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Possible biochemical mechanisms involved in beneficial and adverse effects of folates


Fortification of flour and bakery products with folic acid (FA) to reduce the number of neural tube defects as well, as anemia, is practiced in some countries. The purpose of our review is to discuss is folic acid supplement reasonably everyone?

It is well established, that folic acid has numerous significant beneficial effects. Folic acid prevents neural tube defects like spina bifida and anencephaly, it prevents development of macrocytic anemia. The ability of folic acid to decrease homocysteine level is associated with its protective influence on cardiovascular disease. Moreover, combination of high folate level with vitamin B12 deficiency may be associated with an increased risk of cognitive impairment and anemia. According to available information, folate has a dual effect on cancer, protecting against cancer initiation, but facilitating progression and growth of neoplastic cells and promote methastasis. However, relationship between folate supplementation and cancer, is, perhaps, one of the most controversial subjects in the field.

Whether increased circulating folic acid is a risk factor for certain pathologies, or it might have a beneficial effect is not clear at present. Scientific community does not have a true consensus view on whether mandatory fortification is true approach.


Alla Shaljyan

Yerevan State Medical University

Email: allashaljyan@mail.com

Armenia MD, PhD

Gayane Vardanyan

Yerevan State Medical University

Author for correspondence.
Email: gaya_ysmu@mail.ru

Armenia MD, ScD, prof.

Anahit Saharyan

Yerevan State Medical University

Email: asaharyan@yahoo.com

Armenia MD, PhD

Michael Aghajanov

Yerevan State Medical University

Email: magajanov@gmail.com

Armenia ScD, prof.

  1. Albert CM, Cook NR, Gaziano JM, et al. Effect of Folic Acid and B Vitamins on Risk of Cardiovascular Events and Total Mortality Among Women at High Risk for Cardiovascular Disease. JAMA. 2008;299(17):2027. doi: 10.1001/jama.299.17.2027.
  2. Andreeva VA, Touvier M, Kesse-Guyot E, et al. B Vitamin and/or omega-3 Fatty Acid Supplementation and Cancer: Ancillary Findings From the Supplementation With Folate, Vitamins B6 and B12, and/or Omega-3 Fatty Acids (SU.FOL.OM3) Randomized Trial. Arch. Intern. Med. 2012;172(7):540-547.
  3. Ashokkumar B, Mohhamed ZM, Vaziri ND, Said HM Effect of folate oversupplementation on folate uptake by human intestinal and renal ephithelial cells. Am. J. Clin. Nutr. 2007;86:159-166.
  4. Bailey LB, Gregory JF. Folate. Present Knowledge in Nutrition. International Life Sciences Institute. 2006;I:278-301.
  5. Banerjee D, Mayer-Kuckuk P, Capiaux G, et al. Novel aspects of resistance to drugs targeted to dihydrofolate reductase and thymidylate synthase. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 2002;1587(2-3):164-173. doi: 10.1016/s0925-4439(02)00079-0.
  6. Barry AS, FarrokhDehdashti, Mutch DG,et al. Evaluation of 111In-DTPA- folate as a receptor- targeted diagnostic agent for ovarian cancer: initial clinical results. J. Nucl. Med. 2003;44:700-707.
  7. Barua S, Kuizon S, Junaid MA. Folic acid supplementation in pregnancy and implications in health and disease. J Biomed Sci. 2014;21(1). doi: 10.1186/s12929-014-0077-z.
  8. Bernstein BW, Bamburg JR. ADF/Cofilin: a functional node in cell biology. Trends Cell Biol. 2010;20(4):187-195. doi: 10.1016/j.tcb.2010.01.001.
  9. Bjorklund NK, Gordon R. A hypothesis linking low folate intake to neural tube defects due to failure of post-translation methylations of the cytoskeleton. The International Journal of Developmental Biology. 2006;50(2-3):135-141. doi: 10.1387/ijdb.052102nb.
  10. Chanson A, Sayd T, Rock E, et al. Proteomic analysis reveals changes in the liver protein pattern of rats exposed to dietary folate deficiency. The Journal of nutrition. 2005;135:2524–2529.
  11. Chen C, Ke J, Zhou XE, et al. Structural basis for molecular recognition of folic acid by folate receptors. Nature. 2013;500(7463):486-489. doi: 10.1038/nature12327.
  12. Clarke R. B-vitamins and prevention of dementia. Proc Nutr Soc. 2008;67(01):75-81. doi: 10.1017/s0029665108006046.
  13. Cole BF, Baron JA, Sandler RS, et al. Folic Acid for the Prevention of Colorectal Adenomas. JAMA. 2007;297(21):2351. doi: 10.1001/jama.297.21.2351.
  14. Crott J, Liu Z, Keyes M, et al. Moderate folate depletion modulates the expression of selected genes involved in cell cycle, intracellular signaling and folate uptake in human colonic epithelial cell lines. J Nutr Biochem. 2008;19(5):328-335. doi: 10.1016/j.jnutbio.2007.05.003.
  15. Ebbing M. Cancer Incidence and Mortality After Treatment With Folic Acid and Vitamin B12. JAMA. 2009;302(19):2119. doi: 10.1001/jama.2009.1622.
  16. Figueiredo JC, Mott LA, Giovannucci E, et al. Folic acid and prevention of colorectal adenomas: A combined analysis of randomized clinical trials. Int J Cancer. 2011;129(1):192-203. doi: 10.1002/ijc.25872.
  17. Gao Y. A novel type of regulation of the vimentin intermediate filament cytoskeleton by a Golgi protein. Eur J Cell Biol. 2002;81(7):391-401. doi: 10.1078/0171-9335-00260.
  18. Gibson TM, Weinstein SJ, Pfeiffer RM, et al. Pre- and postfortification intake of folate and risk of colorectal cancer in a large prospective cohort study in the United States. Am J Clin Nutr. 2011;94(4):1053-1062. doi: 10.3945/ajcn.110.002659.
  19. Goldman ID, Chattopadhyay S, Zhao R, Moran R. The antifolates: evolution, new agents in the clinic, and how targeting delivery via specific membrane transporters is driving the development of a next generation of folate analogs. Curr. Opin. Investig. Drugs. 2010;11:1409–1423.
  20. Blom HJ, Smulders Y. Overview of homocysteine and folate metabolism. With special references to cardiovascular disease and neural tube defects. J Inherit Metab Dis. 2010;34(1):75-81. doi: 10.1007/s10545-010-9177-4.
  21. Herrmann W, Obeid R. The mandatory fortification of staple foods with folic acid: a current controversy in Germany. Deutsches Arzteblatt international. 2011;108:249–254.
  22. Hooshmand B, Solomon A, Kåreholt I, et al. Associations between serum homocysteine, holotranscobalamin, folate and cognition in the elderly: a longitudinal study. J Intern Med. 2012;271(2):204-212. doi: 10.1111/j.1365-2796.2011.02484.x.
  23. Huang T, Chen Y, Yang B, et al. Meta-analysis of B vitamin supplementation on plasma homocysteine, cardiovascular and all-cause mortality. Clin Nutr. 2012;31(4):448-454. doi: 10.1016/j.clnu.2011.01.003.
  24. Huang YC, Lee CM, Chen M, et al. Haplotypes, Loss of Heterozygosity, and Expression Levels of Glycine N-Methyltransferase in Prostate Cancer. Clin Cancer Res. 2007;13(5):1412-1420. doi: 10.1158/1078-0432.ccr-06-1551.
  25. Hubner RA, Houlston RS. Folate and colorectal cancer prevention. Br J Cancer. 2008;100(2):233-239. doi: 10.1038/sj.bjc.6604823.
  26. Johnson MA. If high folic acid aggravates vitamin B12 deficiency what should be done about it? Nutr. Rev. 2007;65(10):451-458.
  27. Kelemen LE. The role of folate receptor alpha in cancer development, progression and treatment: cause, consequence or innocent bystander? International journal of cancer Journal international du cancer. 2006;119:243–250.
  28. Kim YI. Folate: a magic bullet or a double edged sword for colorectal cancer prevention? Gut. 2006;55(10):1387-1389. doi: 10.1136/gut.2006.095463.
  29. Leamon CP, Reddy JA, Vlahov IR, et al. Preclinical Antitumor Activity of a Novel Folate-Targeted Dual Drug Conjugate. Mol Pharm. 2007;4(5):659-667. doi: 10.1021/mp070049c.
  30. Lee JE, Willett WC, Fuchs CS, et al. Folate intake and risk of colorectal cancer and adenoma: modification by time. Am J Clin Nutr. 2011;93(4):817-825. doi: 10.3945/ajcn.110.007781.
  31. Homocysteine Lowering with Folic Acid and B Vitamins in Vascular Disease. N Engl J Med. 2006;354(15):1567-1577. doi: 10.1056/NEJMoa060900.
  32. Lucock M, Yates Z. Folic acid fortification: a double-edged sword. Curr Opin Clin Nutr Metab Care. 2009;12(6):555-564. doi: 10.1097/MCO.0b013e32833192bc.
  33. Ly A, Lee H, Chen J, et al. Effect of Maternal and Postweaning Folic Acid Supplementation on Mammary Tumor Risk in the Offspring. Cancer Res. 2010;71(3):988-997. doi: 10.1158/0008-5472.can-10-2379.
  34. Mason JB. Unraveling the complex relationship between folate and cancer risk. Biofactors. 2011;37(4):253-260. doi: 10.1002/biof.174.
  35. Mason JB. Folate status: effects on carcinogenesis. In: Bailey LB, editor. Folate in Health and Disease. New York: Marcel Dekker, Inc. 1995;361–378.
  36. McKay JA, Williams EA, Mathers JC. Gender-specific modulation of tumorigenesis by folic acid supply in the Apc mouse during early neonatal life. Br J Nutr. 2007;99(03). doi: 10.1017/s0007114507819131.
  37. Ohrvik VE, Witthoft CM. Human Folate Bioavailability. Nutrients. 2011;3(12):475-490. doi: 10.3390/nu3040475.
  38. Oleinik NV, Krupenko NI, Krupenko SA. Cooperation between JNK1 and JNK2 in activation of p53 apoptotic pathway. Oncogene. 2007;26(51):7222-7230. doi: 10.1038/sj.onc.1210526.
  39. Oleinik NV, Krupenko NI, Krupenko SA. ALDH1L1 inhibits cell motility via dephosphorylation of cofilin by PP1 and PP2A. Oncogene. 2010;29(47):6233-6244. doi: 10.1038/onc.2010.356.
  40. Oser M, Condeelis J. The cofilin activity cycle in lamellipodia and invadopodia. J Cell Biochem. 2009;108(6):1252-1262. doi: 10.1002/jcb.22372.
  41. Refsum H, Nurk E, Smith AD. The Hordaland Homocystein Study: a community-based of homocysteine, its determinants, and association with disease. J. Nutr. 2006;136:1731S-1740S.
  42. Rycyna KJ, Bacich DJ, O’Keefe DS. Opposing Roles of Folate in Prostate Cancer. Urology. 2013;82(6):1197-1203. doi: 10.1016/j.urology.2013.07.012.
  43. Shen F, Ross JF, Wang X, Ratnam M. Identification of a novel folate receptor, a truncated receptor, and receptor type .beta. in hematopoietic cells: cDNA cloning, expression, immunoreactivity, and tissue specificity. Biochemistry. 1994;33(5):1209-1215. doi: 10.1021/bi00171a021.
  44. Shen F, Wang H, Zheng X, Ratnam M. Expression levels of functional folate receptors α and β are related to the number of N-glycosylated sites. Biochem J. 1997;327(3):759-764. doi: 10.1042/bj3270759.
  45. Shen F, Wu M, Ross JF, et al. Folate Receptor Type .gamma. Is Primarily a Secretory Protein Due to Lack of an Efficient Signal for Glycosylphosphatidylinositol Modification: Protein Characterization and Cell Type Specificity. Biochemistry. 1995;34(16):5660-5665. doi: 10.1021/bi00016a042.
  46. Sweeney MR, McPartlin J, Scott J. Folic acid fortification and public health: Report on threshold doses above which unmetabolised folic acid appear in serum. BMC Public Health. 2007;7(1). doi: 10.1186/1471-2458-7-41.
  47. Tomassetti A, Bottero F, Mazzi M, et al. Molecular requirements for attachment of the glycosylphosphatidylinositol anchor to the human alpha folate receptor. J Cell Biochem. 1999;72(1):111-118. doi: 10.1002/(sici)1097-4644(19990101)72:1<111::aid-jcb12>3.0.co;2-1.
  48. Tomaszewski JJ, Cummings JL, Parwani AV, et al. Increased cancer cell proliferation in prostate cancer patients with high levels of serum folate. The Prostate. 2011:n/a-n/a. doi: 10.1002/pros.21346.
  49. Troen AM, Mitchell B, Sorensen B, et al. Unmetabolized folic acid in plasma is associated with reduced natural killer cell cytotoxicity among postmenopausal women. J. Nutr. 2006; 136: 189–94.
  50. De Wals P, Tairou F, Van Allen MI, et al. Reduction in Neural-Tube Defects after Folic Acid Fortification in Canada. N Engl J Med. 2007;357(2):135-142. doi: 10.1056/NEJMoa067103.
  51. Whitehead AS, Gallagher P, Mills JL, et al. A generic defect in 5,10-methylentetrahydrofolate reductase in neural tube defects. J. Med. 1995; 88: 763-766.
  52. Winter-Vann AM, Kamen BA, Bergo MO, et al. Targeting Ras signaling through inhibition of carboxyl methylation: An unexpected property of methotrexate. Proceedings of the National Academy of Sciences. 2003;100(11):6529-6534. doi: 10.1073/pnas.1135239100.

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Copyright (c) 2016 Шалджян А.Л., Варданян Г.С., Саарян А.В., Агаджанов М.И.

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