Vitamin B9 is a member of the B-vitamin family and is essential for amino acid metabolism, cellular homeostasis, DNA methylation and neurotransmitter synthesis. It also helps control homocysteine levels, which, if too high, can lead to a number of chronic conditions including cancer, heart disease, depression, and diabetes. Vitamin B9 naturally occurs as folate. Folic acid is synthetically produced and used in fortified foods and supplements; it has no physiological activity in the body unless converted into folate.
FOLATE/FOLIC ACID METABOLISM
Dietary sources of natural folate include green leafy vegetables, mushrooms, legumes, and liver. The bioavailability of folate in natural foods, however, is approximately 50% of that of the synthetic form of folic acid and varies greatly, depending on the food consumed. Under normal circumstances, natural dietary folate is absorbed in the intestine and/or liver and metabolised primarily to 5-methyl tetrahydrofolate (5-methylTHF) which is then polyglutamated (attached with glutamic acid) for cellular retention (Barua et al., 2014).
On the other hand, folic acid consumed in fortified foods/supplements is reduced primarily to dihydrofolate by the enzyme dihydrofolate reductase in the liver and finally converted to the tetrahydrofolate (THF) which is then ready to be polyglutamated for cellular retention. The tetrahydrofolate (THF) is converted to 5, 10-methyleneTHF by vitamin B6 and then reduced to 5-methyl tetrahydrofolate (5-MTHF) by 5, 10-methylene tetrahydrofolate reductase. 5-MTHF is the primary metabolite of folate that enters the circulation from the intestinal cells (Stanhewicz & Kenney, 2016). Reduced levels of 5-MTHF would lead to folate deficiency and as a result cause elevated homocysteine levels, birth defects and increased risk of cancer.
Bioavailable folate, primarily the circulating metabolite 5-MTHF, helps break down an amino acid in the blood called homocysteine – which in excess is related to a higher risk of coronary heart disease, stroke and peripheral vascular disease. 5-MTHF also contributes to enhanced endothelial function by increasing nitic oxide (NO) bioavailability within the vascular endothelium. Stanhewicz & Kenney (2016) demonstrated that in patient populations in whom endothelial function was compromised, folic acid supplementation effectively restored endothelium-dependent vasodilation. The mechanisms through which folic acid exert its effects include antioxidant actions, effects on cofactor availability, or direct interactions with the enzyme endothelial NO synthase (Verhaar et al., 2002).
Demand for folate increases during pregnancy because it is required for growth and development of the foetus. Folate deficiency has been associated with abnormalities in both mothers (anaemia, peripheral neuropathy) and babies (congenital abnormalities). Dietary supplementation with folic acid around the time of conception has long been known to reduce the risk of neural tube defects (NTDs) in the offspring (Greenberg et al., 2011). NTDs are congenital malformations that result from failure of the neural tube to close during embryogenesis. Recent evidence suggests that not only folate but also choline, B12 and methylation metabolisms are involved in NTDs. Decreased B12 vitamin and increased total choline or homocysteine in maternal blood have been shown to be associated with increased NTDs risk. Several polymorphisms of genes involved in these pathways have also been implicated in risk of development of NTDs (Imbard et al., 2013).
Folate deficiency is also involved in the aetiology of depression. Alternatively, depressed mood could decrease appetite and lower folate levels. The link between folate and depression is low serotonin levels. Folate deficiency has been associated with low levels of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the cerebrospinal fluid (CSF). In a study done by Botez et al. (1992) supplementation with folate restored 5-HIAA levels to normal. There is also a decrease in serotonin synthesis in patients with 5, 10-methylenetetrahydrofolate reductase (MTHFR) deficiency, a disorder of folate metabolism. The other mechanism relating folate deficiency to low serotonin involves S-adenosylmethionine (SAMe). SAMe is a major methyl donor formed from methionine. A recent review and meta-analysis looked at the results from the limited number of studies that investigated the effect of giving folate to depression patients and suggested that augmentation of antidepressant treatment with folate may improve patient outcome (Taylor et al., 2004).
Homocysteine is associated with higher risk of diabetes. Therefore, folate, which reduces homocysteine, is promising for the prevention and treatment of diabetes. Nutritional deficiencies, particularly those involving B-group vitamins and folate, important cofactors of homocysteine (Hcy) metabolism, are commonly related with high circulating levels of homocysteine. In a study done by Malaguarnera et al. (2015) it was demonstrated that changes in folate status may influence the DNA stability and integrity, and affect the methylation patterns in neural tube tissue predisposing patients to the development of diabetic retinopathy.
Erythropoiesis is the process in which new erythrocytes (red blood cells) are produced. These new erythrocytes replace the oldest erythrocytes that are phagocytosed and destroyed each day. Folate, vitamin B12, and iron have crucial roles in erythropoiesis. Erythroblasts (an immature erythrocyte, containing a nucleus) require folate and vitamin B12 for proliferation during their differentiation. Deficiency of folate or vitamin B12 inhibits purine and thymidylate syntheses, impairs DNA synthesis, and causes erythroblast apoptosis, resulting in anaemia from ineffective erythropoiesis. Erythroblasts also require large amounts of iron for haemoglobin synthesis. Large amounts of iron are recycled daily with haemoglobin breakdown from destroyed old erythrocytes (Koury & Ponka, 2004).
RISKS OF HIGH-DOSE FOLATE SUPPLEMENTATION
The current Recommended Dietary Allowance (RDA) for folate is 400 mcg per day for adults. If taken more than 1000mcg per day, folate supplementation may mask pernicious anaemia (B12 deficiency anaemia).
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Barua, S., Kuizon, S. et al. (2014). Folic acid supplementation in pregnancy and implications in health and disease. Journal of Biomedical Science. 21 (77), 2-9.
Botez, M.I., Young, S.N et al. (1992). Effect of folic acid and vitamin B12 deficiencies on 5-hydroxyindoleacetic acid in human cerebrospinal fluid. Annual Journal of Neurology. 8 (22), 479-484.
Greenberg, J.A., Bell, S.J. et al. (2011). Folic Acid Supplementation and Pregnancy: More Than Just Neural Tube Defect Prevention. Obstetrics and Gynecology. 4 (2), 52–59.
Imbard, A., Benoist, J.F. et al. (2013). Neural Tube Defects, Folic Acid and Methylation. International Journal of Environmental Research and Public Health. 10 (9), 4352–4389.
Koury, M.J., Ponka, P. (2004). New insights into erythropoiesis: The Roles of Folate, Vitamin B12, and Iron. Annual Review of Nutrition. 24 (4), 105-131.
Malaguarnera, G., Gagliano, S. et al. (2015). Folate status in type 2 diabetic patients with and without retinopathy. Clinical Ophthalmology. 15 (9), 1437–1442.
Stanhewicz, A.E., Kenney, W.L. (2016). Role of folic acid in nitric oxide bioavailability and vascular endothelial function. Nutrition Reviews. 75 (1), 61–70.
Taylor, M.J., Carney, S.M. et al. (2004). Folate for depressive disorders: systematic review and meta-analysis of randomized controlled trials. Journal of Psychopharmacology. 4 (18), 251-256.
Verhaar, M.C., Stroes, E., Rabelink, T..J (2002). Folates and Cardiovascular Disease. Atherosclerosis, Thrombosis, and Vascular Biology. 22 (1), 6-13.
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