Folate, folic acid and 5-methyltetrahydrofolate are not the same thing

Xenobiotica

Volumn 44, Issue 5, 2014, Pages 480-488

  Scaglione, Francesco ^a   Panzavolta, Giscardo ^a  

^a UNIVERSITY OF MILAN   (Italy)

Author keywords

Cardiovascular disease; Cognitive dysfunction; Folate deficiency; Methylenetetrahydrofolate reductase gene; Neural tube defects

Indexed keywords

5 METHYLTETRAHYDROFOLIC ACID; 5,10 METHYLENETETRAHYDROFOLATE REDUCTASE (FADH2); DIHYDROFOLATE REDUCTASE; FOLIC ACID; TRACE ELEMENT; 5-METHYLTETRAHYDROFOLATE; FOLINIC ACID; METHYLENETETRAHYDROFOLATE REDUCTASE (NADPH2); MTHFR PROTEIN, HUMAN; TETRAHYDROFOLIC ACID DERIVATIVE;

BIOAVAILABILITY; CARBON METABOLISM; CARDIOVASCULAR DISEASE; COGNITIVE DEFECT; CYANOCOBALAMIN DEFICIENCY; DIETARY INTAKE; ENZYME POLYMORPHISM; FOLATE METABOLISM; FOLIC ACID DEFICIENCY; HEMATOLOGIC DISEASE; HUMAN; INGESTION; MAMMAL; NEURAL TUBE DEFECT; NUTRITIONAL STATUS; PERIPHERAL CIRCULATION; REVIEW; RISK FACTOR; STOMACH PH; SYMPTOMATOLOGY; VITAMIN SUPPLEMENTATION; ANIMAL; DIET SUPPLEMENTATION; DIET THERAPY; GENETIC POLYMORPHISM; GENETICS;

ANIMALS; DIETARY SUPPLEMENTS; FOLIC ACID; FOLIC ACID DEFICIENCY; FOOD, FORTIFIED; HUMANS; LEUCOVORIN; METHYLENETETRAHYDROFOLATE REDUCTASE (NADPH2); POLYMORPHISM, GENETIC; TETRAHYDROFOLATES;

EID: 84898716484     PISSN: 00498254     EISSN: 13665928     Source Type: Journal    
DOI: 10.3109/00498254.2013.845705     Document Type: Review

References (97)

1. Bailey SW, Ayling JE. (2009). The extremely slow and variable activity of dihydrofolate reductase in human liver and its implications for high folic acid intake. Proc Natl Acad Sci USA 106:15424-9.
2. Basten GP, Duthie SJ, Pirie L, et al. (2006). Sensitivity of markers of DNA stability and DNA repair activity to folate supplementation in healthy volunteers. Br J Cancer 94:1942-7.
3. Bergström L. (1994). Nutrient losses and gains in the preparation of foods. Livsmedelsverket (National Food Administration), ed. 2nd ed. Uppsala. Available from: http://www.slv.se/upload/dokument/rapporter/mat-naring/1994-32- Livsmedelsverket-nutrient-losses-and-gains.pdf [last accessed 2 Feb 2014].
4. Bjorkegren K, Svardsudd K. (2003). Reported symptoms and clinical findings in relation to serum cobalamin, folate, methylmalonic acid and total homocysteine among elderly Swedes: a population-based study. J Intern Med 254:343-52.
5. Blakley RL. (1984). Dihydrofolate reductase. In: Blakley RL, Benkovic SJ, eds. Folates and pterins-chemistry and biochemistry of folates. New York: Wiley, 191-244.
6. Blom HJ, Smulders Y. (2011). Overview of homocysteine and folate metabolism. With special references to cardiovascular disease and neural tube defects. J Inherit Metab Dis 34:75-81.
7. Bottiglieri T, Hyland K, Reynolds EH. (1994). The clinical potential of ademetionine (S-adenosylmethionine) in neurological disorders. Drugs 48:137-52.
8. Brattstrom L, Wilcken DE, Ohrvik J, Brudin L. (1998). Common methylenetetrahydrofolate reductase gene mutation leads to hyperhomocysteinemia but not to vascular disease: the result of a metaanalysis. Circulation 98:2520-6.
9. Brouwer IA, van Dusseldorp M, West CE, et al. (1999). Dietary folate from vegetables and citrus fruit decreases plasma homocysteine concentrations in humans in a dietary controlled trial. J Nutr 129: 1135-9.
10. Buttner BE, Ohrvik VE, Witthoft CM, Rychlik M. (2011). Quantification of isotope-labelled and unlabelled folates in plasma, ileostomy and food samples. Anal Bioanal Chem 399:429-39.
11. Carrier J, Medline A, Sohn KJ, et al. (2003). Effects of dietary folate on ulcerative colitis-associated colorectal carcinogenesis in the interleukin 2-and beta(2)-microglobulin-deficient mice. Cancer Epidemiol Biomarkers Prev 12:1262-7.
12. Christensen B, Arbour L, Tran P, et al. (1999). Genetic polymorphisms in methylenetetrahydrofolate reductase and methionine synthase, folate levels in red blood cells, and risk of neural tube defects. Am J Med Genet 84:151-7.
13. Crider KS, Bailey LB, Berry RJ. (2011). Folic acid food fortification-its history, effect, concerns, and future directions. Nutrients 3:370-84.
14. Cuskelly GJ, McNulty H, Scott JM. (1996). Effect of increasing dietary folate on red-cell folate: implications for prevention of neural tube defects. Lancet 347:657-9.
15. Czeizel AE, Dudas I. (1992). Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation. N Engl J Med 327:1832-5.
16. Czeizel AE, Dudas I, Paput L, Banhidy F. (2011). Prevention of neuraltube defects with periconceptional folic acid, methylfolate, or multivitamins? Ann Nutr Metab 58:263-71.
17. Daly LE, Kirke PN, Molloy A, et al. (1995). Folate levels and neural tube defects. Implications for prevention. JAMA 274:1698-702.
18. Dietary Guidelines Advisory Committee. (2010). Report of the Dietary Guidelines Advisory Committee on the Dietary Guidelines for Americans. Part D: The science base. Section 2: Nutrient adequacy. Agricultural Research Service, Washington, DC.
19. Durand P, Prost M, Blache D. (1998). Folate deficiencies and cardiovascular pathologies. Clin Chem Lab Med 36:419-29.
20. Finglas PM, Scott J, Witthoft CM, et al. (1999). The certification of the mass fraction of vitamins in four reference materials: wholemeal flour (CRM 121), milk powder (CRM 421), lyophilised mixed vegetables (CRM 485) and lyophilised pig's liver (CRM 487). Office for Official Publications, Commission of the European Union: Luxembourg, Luxembourg.
21. Fohr IP, Prinz-Langenohl R, Bronstrup A, et al. (2002). 5,10-Methylenetetrahydrofolate reductase genotype determines the plasma homocysteine-lowering effect of supplementation with 5-methyltetrahydrofolate or folic acid in healthy young women. Am J Clin Nutr 75:275-82.
22. Forman JP, Rimm EB, Stampfer MJ, Curhan GC. (2005). Folate intake and the risk of incident hypertension among US women. JAMA 293: 320-9.
23. Forssen KM, Jagerstad MI, Wigertz K, Witthoft CM. (2000). Folates and dairy products: a critical update. J Am Coll Nutr 19: 100S-10S.
24. Frosst P, Blom HJ, Milos R, et al. (1995). A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 10:111-13.
25. Ganeshaguru K, Hoffbrand AV. (1978). The effect of deoxyuridine, vitamin B12, folate and alcohol on the uptake of thymidine and on the deoxynucleoside triphosphate concentrations in normal and megaloblastic cells. Br J Haematol 40:29-41.
26. Gregory JF. (1995). The bioavailability of folate. In: Bailey LB, ed. Folate in health and disease. New York: Marcel Dekker, 195-235.
27. Gregory III JF, Cuskelly GJ, Shane B, et al. (2000). Primed, constant infusion with [2H3]serine allows in vivo kinetic measurement of serine turnover, homocysteine remethylation, and transsulfuration processes in human one-carbon metabolism. Am J Clin Nutr 72: 1535-41.
28. Gudnason V, Stansbie D, Scott J, et al. (1998). C677T (thermolabile alanine/valine) polymorphism in methylenetetrahydrofolate reductase (MTHFR): its frequency and impact on plasma homocysteine concentration in different European populations. EARS group. Atherosclerosis 136:347-54.
29. Halsted CH. (1989). The intestinal absorption of dietary folates in health and disease. J Am Coll Nutr 8:650-8.
30. Hannon-Fletcher MP, Armstrong NC, Scott JM, et al. (2004). Determining bioavailability of food folates in a controlled intervention study. Am J Clin Nutr 80:911-18.
31. Hooshmand B, Solomon A, Kareholt I, et al. (2012). Associations between serum homocysteine, holotranscobalamin, folate and cognition in the elderly: a longitudinal study. J Intern Med 271:204-12.
32. Houghton LA, Sherwood KL, Pawlosky R, et al. (2006). [6S]-5- Methyltetrahydrofolate is at least as effective as folic acid in preventing a decline in blood folate concentrations during lactation. Am J Clin Nutr 83:842-50.
33. Hwang C, Ross V, Mahadevan U. (2012). Micronutrient deficiencies in inflammatory bowel disease: from A to zinc. Inflamm Bowel Dis 18: 1961-81.
34. Inskip HM, Crozier SR, Godfrey KM, et al. (2009). Women's compliance with nutrition and lifestyle recommendations before pregnancy: general population cohort study. BMJ 338:b481. doi:10.1136/bmj.b481.
35. Jardine MJ, Kang A, Zoungas S, et al. (2012). The effect of folic acid based homocysteine lowering on cardiovascular events in people with kidney disease: systematic review and meta-analysis. BMJ 344:e3533. doi:10.1136/bmj.e3533.
36. Johnson WG, Stenroos ES, Spychala JR, et al. (2004). New 19 bp deletion polymorphism in intron-1 of dihydrofolate reductase (DHFR): a risk factor for spina bifida acting in mothers during pregnancy? Am J Med Genet A 124A:339-45.
37. Kang SS, Zhou J, Wong PW, et al. (1988). Intermediate homocysteinemia: a thermolabile variant of methylenetetrahydrofolate reductase. Am J Hum Genet 43:414-21.
38. Kelly GS. (1998). Folates: supplemental forms and therapeutic applications. Altern Med Rev 3:208-20.
39. Klerk M, Verhoef P, Clarke R, et al. (2002). MTHFR 677C-T polymorphism and risk of coronary heart disease: a meta-analysis. JAMA 288:2023-31.
40. Knudsen VK, Orozova-Bekkevold I, Rasmussen LB, et al. (2004). Low compliance with recommendations on folic acid use in relation to pregnancy: is there a need for fortification? Public Health Nutr 7: 843-50.
41. Konings EJ, Troost FJ, Castenmiller JJ, et al. (2002). Intestinal absorption of different types of folate in healthy subjects with an ileostomy. Br J Nutr 88:235-42.
42. Lamers Y, Prinz-Langenohl R, Bramswig S, Pietrzik K. (2006). Red blood cell folate concentrations increase more after supplementation with [6S]-5-methyltetrahydrofolate than with folic acid in women of childbearing age. Am J Clin Nutr 84:156-61.
43. Lamers Y, Prinz-Langenohl R, Moser R, Pietrzik K. (2004). Supplementation with [6S]-5-methyltetrahydrofolate or folic acid equally reduces plasma total homocysteine concentrations in healthy women. Am J Clin Nutr 79:473-8.
44. Lee JE, Willett WC, Fuchs CS, et al. (2011). Folate intake and risk of colorectal cancer and adenoma: modification by time. Am J Clin Nutr 93:817-25.
45. Li D, Karp N, Wu Q, et al. (2008). Mefolinate (5-methyltetrahydrofolate), but not folic acid, decreases mortality in an animal model of severe methylenetetrahydrofolate reductase deficiency. J Inherit Metab Dis 31:403-11.
46. Lucock M. (2004). Is folic acid the ultimate functional food component for disease prevention? BMJ 328:211-14.
47. Medical Research Council Vitamin Study Research Group. (1991). Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. Lancet 338:131-7.
48. Meleady R, Ueland PM, Blom H, et al. (2003). Thermolabile methylenetetrahydrofolate reductase, homocysteine, and cardiovascular disease risk: the European Concerted Action Project. Am J Clin Nutr 77:63-70.
49. Melse-Boonstra A, Verhoef P, West C. (2004). Quantifying folate bioavailability: a critical appraisal of methods. Curr Opin Clin Nutr Metab Care 7:539-45.
50. Mischoulon D, Fava M. (2002). Role of S-adenosyl-L-methionine in the treatment of depression: a review of the evidence. Am J Clin Nutr 76: 1158S-61S.
51. Mitchell LE, Adzick NS, Melchionne J, et al. (2004). Spina bifida. Lancet 364:1885-95.
52. Morin I, Devlin AM, Leclerc D, et al. (2003). Evaluation of genetic variants in the reduced folate carrier and in glutamate carboxypeptidase II for spina bifida risk. Mol Genet Metab 79: 197-200.
53. Morris MC. (2012). Nutritional determinants of cognitive aging and dementia. Proc Nutr Soc 71:1-13.
54. Obeid R, Holzgreve W, Pietrzik K. (2013). Is 5-methyltetrahydrofolate an alternative to folic acid for the prevention of neural tube defects? J Perinat Med 41:469-83.
55. Ohrvik VE, Buttner BE, Rychlik M, et al. (2010). Folate bioavailability from breads and a meal assessed with a human stable-isotope area under the curve and ileostomy model. Am J Clin Nutr 92:532-8.
56. Ohrvik VE, Witthoft CM. (2011). Human folate bioavailability. Nutrients 3:475-90.
57. Parle-McDermott A, Pangilinan F, Mills JL, et al. (2007). The 19-bp deletion polymorphism in intron-1 of dihydrofolate reductase (DHFR) may decrease rather than increase risk for spina bifida in the Irish population. Am J Med Genet A 143A:1174-80.
58. Pentieva K, McNulty H, Reichert R, et al. (2004). The short-term bioavailabilities of [6S]-5-methyltetrahydrofolate and folic acid are equivalent in men. J Nutr 134:580-5.
59. Perez L, Heim L, Sherzai A, Jaceldo-Siegl K. (2012). Nutrition and vascular dementia. J Nutr Health Aging 16:319-24.
60. Pfeiffer CM, Fazili Z, Zhang M. (2010). Folate analytical methodology. Folate in health and disease, 2nd ed. Boca Raton (FL): CRC Press, 517-74.
61. Pietrzik K, Bailey L, Shane B. (2010). Folic acid and L-5-methyltetrahydrofolate: comparison of clinical pharmacokinetics and pharmacodynamics. Clin Pharmacokinet 49:535-48.
62. Prinz-Langenohl R, Bramswig S, Tobolski O, et al. (2009). [6S]-5-methyltetrahydrofolate increases plasma folate more effectively than folic acid in women with the homozygous or wild-type 677C-T polymorphism of methylenetetrahydrofolate reductase. Br J Pharmacol 158:2014-21.
63. Prinz-Langenohl R, Bronstrup A, Thorand B, et al. (1999). Availability of food folate in humans. J Nutr 129:913-16.
64. Prinz-Langenohl R, Lamers Y, Moser R, Pietrzik K. (2003). Effect of folic acid preload on the bioequivalence of [6S]-5-methyltetrahydrofolate and folic acid in healthy volunteers. J Inherit Metab Dis 26: 124.
65. Rajagopalan PT, Zhang Z, McCourt L, et al. (2002). Interaction of dihydrofolate reductase with methotrexate: ensemble and singlemolecule kinetics. Proc Natl Acad Sci USA 99:13481-6.
66. Rallidis LS, Gialeraki A, Komporozos C, et al. (2008). Role of methylenetetrahydrofolate reductase 677C-T polymorphism in the development of premature myocardial infarction. Atherosclerosis 200: 115-20.
67. Reynolds EH. (2002). Folic acid, ageing, depression, and dementia. BMJ 324:1512-15.
68. Rozen R. (2004). Folate and genetics. J Food Sci 69:S65-7.
69. Russell RM, Golner BB, Krasinski SD, et al. (1988). Effect of antacid and H2 receptor antagonists on the intestinal absorption of folic acid. J Lab Clin Med 112:458-63.
70. Russell RM, Krasinski SD, Samloff IM, et al. (1986). Folic acid malabsorption in atrophic gastritis. Possible compensation by bacterial folate synthesis. Gastroenterology 91:1476-82.
71. Sanjoaquin MA, Allen N, Couto E, et al. (2005). Folate intake and colorectal cancer risk: a meta-analytical approach. Int J Cancer 113: 825-8.
72. Savage DG, Lindenbaum J. (1994). Folate-cobalamin interactions. In: Bailey LB, ed. Folate in health and disease. New York: Marcel Dekker, 237-85.
73. Scott J. (2001). Methyltetrahydrofolate: the superior alternative to folic acid. In: Kramer K, Hoppe P-P, Packer L, eds. Nutraceuticals in health and disease prevention. New York: Marcel Dekkar.
74. Selhub J, Powell GM, Rosenberg IH. (1984). Intestinal transport of 5-methyltetrahydrofolate. Am J Physiol 246:G515-20.
75. Shields DC, Kirke PN, Mills JL, et al. (1999). The " thermolabile" variant of methylenetetrahydrofolate reductase and neural tube defects: an evaluation of genetic risk and the relative importance of the genotypes of the embryo and the mother. Am J Hum Genet 64: 1045-55.
76. Sirotnak FM, Tolner B. (1999). Carrier-mediated membrane transport of folates in mammalian cells. Annu Rev Nutr 19:91-122.
77. Smulders YM, Stehouwer CD. (2005). Folate metabolism and cardiovascular disease. Semin Vasc Med 5:87-97.
78. Stolzenberg-Solomon RZ, Chang SC, Leitzmann MF, et al. (2006). Folate intake, alcohol use, and postmenopausal breast cancer risk in the prostate, lung, colorectal, and ovarian cancer screening trial. Am J Clin Nutr 83:895-904.
79. Subramanian VS, Marchant JS, Said HM. (2008). Apical membrane targeting and trafficking of the human proton-coupled transporter in polarized epithelia. Am J Physiol Cell Physiol 294:C233-40.
80. Summers CM, Mitchell LE, Stanislawska-Sachadyn A, et al. (2010). Genetic and lifestyle variables associated with homocysteine concentrations and the distribution of folate derivatives in healthy premenopausal women. Birth Defects Res A Clin Mol Teratol 88: 679-88.
81. Tamura T, Stokstad EL. (1973). The availability of food folate in man. Br J Haematol 25:513-32.
82. Vahteristo L, Finglas PM, Witthoft CM, et al. (1996). Third EU MAT intercomparison study on food folate analysis using HPLC procedures. Food Chemistry 57:109-11.
83. van der Linden IJ, Nguyen U, Heil SG, et al. (2007). Variation and expression of dihydrofolate reductase (DHFR) in relation to spina bifida. Mol Genet Metab 91:98-103.
84. van der Put NM, Blom HJ. (2000). Neural tube defects and a disturbed folate dependent homocysteine metabolism. Eur J Obstet Gynecol Reprod Biol 92:57-61.
85. Venn BJ, Green TJ, Moser R, Mann JI. (2003). Comparison of the effect of low-dose supplementation with L-5-methyltetrahydrofolate or folic acid on plasma homocysteine: a randomized placebo-controlled study. Am J Clin Nutr 77:658-62.
86. Wagner C. (1995). Biochemical role of folate in cellular metabolism. In: Bailey LB, ed. Folate in health and disease. New York: Marcel Dekker, 23-42.
87. Webb PM, Ibiebele TI, Hughes MC, et al. (2011). Folate and related micronutrients, folate-metabolising genes and risk of ovarian cancer. Eur J Clin Nutr 65:1133-40.
88. Wei MM, Gregory III JF. (1998). Organic acids in selected foods inhibit intestinal brush border pteroylpolyglutamate hydrolase in vitro: potential mechanism affecting the bioavailability of dietary polyglutamyl folate. J Agric Food Chem 46:211-19.
89. Wilcken B, Bamforth F, Li Z, et al. (2003). Geographical and ethnic variation of the 677CT allele of 5,10 methylenetetrahydrofolate reductase (MTHFR): findings from over 7000 newborns from 16 areas world wide. J Med Genet 40:619-25.
90. Willems FF, Boers GH, Blom HJ, et al. (2004). Pharmacokinetic study on the utilisation of 5-methyltetrahydrofolate and folic acid in patients with coronary artery disease. Br J Pharmacol 141: 825-30.
91. Wolffe AP, Jones PL, Wade PA. (1999). DNA demethylation. Proc Natl Acad Sci USA 96:5894-6.
92. Wright AJ, Finglas PM, Dainty JR, et al. (2003). Single oral doses of 13C forms of pteroylmonoglutamic acid and 5-formyltetrahydrofolic acid elicit differences in short-term kinetics of labelled and unlabelled folates in plasma: potential problems in interpretation of folate bioavailability studies. Br J Nutr 90:363-71.
93. Wright AJ, Finglas PM, Dainty JR, et al. (2005). Differential kinetic behavior and distribution for pteroylglutamic acid and reduced folates: a revised hypothesis of the primary site of PteGlu metabolism in humans. J Nutr 135:619-23.
94. Yang HT, Lee M, Hong KS, et al. (2012). Efficacy of folic acid supplementation in cardiovascular disease prevention: an updated meta-analysis of randomized controlled trials. Eur J Intern Med 23: 745-54.
95. Zhao R, Matherly LH, Goldman ID. (2009). Membrane transporters and folate homeostasis: intestinal absorption and transport into systemic compartments and tissues. Expert Rev Mol Med 11:e4. doi: 10.1017/S1462399409000969.
96. Zhou YH, Tang JY, Wu MJ, et al. (2011). Effect of folic acid supplementation on cardiovascular outcomes: a systematic review and meta-analysis. PLoS One 6:e25142.
97. Zittoun J, Marquet J, Zittoun R. (1978). Effect of folate and cobalamin compounds on the deoxyuridine suppression test in vitamin B12 and folate deficiency. Blood 51:119-28.