the distribution of folate forms, including unmetabolized folic acid (UMFA), in Canadian children with SCD supplemented with 1 mg/d folic acid (current routine practice). Non-fasted serum and plasma samples were analyzed for concentrations of folate, and vitamins B-2, B-6, and B-12. Eleven individuals (45% male; SCD type: HbSS n = 8, HbSC n = 2, HbSβ0-Thal n = 1), with a median (IQR) age of 14 (7, 18) years, were included. Total folate concentrations were 3-27 times above the deficiency cut-off (10 nmol/L), and 64% of children had elevated folate levels (>45.3 nmol/L). UMFA (>0.23 nmol/L) was detected in all children, and 36% of participants had elevated levels of UMFA (>5.4 nmol/L). All children were vitamin B-12 sufficient (>150 pmol/L), and the majority (55%) had sufficient B-6 status (>30 nmol/L). Among this sample of Canadian children with SCD, there was limited evidence of B-vitamin deficiencies, but UMFA was detectable in all children. | Winiarski JP, Rampanelli R, Bassani JC, Mezalira DZ, Jost CL (2021)
Multi-walled carbon nanotubes/nickel hydroxide composite applied as electrochemical sensor for folic acid (vitamin B9) in food samples
Journal of Food Composition and Analysis. 92, Not Available [Agricola:IND606960789]
[show Abstract]
Folic acid (FA) acts as an essential nutrient for body functions. Several countries have already proposed a resolution for flour fortification with iron and FA; thus, of food industry concern. Therefore, a new electroanalytical method based on a composite material of functionalized MWCNTs with nickel hydroxide (f-MWCNT-Ni(OH)₂) is hereby proposed. This composite material was characterized by FT-IR, TGA, SEM and TEM techniques. An inorganic ionic silsesquioxane polymer (Si4Pic⁺Cl⁻) was used to disperse the composite and applied on the modification of a glassy carbon electrode (GCE). Linear response from 0.5–26 μmol L⁻¹ was obtained based on FA electrochemical oxidation through differential pulse voltammetry. The LoD and LoQ values obtained were 0.095 μmol L⁻¹ and 0.3 μmol L⁻¹ of FA, respectively. The GCE/f-MWCNT-Ni(OH)₂-Si4Pic⁺Cl⁻ was applied for the quantification of FA in wheat flour, fortifier, and dietary supplement. Validation was performed through a comparison with molecular absorption spectrometry, showing the accuracy of the newly proposed method. | Modupe O, Diosady LL (2021)
Quadruple fortification of salt for the delivery of iron, iodine, folic acid, and vitamin B12 to vulnerable populations.
Journal of food engineering 300, 110525 [PubMed:34219855]
[show Abstract]
A process for simultaneous delivery of iron, iodine, folic acid, and vitamin B12 through salt as a potential and holistic approach to ameliorate anaemia and reduce maternal and infant mortality is presented. Two approaches for adding folic acid and B12 to salt during double fortification with iron and iodine were investigated. Attempts to add both micronutrients through the iodine spray solution were unsuccessful. Hence, folic acid was added through a stabilized iodine solution, and B12 was added through the iron premix. Four approaches used to incorporate B12 into the iron premix were investigated: (1) co-extruding B12 with iron, (2) spraying B12 on the surface of the iron extrudate, (3) adding B12 to the colour masking agent, and (4) adding B12 to the outer coating. Of these approaches, coextrusion (1) was the best, based on the ease of production and stability of fortificants. The salt formulated with the solid iron-B12 premix and sprayed iodine and folic acid solution contained 1000 ppm iron, 50 ppm iodine, 25 ppm folic acid, and 0.25 ppm B12. Over 98% of B12, 93% folic acid, and 94% iodine were retained after 6-month storage in the best formulation. This technology can simultaneously deliver iron, iodine, folic acid, and vitamin B12 in a safe and stable salt enabling public health measures for improved health at a minimal additional cost. | Shulpekova Y, Nechaev V, Kardasheva S, Sedova A, Kurbatova A, Bueverova E, Kopylov A, Malsagova K, Dlamini JC, Ivashkin V (2021)
The Concept of Folic Acid in Health and Disease.
Molecules (Basel, Switzerland) 26, 3731 [PubMed:34207319]
[show Abstract]
Folates have a pterine core structure and high metabolic activity due to their ability to accept electrons and react with O-, S-, N-, C-bounds. Folates play a role as cofactors in essential one-carbon pathways donating methyl-groups to choline phospholipids, creatine, epinephrine, DNA. Compounds similar to folates are ubiquitous and have been found in different animals, plants, and microorganisms. Folates enter the body from the diet and are also synthesized by intestinal bacteria with consequent adsorption from the colon. Three types of folate and antifolate cellular transporters have been found, differing in tissue localization, substrate affinity, type of transferring, and optimal pH for function. Laboratory criteria of folate deficiency are accepted by WHO. Severe folate deficiencies, manifesting in early life, are seen in hereditary folate malabsorption and cerebral folate deficiency. Acquired folate deficiency is quite common and is associated with poor diet and malabsorption, alcohol consumption, obesity, and kidney failure. Given the observational data that folates have a protective effect against neural tube defects, ischemic events, and cancer, food folic acid fortification was introduced in many countries. However, high physiological folate concentrations and folate overload may increase the risk of impaired brain development in embryogenesis and possess a growth advantage for precancerous altered cells. | Bottari E, D'Ambrosio A, De Tommaso G, Festa MR, Iuliano M, Meschino M (2021)
Solubility of folic acid and protonation of folate in NaCl at different concentrations, even in physiological solution.
The Analyst 146, 2339-2347 [PubMed:33624660]
[show Abstract]
The solubility of folic acid was determined at 25 °C in 1.00 mol dm-3 and in 0.15 mol dm-3 NaCl (physiological solution) spectrophotometrically by measuring the absorbance of saturated solution at different hydrogen ion concentrations. Five protonation constants of folate were determined both from the dependence of the solubility on the hydrogen ion concentration as well as from potentiometric titrations carried out in the presence of solid folic acid and in alkaline solution, in which folate is relatively soluble. Corresponding to the protonation constants, nuclear magnetic resonance and florescence spectra were also obtained at different hydrogen ion concentrations to determine the protonation positions in acid, neutral and alkaline solutions. An approach through circular dichroism was also applied to study the eventual polymerization of folate in alkaline solution. | Kocic G, Bjelakovic L, Bjelakovic B, Jevtoci-Stoimenov T, Sokolovic D, Cvetkovic T, Kocic H, Stojanovic S, Langerholc T, Jonovic M (2014)
Impact of folic acid supplementation on single- and double-stranded RNA degradation in human colostrum and mature milk.
Journal of medicinal food 17, 804-809 [PubMed:24650098]
[show Abstract]
Sufficient intake of folic acid is necessary for normal embryogenesis, fetal, and neonatal development. Folic acid facilitates nucleic acid internalization, and protects cellular DNA from nuclease degradation. Human milk contains enzymes, antimicrobial proteins, and antibodies, along with macrophages, that protect against infections and allergies. However, little to no information is available on the effects of folic acid supplementation on degradation of nucleic acids in human milk. In the present study, we aimed to determine the RNase activity (free and inhibitor-bound) in colostrum and mature milk, following folic acid supplementation. The study design included a total of 59 women, 27 of whom received 400 μg of folic acid daily periconceptionally and after. Folic acid supplementation increased the free RNase and polyadenylase activity following lactation. However, the increased RNase activity was not due to de novo enzyme synthesis, as the inhibitor-bound (latent) RNase activity was significantly lower and disappeared after one month. Folic acid reduced RNase activity by using double-stranded RNA as substrate. Data suggests that folic acid supplementation may improve viral RNAs degradation and mRNA degradation, but not dsRNA degradation, preserving in this way the antiviral defense. | Wu X, Liang Z, Zou T, Wang X (2009)
Effects of folic acid deficiency and MTHFRC677T polymorphisms on cytotoxicity in human peripheral blood lymphocytes.
Biochemical and biophysical research communications 379, 732-737 [PubMed:19121630]
[show Abstract]
Apoptosis (APO) and necrosis (NEC) are two different types of cell death occurring in response to cellular stress factors. Cells with DNA damage may undergo APO or NEC. Folate is an essential micronutrient associated with DNA synthesis, repair and methylation. Methylenetetrahydrofolate reductase (MTHFR) regulates intracellular folate metabolism. Folate deficiency and MTHFR C677T polymorphisms have been shown to be related to DNA damage. To verify the cytotoxic effects of folate deficiency on cells with different MTHFR C677T genotypes, 15 human peripheral lymphocyte cases with different MTHFR C677T genotypes were cultured in folic acid (FA)-deficient and -sufficient media for 9 days. Cytotoxicity was quantified using the frequencies of APO and NEC as endpoints, the nuclear division index (NDI), and the number of viable cells (NVC). These results showed that FA is an important factor in reducing cytotoxicity and increasing cell proliferation. Lymphocytes with the TT genotype proliferated easily under stress and exhibited different responses to FA deficiency than lymphocytes with the CC and CT genotypes. A TT individual may accumulate more cytotoxicity under cytotoxic stress, suggesting that the effects of FA deficiency on cytotoxicity are greater than the effects in individuals with the other MTHFR C677T variants. | Kronenberg G, Colla M, Endres M (2009)
Folic acid, neurodegenerative and neuropsychiatric disease.
Current molecular medicine 9, 315-323 [PubMed:19355913]
[show Abstract]
Folic acid plays an important role in neuroplasticity and in the maintenance of neuronal integrity. Folate is a co-factor in one-carbon metabolism during which it promotes the regeneration of methionine from homocysteine, a highly reactive sulfur-containing amino acid. Methionine may then be converted to S-adenosylmethionine (SAM), the principal methyl donor in most biosynthetic methylation reactions. On the cellular level, folate deficiency and hyperhomocysteinemia exert multiple detrimental effects. These include induction of DNA damage, uracil misincorporation into DNA and altered patterns of DNA methylation. Low folate status and elevated homocysteine increase the generation of reactive oxygen species and contribute to excitotoxicity and mitochondrial dysfunction which may lead to apoptosis. Strong epidemiological and experimental evidence links derangements of one-carbon metabolism to vascular, neurodegenerative and neuropsychiatric disease, including most prominently cerebral ischemia, Alzheimer's dementia and depression. Although firm evidence from controlled clinical trials is largely lacking, B-vitamin supplementation and homocysteine reduction may have a role especially in the primary prevention of stroke and dementia as well as as an adjunct to antidepressant pharmacotherapy. | Dary O (2009)
Nutritional interpretation of folic acid interventions.
Nutrition reviews 67, 235-244 [PubMed:19335717]
[show Abstract]
Folate is an essential micronutrient, and its nutritional inadequacy is widespread; hence, programs to increase its intake are necessary. However, many concerns about possible adverse effects due to excesses have been raised. Serum folate levels are directly correlated with intake and, when low, are associated with neural tube defects (NTD), high blood homocysteine levels, and megaloblastic anemia. Serum folate cutoff points have been identified for each abnormality, and all can be associated with intakes related to the current recommended dietary parameters. Likewise, high intakes that overwhelm the physiological capacity to process folic acid into biologically active folate derivatives are near the recommended tolerable upper intake level. Although we do not know with certainty the minimum efficacious dose that prevents all folate-dependent NTD, it may actually be much lower than the current recommendation, especially when provided through food fortification; supplemental intakes around 100 microg/day appear to be appropriate. | Ahlin G, Karlsson J, Pedersen JM, Gustavsson L, Larsson R, Matsson P, Norinder U, Bergström CA, Artursson P (2008)
Structural requirements for drug inhibition of the liver specific human organic cation transport protein 1.
Journal of medicinal chemistry 51, 5932-5942 (Source: ChEMBL) [PubMed:18788725]
[show Abstract]
The liver-specific organic cation transport protein (OCT1; SLC22A1) transports several cationic drugs including the antidiabetic drug metformin and the anticancer agents oxaliplatin and imatinib. In this study, we explored the chemical space of registered oral drugs with the aim of studying the inhibition pattern of OCT1 and of developing predictive computational models of OCT1 inhibition. In total, 191 structurally diverse compounds were examined in HEK293-OCT1 cells. The assay identified 47 novel inhibitors and confirmed 15 previously known inhibitors. The enrichment of OCT1 inhibitors was seen in several drug classes including antidepressants. High lipophilicity and a positive net charge were found to be the key physicochemical properties for OCT1 inhibition, whereas a high molecular dipole moment and many hydrogen bonds were negatively correlated to OCT1 inhibition. The data were used to generate OPLS-DA models for OCT1 inhibitors; the final model correctly predicted 82% of the inhibitors and 88% of the noninhibitors of the test set. | Lu Y, You F, Vlahov I, Westrick E, Fan M, Low PS, Leamon CP (2007)
Folate-targeted dinitrophenyl hapten immunotherapy: effect of linker chemistry on antitumor activity and allergic potential.
Molecular pharmaceutics 4, 695-706 [PubMed:17784727]
[show Abstract]
Targeting of malignancies with folate-linked therapeutics has proven to be a promising endeavor due to the preferential expression of folate receptors (FR) on human tumors. We have shown that folic acid (pteroyl-glutamate) can be used to deliver an antigenic hapten, fluorescein, to the surface of tumor cells to promote their opsonization within a fluorescein-immunized host. Here, we investigate structure-activity relationships among members of another class of folate-hapten conjugates ( EC57, EC63, EC0293, and EC0294), namely, those containing the dinitrophenyl (DNP) group as the antigenic hapten. We report that despite exhibiting similar affinities for the FR, the antitumor activity and allergic potential of these DNP conjugates varied depending on their linker chemistries and abilities to bind anti-DNP IgG/IgE antibodies. Unlike EC57 and EC63, both EC0293 and EC0294 (i) share the identical DNP bridging chemistry to that found in keyhole limpet hemocyanin (KLH)-DNP (i.e., the immunogen), (ii) efficiently recognize DNP-specific IgG, and (iii) mediate more pronounced antitumor responses. However, EC0293 and EC0294 were also found to recognize DNP-specific IgE, and they displayed a greater risk of allergy when evaluated in a passive cutaneous anaphylaxis assay. Nonetheless, upon co-stimulation with the appropriate cytokines (IL-2/IFN-alpha), the folate-targeted "haptenization" process allowed for tumor rejection and protective antitumor immunity without causing any visible allergy in immunized mice. Our data further support the concept that folate-hapten-targeted immunotherapy may offer an effective therapeutic option for treatment of FR-positive cancers, but such treatment should proceed with caution given the risk of a potential allergic reaction. | Asadi-Pooya AA, Ghetmiri E (2006)
Folic acid supplementation reduces the development of some blood cell abnormalities in children receiving carbamazepine.
Epilepsy & behavior : E&B 8, 228-231 [PubMed:16380297]
[show Abstract]
BackgroundCarbamazepine is a commonly used anticonvulsant agent; however, it has been linked with various blood cell abnormalities. This study evaluated the effect of low-dose folic acid supplementation on the prevention of carbamazepine-induced hematological derangements in children.MethodsThis randomized clinical trial was conducted in children with epilepsy who received carbamazepine monotherapy. Group 1 received carbamazepine alone, and group 2 received carbamazepine plus folic acid. The two groups were age- and sex-matched. Each group comprised 41 children with epilepsy. Complete blood counts were obtained before starting medication (baseline) and then serially. The patients were followed for at least 1 year.ResultsIn group 1, 31.4% of the patients developed leukopenia and 17.1% neutropenia, but in group 2, these figures were 14.6 and 9.8% (P = 0.067 and P = 0.331, respectively). At the end of the first year of follow up, white blood cell and polymorphonuclear cell counts were significantly higher in group 2 (P = 0.007 and P = 0.001, respectively). Hemoglobin concentration dropped in group 1, but rose slightly in group 2; these changes were significant. Platelet, lymphocyte, and monocyte counts and changes in serial blood tests did not differ significantly between the two groups.ConclusionsFolic acid is a safe drug that can reduce the development of some blood cell abnormalities linked to carbamazepine. It has a favorable effect on preventing the leukopenia and drop in hemoglobin observed in patients receiving carbamazepine, but its exact effect and the optimal dose required to enhance its benefits require further investigation. | Olthof MR, Bots ML, Katan MB, Verhoef P (2006)
Effect of folic acid and betaine supplementation on flow-mediated dilation: a randomized, controlled study in healthy volunteers.
PLoS clinical trials 1, e10 [PubMed:16871332]
[show Abstract]
ObjectivesWe investigated whether lowering of fasting homocysteine concentrations, either with folic acid or with betaine supplementation, differentially affects vascular function, a surrogate marker for risk of cardiovascular disease, in healthy volunteers. As yet, it remains uncertain whether a high concentration of homocysteine itself or whether a low folate status--its main determinant--is involved in the pathogenesis of cardiovascular disease. To shed light on this issue, we performed this study.DesignThis was a randomized, placebo-controlled, double-blind, crossover study.SettingThe study was performed at Wageningen University in Wageningen, the Netherlands.ParticipantsParticipants were 39 apparently healthy men and women, aged 50-70 y.InterventionsParticipants ingested 0.8 mg/d of folic acid, 6 g/d of betaine, and placebo for 6 wk each, with 6-wk washout in between.Outcome measuresAt the end of each supplementation period, plasma homocysteine concentrations and flow-mediated dilation (FMD) of the brachial artery were measured in duplicate.ResultsFolic acid supplementation lowered fasting homocysteine by 20% (-2.0 micromol/l, 95% confidence interval [CI]: -2.3; -1.6), and betaine supplementation lowered fasting plasma homocysteine by 12% (-1.2 micromol/l; -1.6; -0.8) relative to placebo. Mean (+/- SD) FMD after placebo supplementation was 2.8 (+/- 1.8) FMD%. Supplementation with betaine or folic acid did not affect FMD relative to placebo; differences relative to placebo were -0.4 FMD% (95%CI, -1.2; 0.4) and -0.1 FMD% (-0.9; 0.7), respectively.ConclusionsFolic acid and betaine supplementation both did not improve vascular function in healthy volunteers, despite evident homocysteine lowering. This is in agreement with other studies in healthy participants, the majority of which also fail to find improved vascular function upon folic acid treatment. However, homocysteine or folate might of course affect cardiovascular disease risk through other mechanisms. | Chiang EP, Smith DE, Selhub J, Dallal G, Wang YC, Roubenoff R (2005)
Inflammation causes tissue-specific depletion of vitamin B6.
Arthritis research & therapy 7, R1254-62 [PubMed:16277678]
[show Abstract]
Previously we observed strong and consistent associations between vitamin B6 status and several indicators of inflammation in patients with rheumatoid arthritis. Clinical indicators, including the disability score, the length of morning stiffness, and the degree of pain, and biochemical markers, including the erythrocyte sedimentation rate and C-reactive protein levels, were found to be inversely correlated with circulating vitamin B6 levels. Such strong associations imply that impaired vitamin B6 status in these patients results from inflammation. In the present study we examined whether inflammation directly alters vitamin B6 tissue contents and its excretion in vivo. A cross-sectional case-controlled human clinical trial was performed in parallel with experiments in an animal model of inflammation. Plasma and erythrocyte and pyridoxal 5'-phosphate concentrations, urinary 4-pyridoxic acid excretion, and the activity coefficient of erythrocyte aspartate aminotransferase were compared between patients and healthy subjects. Adjuvant arthritis was induced in rats for investigating hepatic and muscle contents as well as the urinary excretion of vitamin B6 during acute and chronic inflammation. Patients with rheumatoid arthritis had low plasma pyridoxal 5'-phosphate compared with healthy control subjects, but normal erythrocyte pyridoxal 5'-phosphate and urinary 4-pyridoxic acid excretion. Adjuvant arthritis in rats did not affect 4-pyridoxic acid excretion or muscle storage of pyridoxal 5'-phosphate, but it resulted in significantly lower pyridoxal 5'-phosphate levels in circulation and in liver during inflammation. Inflammation induced a tissue-specific depletion of vitamin B6. The low plasma pyridoxal 5'-phosphate levels seen in inflammation are unlikely to be due to insufficient intake or excessive vitamin B6 excretion. Possible causes of decreased levels of vitamin B6 are discussed. | Pufulete M, Al-Ghnaniem R, Khushal A, Appleby P, Harris N, Gout S, Emery PW, Sanders TA (2005)
Effect of folic acid supplementation on genomic DNA methylation in patients with colorectal adenoma.
Gut 54, 648-653 [PubMed:15831910]
[show Abstract]
Background and aimsA low dietary folate intake can cause genomic DNA hypomethylation and may increase the risk of colorectal neoplasia. The hypothesis that folic acid supplementation increases DNA methylation in leucocytes and colorectal mucosa was tested in 31 patients with histologically confirmed colorectal adenoma using a randomised, double blind, placebo controlled, parallel design.MethodsSubjects were randomised to receive either 400 microg/day folic acid supplement (n = 15) or placebo (n = 16) for 10 weeks. Genomic DNA methylation, serum and erythrocyte folate, and plasma homocysteine concentrations were measured at baseline and post intervention.ResultsFolic acid supplementation increased serum and erythrocyte folate concentrations by 81% (95% confidence interval (CI) 57-104%; p<0.001 v placebo) and 57% (95% CI 40-74%; p<0.001 v placebo), respectively, and decreased plasma homocysteine concentration by 12% (95% CI 4-20%; p = 0.01 v placebo). Folic acid supplementation resulted in increases in DNA methylation of 31% (95% CI 16-47%; p = 0.05 v placebo) in leucocytes and 25% (95% CI 11-39%; p = 0.09 v placebo) in colonic mucosa.ConclusionsThese results suggest that DNA hypomethylation can be reversed by physiological intakes of folic acid. | Rodríguez Flores J, Peñalvo GC, Mansilla AE, Gómez MJ (2005)
Capillary electrophoretic determination of methotrexate, leucovorin and folic acid in human urine.
Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 819, 141-147 [PubMed:15797531]
[show Abstract]
A simple, rapid and sensitive procedure using capillary zone electrophoresis (CZE) to measure methotrexate, folinic acid and folic acid in human urine has been developed and validated. Optimum separation of methotrexate, folinic acid and folic acid was obtained on a 60 cm x 75 microm capillary using a 15 mM phosphate buffer solution (pH 12.0), temperature and voltage 20 degrees C and 25 kV, respectively and hydrodynamic injection. Under these conditions the analysis takes approximately 9.0 min. Good results were obtained for different aspects including stability of the solutions, linearity, accuracy and precision. Before CZE determination, the urine samples were purified and enriched by means of a solid phase extraction step with a preconditioned C(18) cartridge and eluting the compound with a mixture 1:1 of methanol:water. A linear response over the urine concentration range 1.0-6.0 mgL(-1) for MTX and 0.5-6.0 mgL(-1) for folinic acid and folic acid was observed. Detection limits for the three compound in urine were 0.35 mgL(-1). CZE was shown to be a good method with regard to simplicity, satisfactory precision, and sensitivity. | Dietrich M, Brown CJ, Block G (2005)
The effect of folate fortification of cereal-grain products on blood folate status, dietary folate intake, and dietary folate sources among adult non-supplement users in the United States.
Journal of the American College of Nutrition 24, 266-274 [PubMed:16093404]
[show Abstract]
ObjectiveSince January 1998, the Federal Drug Administration has required folic acid fortification of all enriched cereal-grain products in the U.S. This program intended to increase folic acid intake among women of childbearing age in order to decrease their risk of pregnancies affected by neural tube defects. The aim of this study was to explore the changes in serum and erythrocyte folate status of the adult U.S. population following folic acid fortification of enriched cereal-grain products and to explore accompanying changes in food sources and dietary total folate intake.MethodsWe compared data from two National Health and Nutrition Examination Surveys (NHANES): NHANES III, conducted during 1988 to 1994, reflecting the time prior to folate fortification, and NHANES 1999-2000, reflecting the time period after fortification.ResultsMandatory folic acid fortification led to significant increases in both serum and erythrocyte folate concentrations in all sex and age groups. In the overall study population the mean serum folate concentration increased more than two-fold (136%), from 11.4 nmol/L to 26.9 nmol/L, and the mean erythrocyte folate concentration increased by 57 percent, from 375 nmol/L to 590 nmol/L. Less than 10% of women of childbearing age reached the recommended erythrocyte folate concentration of greater than 906 nmol/L that has been shown to be associated with a significant reduction in neural tube defect (NTD) risk. After fortification, the category "bread, rolls, and crackers" became the single largest contributor of total folate to the American diet, contributing 15.6% of total intake, surpassing vegetables, which were the number one folate food source prior to fortification. Dietary intake of total folate increased significantly in almost all sex and age groups, except in females over 60 years of age. The mean dietary total folate intake of the study population increased by 76 microg/d (28%), from 275 microg/d to 351 microg/d.ConclusionsThe fortification of enriched cereal-grain products with folic acid led to a significant improvement of blood folate status of the overall adult, non-supplement using, US population. However, women of childbearing age may take folic acid supplements to reach erythrocyte folate levels that have been associated with decreased risk of NTDs. | Stuerenburg HJ, Ganzer S, Arlt S, Müller-Thomsen T (2005)
The influence of smoking on plasma folate and lipoproteins in Alzheimer disease, mild cognitive impairment and depression.
Neuro endocrinology letters 26, 261-263 [PubMed:15990733]
[show Abstract]
The risk for Alzheimer's disease (AD) is associated with lifestyle factors, especially cigarette smoking. In this study we investigated the influence of smoking on the serum levels of folic acid, LDL and HDL in AD patients, patients with minimal cognitive impairment (MCI) and patients with major depression. We investigated a total of n = 374 patients in the diagnostic categories:, AD: n = 272, MCI: n = 60, Major depression: n = 42. We found significantly lower HDL levels in smokers and previous smokers in comparison to non-smokers, p<0,05. The LDL: HDL ratio in smokers was significant higher (+20%) compared to previous smokers and non-smokers, p < 0.05. The mean levels of folic acid were statistically significant (p<0.05) lower (-24%) in smokers compared to non-smokers. Patients with MCI and Alzheimer;s disease (and also major depression) who are "smokers" show serum levels of HDL and folic acid that are known to be strong risk factors for vascular damage and increased risk for vascular brain damage and impaired cognitive function. Therefore cessation of smoking, substitution with folate or statin therapy of smoking patients with MCI or AD might be beneficial to slow down further cognitive decline. | Baydar T, Nagymajtényi L, Isimer A, Sahin G (2005)
Effect of folic acid supplementation on aluminum accumulation in rats.
Nutrition (Burbank, Los Angeles County, Calif.) 21, 406-410 [PubMed:15797685]
[show Abstract]
ObjectiveExposure to many xenobiotics may cause depletion of folic acid (folate), which is an essential vitamin for humans. Replacement of folate can be effective in protection against some diseases and in partial or total prevention of adverse effects related to xenobiotics. Aluminum (Al) is the most widely distributed metal in the outer crust of the earth. Its toxicity in humans is well known. However, there is no evidence that folate can decrease accumulation of Al to which humans can be exposed in many ways. The aim of the present study was to quantify organ Al accumulation and to evaluate whether there is any protective (or reductive) effect of folic acid on Al accumulation.MethodsMale Wistar rats were assigned oral Al chloride (200 mg x kg(-1) x d(-1), n = 10, group 1) alone or in combination with folic acid (20 mg x kg(-1) x d(-1), n = 10, group 2) for 8 wk. At the end of the period, bone, kidney, brain, and blood samples were collected, and Al concentrations were determined by electrothermal atomic absorption spectrophotometry.ResultsMean values of Al in the tissue samples from group 1 were higher than those from group 2 (all P < 0.05). No difference was observed in serum Al levels between groups (P > 0.05).ConclusionThese results suggest that folate supplementation might be useful to decrease Al accumulation in its main target organs, i.e., bone, kidney, and brain. | Griffiths B (2005)
Folic acid: a vital nutrient throughout life.
Professional nurse (London, England) 20, 52 [PubMed:15754725] | Kopczyńska E, Ziółkowski M, Jendryczka-Maćkiewicz E, Odrowaz-Sypniewska G, Opozda K, Tyrakowski T (2004)
[The concentrations of homocysteine, folic acid and vitamin B12 in alcohol dependent male patients].
Psychiatria polska 38, 947-956 [PubMed:15523939]
[show Abstract]
UnlabelledMetabolism of homocysteine (sulphur-containing amino acid) is accomplished in the remethylation cycle where vitamin B12 and folic acid are essential coenzymes. Markedly elevated homocysteine concentrations have been observed in patients with nutritional deficiencies of vitamin B12 and folate. Hyperhomocysteinemia in alcohol abusers may result from malnutrition and disorder of intestine absorption.AimThe aim of the study was the estimation of homocysteine, folic acid and vitamin B12 concentrations in alcohol dependent male patients.Method71 males with a clinical diagnosis of alcohol dependence (ICD-10) have been examined. The investigated parameters have been determined in the blood serum, the homocysteine by means of immunochemical method, vitamin B12 and folic acid by means of immunoenzymatic assay.ResultsSerum homocysteine concentration was significantly higher and serum folic acid concentration was lower in alcohol dependent men than in controls. Mean concentrations of folic acid and vitamin B12 were significantly lower in patients with hyperhomocysteinemia than in men with normal homocysteine concentration. The highest correlation was indeed noticed between folate deficiency and the intensity of hyperhomocysteinemia.ConclusionsThe development of hyperhomocysteinemia is associated with alcohol dependence that is also a probable cause of folate and vitamin B12 deficiency. | Lin Y, Dueker SR, Follett JR, Fadel JG, Arjomand A, Schneider PD, Miller JW, Green R, Buchholz BA, Vogel JS, Phair RD, Clifford AJ (2004)
Quantitation of in vivo human folate metabolism.
The American journal of clinical nutrition 80, 680-691 [PubMed:15321809]
[show Abstract]
BackgroundA quantitative understanding of human folate metabolism is needed.ObjectiveThe objective was to quantify and interpret human folate metabolism as it might occur in vivo.DesignAdults (n = 13) received 0.5 nmol [(14)C]pteroylmonoglutamate (100 nCi radioactivity) plus 79.5 nmol pteroylmonoglutamate in water orally. (14)C was measured in plasma, erythrocytes, urine, and feces for >/=40 d. Kinetic modeling was used to analyze and interpret the data.ResultsAccording to the data, the population was healthy and had a mean dietary folate intake of 1046 nmol/d, and the apparent dose absorption of (14)C was 79%. The model predictions showed that only 0.25% of plasma folate was destined for marrow, mean bile folate flux was 5351 nmol/d, and the digestibility of the mix (1046 + 5351 nmol/d) was 92%. About 33% of visceral pteroylmonoglutamate was converted to the polyglutamate form, most of the body folate was visceral (>99%), most of the visceral folate was pteroylpolyglutamate (>98%), total body folate was 225 micromol, and pteroylpolyglutamate synthesis, recycling, and catabolism were 1985, 1429, and 556 nmol/d, respectively. Mean residence times were 0.525 d as visceral pteroylmonoglutamate, 119 d as visceral pteroylpolyglutamate, 0.0086 d as plasma folate, and 0.1 d as gastrointestinal folate.ConclusionsAcross subjects, folate absorption, bile folate flux, and body folate stores were larger than prior estimates. Marrow folate uptake and pteroylpolyglutamate synthesis, recycling, and catabolism are saturable processes. Visceral pteroylpolyglutamate was an immediate precursor of plasma p-aminobenzoylglutamate. The model is a working hypothesis with derived features that are explicitly model-dependent. It successfully quantitated folate metabolism, encouraging further rigorous testing. | Selley ML, Close DR, Stern SE (2002)
The effect of increased concentrations of homocysteine on the concentration of (E)-4-hydroxy-2-nonenal in the plasma and cerebrospinal fluid of patients with Alzheimer's disease.
Neurobiology of aging 23, 383-388 [PubMed:11959400]
[show Abstract]
There is evidence that increased blood concentrations of homocysteine may be a risk factor for Alzheimer's disease. (E)-4-hydroxy-2-nonenal (HNE) is a neurotoxic product of lipid peroxidation that is increased in the ventricular fluid and brains of patients with Alzheimer's disease. We measured the concentrations of homocysteine, HNE, vitamin B(12) and folate in the plasma of 27 patients with Alzheimer's disease and 25 control subjects. There was a statistically significant increase in the plasma concentration of homocysteine (P < 0.001) and HNE (P < 0.001) in the Alzheimer's disease patients compared to the control group. There was a significant decrease in the plasma concentration of vitamin B(12) (P < 0.001) and folate (P = 0.002) in the Alzheimer's group compared to the controls. There was a significant positive correlation between the plasma concentrations of homocysteine and HNE in the patients with Alzheimer's disease (r = 0.661, P < 0.001). A significant negative correlation was found between the plasma concentration of homocysteine and the plasma concentrations of vitamin B(12) (r = -0.605, P = 0.0006) and folate (r = 0.586, P = 0.001). We also measured the concentrations of homocysteine, HNE, vitamin B(12) and folate in the cerebrospinal fluid (CSF) of 8 patients with Alzheimer's disease compared to 6 control subjects. The concentrations of homocysteine (P = 0.032) and HNE (P = 0.001) were significantly higher in the CSF of Alzheimer's patients than in the control subjects. There were significant positive correlations between the CSF concentrations of homocysteine and HNE (r = 0.924, P = 0.001). There was also a significant positive correlation between the plasma concentration of homocysteine and the CSF concentrations of homocysteine (r = 0.850, P = 0.007) and HNE (r = 0.092, P = 0.002). These results demonstrate that there is a relationship between increased homocysteine concentrations and increased HNE concentrations in Alzheimer's disease. | Donnelly JG (2001)
Folic acid.
Critical reviews in clinical laboratory sciences 38, 183-223 [PubMed:11451208]
[show Abstract]
Folic acid is an essential nutrient from the B complex group of vitamins. Folate, as a cofactor, is involved in numerous intracellular reactions, and this is reflected in the various derivatives that have been isolated from biological sources. Folic acid is involved in single carbon transfer reactions and serves as a source of single carbon units in different oxidative states. The processes involved in the absorption, transport, and intracellular metabolism of this cofactor are complex. Much of folate is bound tightly to enzymes, indicating that there is not excess of this cofactor and that its cellular availability is protected as well as being strictly regulated. In animals, the liver controls the supply of folate through first pass metabolism, biliary secretion, enterohepatic recirculation, as well as through senescent erythrocyte recycling. Deficiencies of folate can occur for many reasons, including reduced intake, increased metabolism, and/or increased requirements as well as through genetic defects. The effects of folate deficiency include hyperhomocysteinemia, megaloblastic anemia, and mood disorders. Folate deficiency has also been implicated in disorders associated with neural tube defects. Supplementation of grain products such as cereals has been undertaken in several countries as a cost-effective means of reducing the prevelance of neural tube defects. Recently, common polymorphisms have been discovered in several genes associated with folate pathways that may play a role in diseases associated with folate deficiency, particularly mild folate deficiency. | Thurmon TF (2001)
Folic acid: miscarriages, anomalies, thromboses, cancers.
The Journal of the Louisiana State Medical Society : official organ of the Louisiana State Medical Society 153, 98-103 [PubMed:11261364]
[show Abstract]
Folic acid is an essential micronutrient that merits special attention. In spite of plentiful sources in a balanced diet, recent data indicate that folic acid intake of many persons has long been inadequate. To some degree, this is due to destruction of folic acid by storage and processing of foodstuffs and to dietary practices that vary from recommendations. However, the common hereditary thermolabile variant of methylenetetrahydrofolate reductase (MTHFR) imposes an increased folic acid requirement which, if not met, may result in recurrent early pregnancy loss, anomalous progeny, thrombotic disorders, and cancers. There are recent reports that folic acid metabolism is also altered by other hereditary variations of MTHFR and other enzymes involved in folic acid metabolism. Optimal management requires dietary guidance and, for many patients, folate supplements. Caution is required because mandated folate fortification of grain products may produce levels that are inadequate for some patients and excessive for others. Laboratory tests for red cell folate and serum homocysteine are valuable adjuncts. | Litwin M, Abuauba M, Wawer ZT, Grenda R, Kurył T, Pietraszek E (2000)
[Sulphur amino acids, vitamin B12 and folic acid in children with chronic renal failure].
Polski merkuriusz lekarski : organ Polskiego Towarzystwa Lekarskiego 8, 268-269 [PubMed:10897644]
[show Abstract]
UnlabelledAim of the study was to: 1) estimate plasma profile of sulphur AA in children with chronic renal failure (CRF) and in children on hemodialysis (HD), and 2) to evaluate any correlation with serum folic acid (FA) and vitamin B12.Patients32 pts with CRF: 9 with GFR > 20 ml/min/1.73 m2 (group 1), 9 with GFR < 20 ml/min/1.73 m2 (group 2), and 14 pts on HD (group 3).Methodsplasma homocysteine (Hcys), methionine (Met), cysteine (Cys), serine (Ser) were measured with gas chromatography. Serum FA and vit. B12 were measured using MEIA method.Resultsmedian Hcys concentrations were the lowest in group 1: 5 mumol/l vs 9 mumol/l (group 2) and 20 mumol/l (group 3) (p = 0.03). Similarly, the lowest Met levels were observed in group 1--26 mumol/l, vs 66 mumol/l (group 2) and 281 mumol/l (group 3) (p = 0.001). Median Cys level in group 1 was 98 mumol/l vs 54 mumol/l (group 2), and 122 mumol/l (group 3) (p = 0.02). No differences were found in median Ser levels: 153 mumol/l (group 1) vs 239 mumol/l (group 2) and 240 mumol/l (group 3). The median concentrations of FA were 6.3 ng/ml (group 1) vs 8 ng/ml (group 2) and 15 ng/ml (group 3) (NS). Median concentrations of vit. B12 were 256 pg/ml (group 1) vs 379 pg/ml (group 2) and 322 pg/ml (group 3) (NS). There were no correlation between sulphur AA and FA and vit. B12 levels. The only difference between pts with Hcys levels remaining in lower and upper quartile concerned Met concentration (38 vs 263 mumol/l, p < 0.02) and GFR (p < 0.01).ConclusionsHyperhomocysteinemia develops already in moderate CRF. In pts on HD levels of Met and Cys are also raised. FA and vit. B12 concentrations are normal and do not correlate with plasma concentrations of sulphur AA. | Stern LL, Bagley PJ, Rosenberg IH, Selhub J (2000)
Conversion of 5-formyltetrahydrofolic acid to 5-methyltetrahydrofolic acid is unimpaired in folate-adequate persons homozygous for the C677T mutation in the methylenetetrahydrofolate reductase gene.
The Journal of nutrition 130, 2238-2242 [PubMed:10958818]
[show Abstract]
Methylenetetrahydrofolate reductase (MTHFR) catalyzes the synthesis of 5-methyltetrahydrofolic acid (5-CH(3)-H(4) folic acid), the methyl donor for the formation of methionine from homocysteine. A common C677T transition in the MTHFR gene results in a variant with a lower specific activity and a greater sensitivity to heat than the normal enzyme, as measured in vitro. This study was undertaken to determine the capacity of homozygotes for the MTHFR C677T transition to convert 5-formyltetrahydrofolic acid (5-HCO-H(4) folic acid) to 5-CH(3)-H(4) folic acid, a process that requires the action of MTHFR. Six subjects homozygous for the C677T transition (T/T) and 6 subjects with wild-type MTHFR (C/C) were given a 5-mg oral dose of (6R:,S:)-5-HCO-H(4) folic acid. Plasma and urine were analyzed for 5-CH(3)-H(4) folic acid concentrations using affinity/HPLC coupled with fluorescence or UV detection. The mean areas under the curves created by the rise and fall of plasma 5-CH(3)-H(4) folic acid after the oral dose did not differ between the two genotypes, 424.5 +/- 140.3 (T/T) vs. 424.1+/- 202.4 h.nmol/L (C/C). There also was no significant difference in the mean cumulative 7-h urinary excretion of 5-CH(3)-H(4) folic acid between the T/T (2.5 +/- 1.4 micromol) and C/C (1.9 +/- 1.0 micromol) genotypes. Under the conditions employed, the conversion of oral 5-HCO-H(4) folic acid to 5-CH(3)-H(4) folic acid is not impaired in persons with the T/T MTHFR genotype. Possible reasons for these findings are discussed. | Clifford AJ, Arjomand A, Dueker SR, Schneider PD, Buchholz BA, Vogel JS (1998)
The dynamics of folic acid metabolism in an adult given a small tracer dose of 14C-folic acid.
Advances in experimental medicine and biology 445, 239-251 [PubMed:9781393]
[show Abstract]
Folate is an essential nutrient that is involved in many metabolic pathways, including amino acid interconversions and nucleotide (DNA) synthesis. In genetically susceptible individuals and populations, dysfunction of folate metabolism is associated with severe illness. Despite the importance of folate, major gaps exist in our quantitative understanding of folate metabolism in humans. The gaps exist because folate metabolism is complex, a suitable animal model that mimics human folate metabolism has not been identified, and suitable experimental protocols for in vivo studies in humans are not developed. In general, previous studies of folate metabolism have used large doses of high specific activity tritium and 14C-labeled folates in clinical patients. While stable isotopes such as deuterium and 13C-labeled folate are viewed as ethical alternatives to radiolabeled folates for studying metabolism, the lack of sensitive mass spectrometry methods to quantify them has impeded advancement of the field using this approach. In this chapter, we describe a new approach that uses a major analytical breakthrough, Accelerator Mass Spectrometry (AMS). Because AMS can detect attomole concentrations of 14C, small radioactive dosages (nCi) can be safely administered to humans and traced over long periods of time. The needed dosages are sufficiently small that the total radiation exposure is only a fraction of the natural annual background radiation of Americans, and the generated laboratory waste may legally be classified non-radioactive in many cases. The availability of AMS has permitted the longest (202 d) and most detailed study to date of folate metabolism in a healthy adult human volunteer. Here we demonstrate the feasibility of our approach and illustrate its potential by determining empirical kinetic values of folate metabolism. Our data indicate that the mean sojourn time for folate is in the range of 93 to 120 d. It took > or = 350 d for the absorbed portion of small bolus dose of 14C-folic acid to be eliminated completely from the body. | Fenech M, Aitken C, Rinaldi J (1998)
Folate, vitamin B12, homocysteine status and DNA damage in young Australian adults.
Carcinogenesis 19, 1163-1171 [PubMed:9683174]
[show Abstract]
We performed a cross-sectional study (n = 49 males, 57 females) and a randomized double-blind placebo-controlled dietary intervention study (n = 31/32 per group) to determine the effect of folate and vitamin B12 (B12) on DNA damage (micronucleus formation and DNA methylation) and plasma homocysteine (HC) in young Australian adults aged 18-32 years. None of the volunteers were folate deficient (i.e. red blood cell folate <136 nmol/l) and only 4.4% (all females) were vitamin B12 deficient (i.e. serum vitamin B12 <150 pmol/l). The cross-sectional study showed that (i) the frequency of micronucleated cells (MNCs) was positively correlated with plasma HC in males (R = 0.293, P < 0.05) and (ii) in females MNC frequency was negatively correlated with serum vitamin B12 (R = -0.359, P < 0.01) but (iii) there was no significant correlation between micronucleus index and folate status. The results also showed that the level of unmethylated CpG (DNA) was not significantly related to vitamin B12 or folate status. The dietary intervention involved supplementation with 3.5x the recommended dietary intake (RDI) of folate and vitamin B12 in wheat bran cereal for three months followed by ten times the RDI of these vitamins via tablets for a further three months. In the supplemented group, MNC frequency was significantly reduced during the intervention by 25.4% in those subjects with initial MNC frequency in the high 50th percentile but there was no change in those subjects in the low 50th percentile for initial MNC frequency. The reduction in MNC frequency was significantly correlated with serum vitamin B12 (R = -0.49, P < 0.0005) and plasma HC (R = 0.39, P < 0.006), but was not significantly related to red blood cell folate. DNA methylation status was not altered in the supplemented group. The greatest decrease in plasma HC (by 37%) during the intervention was observed in those subjects in the supplemented group with initial plasma HC in the high 50th percentile, and correlated significantly with increases in red blood cell folate (R = -0.64, P < 0.0001) but not with serum vitamin B12. The results from this study suggest that (i) MNC frequency is minimized when plasma HC is below 7.5 micromol/l and serum vitamin B12 is above 300 pmol/l and (ii) dietary supplement intake of 700 microg folic acid and 7 microg vitamin B12 is sufficient to minimize MNC frequency and plasma HC. Thus, it appears that elevated plasma HC, a risk factor for cardiovascular disease, may also be a risk factor for chromosome damage. | Cahill E, McPartlin J, Gibney MJ (1998)
The effects of fasting and refeeding healthy volunteers on serum folate levels.
International journal for vitamin and nutrition research. Internationale Zeitschrift fur Vitamin- und Ernahrungsforschung. Journal international de vitaminologie et de nutrition 68, 142-145 [PubMed:9565830]
[show Abstract]
Fasting serum folate levels are commonly used in assessing folate status and also in estimating the bioavailability of synthetic folic acid and food folate. Previous work has shown that serum folate more than doubles in concentration during a 48 hour fast. Following a 24-hour standardisation procedure, serum and urinary folate levels were measured in nine healthy female volunteers fasting for 36 hours and in the first 6 hours during refeeding. Serum folate concentration increased from a mean of 14.8 ng/ml to 29.3 ng/ml during the 36 hour fast and fell to 22.1 ng/ml during the 6 hour refeeding period. The rise in serum folate concentration during the fast was negatively related to serum folate concentration at 0 hours fasting. It is hypothesised that the enterohepatic recirculation of folate plays an important role in the underlying physiological mechanism. These findings highlight the need to standardise energy intake to control for hepatic influences on folate metabolism in future studies assessing the bioavailability of folate in food. | Gregory JF, Williamson J, Liao JF, Bailey LB, Toth JP (1998)
Kinetic model of folate metabolism in nonpregnant women consuming [2H2]folic acid: isotopic labeling of urinary folate and the catabolite para-acetamidobenzoylglutamate indicates slow, intake-dependent, turnover of folate pools.
The Journal of nutrition 128, 1896-1906 [PubMed:9808640]
[show Abstract]
In a 10-wk study of folate metabolism in nonpregnant women (21-27 y, n -6 per group), subjects were fed a diet containing approximately 68 nmol/d (30 microg/d) folate from food. The remainder of the ingested folate was provided as folic acid in apple juice (as nonlabeled during wk 1-2, as [2H2]folic acid during wk 3-10) to yield a constant intake of 454, 680 or 907 nmol/d (200, 300 or 400 microg/d). Isotopic enrichment of total urinary folate and the primary catabolite para-acetamidobenzoylglutamate (ApABG) was determined. Isotopic enrichment of ApABG served as an indicator of labeling of tissue folates. A kinetic model consisting of fast- and slow-turnover nonsaturable pools and a saturable slow-turnover pool, with provisions for urinary and fecal excretion, catabolism and enterohepatic circulation, yielded a close fit to the data. Mean residence times for total body folate were 212, 169 and 124 d for folate intakes of 454, 680, and 907 nmol/d, respectively. The model predicted that variation in folate intake over this range had little effect on the mass of the large saturable folate pool; however, the fast-turnover nonsaturable pools increased in proportion to folate intake, whereas the slow nonsaturable pool also tended to increase. This model will aid in evaluation of folate turnover and in predicting kinetic consequences of physiologic conditions associated with altered folate requirements. | Gregory JF, Williamson J, Bailey LB, Toth JP (1998)
Urinary excretion of [2H4]folate by nonpregnant women following a single oral dose of [2H4]folic acid is a functional index of folate nutritional status.
The Journal of nutrition 128, 1907-1912 [PubMed:9808641]
[show Abstract]
In a 10-wk study with nonpregnant women (21-27 y, n = 5-6 per group), subjects were fed a diet containing approximately 68 nmol/d (30 microg/d) folate from food that was supplemented with folic acid in apple juice to yield a constant intake of 454, 680 or 907 nmol/d (200, 300 or 400 microg/d) to evaluate folate status and long-term in vivo kinetics. Reported here is an additional phase of this protocol conducted to determine the relationship between short-term urinary excretion after a single isotopically labeled dose and various measures of folate nutritional status. It was hypothesized that urinary excretion from a single [glutamate-2H4]folic acid ([2H4]folic acid) dose would increase in proportion to folate nutritional status due to saturable cellular uptake and retention processes along with saturation of renal reabsorption. Each subject was given 1.13 micromol (500 microg) of [2H4]folic acid orally on the morning of d 70 of the study, followed by a complete 24-h urine collection. Urine was analyzed to determine the isotopic enrichment of urinary folate by gas chromatography-mass spectrometry and the concentration of urinary folate by HPLC. Urinary excretion of [2H4]folate was greatest at the 907 nmol/d intake and was positively correlated with serum folate concentration but was not correlated with erythrocyte folate. Excretion of [2H4]folate tended to be greatest when plasma homocysteine concentrations were low (<8 micromol/L), although this relation was not significant. These results suggest that 24-h urinary excretion after a single oral dose of isotopically labeled folate is a functional indicator of folate nutritional status that complements other measures of folate nutriture. | Kamen B (1997)
Folate and antifolate pharmacology.
Seminars in oncology 24, S18-30-S18-39 [PubMed:9420019]
[show Abstract]
Folic acid is a water-soluble vitamin associated with the other B vitamins. In its fully reduced form (tetrahydrofolate), folate serves as a 1-carbon donor for synthesis of purines and thymidine as well as in the remethylation cycle of homocysteine to methionine. Folate is essential for normal cell growth and replication. It therefore is not surprising that folate analogues have served and continue to serve well as antibiotics and cytotoxic drugs in the treatment of cancer, autoimmune diseases, psoriasis, and bacterial and protozoal infections. During the past 50 years, many of the enzymes requiring folate as a co-factor (ie, thymidylate synthase), and molecules critical in folate homeostasis (ie, the reduced folate carrier, folylpolyglutamate synthase), have been purified and even crystallized. The genes have been cloned, sequenced, and mapped, providing detailed knowledge of their regulation and three-dimensional structure. This has, in part, led to the rational synthesis of a large number of folate analogues that differ from methotrexate, the "classical antifolate," in transport, metabolism, and intracellular targets. Currently, several new folate analogues with unique biochemical properties and clinical applications are being tested. The goals of this brief review are to review folate homeostasis, to highlight the similarities and differences between natural folate and antifolates with respect to biochemistry and metabolism, and to present the pharmacology of methotrexate and several next-generation folate analogues, such as trimetrexate and raltritrexed, with an emphasis on mechanisms of drug resistance. | Swain RA, St Clair L (1997)
The role of folic acid in deficiency states and prevention of disease.
The Journal of family practice 44, 138-144 [PubMed:9040515]
[show Abstract]
Folic acid, a water-soluble vitamin, has been used since the 1940s to treat some cases of macrocytic anemia without neurologic disease. Folate deficiency is best diagnosed with red blood cell folate levels along with macrocytosis and/or megaloblastic anemia. In addition to reversing overt deficiency, the vitamin may reduce the incidence of neural tube defects by 45% in women who receive 400 micrograms per day. It is recommended that all women of childbearing age take 400 micrograms of folate per day. Elevations in homocysteine levels, a metabolite intimately associated with folate, are also being found with increasing regularity in those with cardiovascular diseases. Homocysteine levels are reduced by folic acid administration. Therefore, there is some biologic plausibility, but not currently direct proof, for the assumption that folate supplements may prevent heart disease, stroke, and peripheral arterial disease. Controlled trials should take place before widespread food supplementation with folate is carried out on a large scale because of the possibility of outbreaks of permanent B12-related neurologic damage in those with undiagnosed pernicious anemia. However, if a patient has a premature cardiovascular event and has minimal risk factors, ordering a test to determine homocysteine level may be advisable, and if elevated, treating with folic acid supplement as long as B12 deficiency does not coexist. | 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, 1371S-1398S [PubMed:7738698] | 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 data1-28 [PubMed:10138938]
[show Abstract]
Intervention strategies aimed at reducing the prevalence of nutrition-related diseases, including designing nutrition policies and nutrition education and assistance programs, require effective monitoring of what Americans are eating. Nutrient reference data from the third National Health and Nutrition Examination Survey provide essential information to achieve these goals. Mean and median iron intakes were adequate in males of all race-ethnic groups but were generally low in females and young children. Mean and median calcium intakes were also higher in males than in females and were lower than recommendations in adolescents and in women of all ages. Mean sodium intakes for all age, sex, and race-ethnic groups exceeded the minimum requirements of healthy persons and were higher in non-Hispanic black children and adolescents than in non-Hispanic white and Mexican American children and adolescents. Mean fiber intakes also did not meet recommendations in most subgroups and were higher in Mexican American adults followed by non-Hispanic white adults and non-Hispanic black adults. Further research is planned to compare the food sources of energy and nutrients consumed by different population groups in NHANES III to similar results from earlier nation surveys. NHANES III, Phase 2 (1991-94) recalls were collected using the same dietary method as those collected in Phase 1 (1988-91), and other analyses will compare findings from both phases of NHANES III. | Zittoun J (1993)
[Anemias due to disorder of folate, vitamin B12 and transcobalamin metabolism].
La Revue du praticien 43, 1358-1363 [PubMed:8235383]
[show Abstract]
Macrocytic megaloblastic anemia is the most typical but the latest sign of a cobalamin (vitamin B12) and/or folic acid deficiency or of a congenital abnormality of cobalamin and folate metabolism. Macrocytosis in blood and megaloblastosis in bone marrow are the morphological features of a disturbance in cell division related to a defect in DNA biosynthesis. Macrocytosis without anemia, normocytic normochronic anemia with a low reticulocyte cell count or microcytic hypochromic anemia in case of associated iron deficiency do not exclude a vitamin deficiency. Neurological or psychiatric disorders and immune abnormalities have been reported in patients with vitamin B12 or folate deficiencies or in children with congenital abnormalities of these 2 vitamins; such manifestations may even occur without anemia. | LAMANNA A, TAVIANI L (1955)
[Influence of folic acid, pantothenic acid and vitamin B6 on the production of agglutinating antibodies].
Acta vitaminologica 9, 57-60 [PubMed:14387833] |
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