Folate and Folic Acid Metabolism: A Significant Nutrient-Gene-Environment Interaction
Main Article Content
Abstract
Folate has an important metabolic role by providing one carbon units that are used for nucleotide biosynthesis and methylation reactions that are both vital for epigenetic control, genomic stability and the maintenance of health.
Important not only for its availability as an essential nutrient but folate also intertwines us firmly within the environment as part of an unexpected link between light and the genome.
Folate deficiency has been overcome by replacement with folic acid, taken as a supplement and/or through food fortification but is this solving one problem but risking others with the wider long-term implication of this manipulation in its potential to alter the human genome.
The mandatory folic acid food fortification public health policy and implementation needs to be re-examined and possibly debated in the public arena, particularly in view of the risk of altering the human genome. Have the public been adequately informed and are there implications for the whole vitamin and mineral supplement industry?
Article Details
How to Cite
SMITH, David John Mackay.
Folate and Folic Acid Metabolism: A Significant Nutrient-Gene-Environment Interaction.
Medical Research Archives, [S.l.], v. 11, n. 5, may 2023.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/3824>. Date accessed: 19 apr. 2024.
doi: https://doi.org/10.18103/mra.v11i5.3824.
Section
Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Shane, B., In: Baile, L. (Ed), Folate chemistry and metabolism. In Folate in health and disease. 1995. Marcel Dekker. N.Y. 174: 1-22.
2. Bailey, L., Gregory III, J. Folate metabolism and requirements. 1999. J Nutr. 129:779-782.
3. Kim, Y. MTHFR polymorphism, folate and cancer risk: a paradigm of gene-nutrition interaction in carcinogenesis. 2000. Nutr Review; 58: 205-217.
4. Hubner, R., Houston, R. Folate and colorectal cancer prevention. 2009. Br J Cancer; 100: 233-239.
5. Choi, S-W., Mason, J. Folate status: effects on pathways of colorectal carcinogenesis. 2002. J Nutr; 132 2413S-2418S.
6. Blout, B., Mack, M., Wehr, C., et al. Folate deficiency causes uracil misincorporation into human DNA and chromosome breakages; implications for cancer and neuronal damage.1997. Pro Natl Acad Sci USA; 94: 3290-3295.
7. Kelly, P., McPartlin, J., Goggins, M., et al. Unmetabolised folic acid in serum: acute studies in subjects consuming fortified foods and supplements. 1997. Am J Clin Nutr; 65:1790-1795.
8. Roger, L., Pfeiffer, C., Bailey, L., et al. A dual-label stable-isotope protocol is suitable for determination of folate bioavaiability: evaluation of urinary excretion and plasma folate kinetics of intravenous and oral doses of [13C5] and [2H2] folic acid. 1997. J nutr; 127: 2321-2327.
9. Gregory, J. Case study: folate bioavailability. 2001. J Nutr; 131: 1376S-1382S.
10. Steinberg, S., Campbell, C., Hillman, R. Kinetics of the normal folate enterohepatic cycle. !979. J Clin invest; 64: 83-88.
11. Melikian, V., Paton, A., Leeming, R., et al. Site of reduction and methylation of folic acid in man. 1971. Lancet; 2: 955-957.
12. Shane, B. Folylpolyglutamate synthesis and role in the regulation of one-carbon metabolism. 1989. Vitamins & hormones; 45:263-335.
13. Trippett, T., Garcia, S., Monova, K., et al. Localisation of a human reduced folate carrier protein in the mitochondrial as well as cell membrane of leukaemia cells. 2001. Cancer Res; 61: 1941-1947.
14. Tibbetts, A. Appling, D. Compartmentalisation of mammalian folate-related one-carbon metabolism.2010. Annu Res Nutr; 30: 57-81.
15. Frosst, P., et al. Identification of a candidate genetic risk factor for vascular disease: a common mutation at the methylenetetrahydrofolate reductase locus. 1995. Nat Genet; 10: 111-113.
16. Brattstrom, L., et al. common methylenetetrahydrofolate reductase gene mutation leads to hyperhomocysteinemia but not to vascular disease. 1998. Circulation; 98: 2520-2526.
17. Botto, L., Yang, Q. 5,10-methylenetetrahydorfolate reductase gene variants and congenital abnormalities: a HuGE review. 2000. Am J Epideiomiol; 151: 862-877.
18. Malinow, M., et al. The effects of folic acid supplementation on total homocysteinemia are modified by multivitamin use and methylenetetrahydrofolate reductase genotypes. 1997. Arterioscler. Thromb vasc Biol; 17: 1157-1162.
19. Nelen, W., et al. methylenetetrahydrofolate reductase polymorphism affects the change in homocysteine and folate concentrations resulting from low dose folic acid supplementation in women with unexplained recurrent miscarriages. 1998. J Nutr;128:1336-1341.
20. Hustad, B., et al. Riboflavin as a determinant of plasma total homocysteine: effect modified by methylenetetrahydrofolate reductase C677T polymorphism. 2000. Clin Chem ; 46:1065-1071.
21. Guenther, B., et al. The structure and properties of methylenetetrahydrofolate reductase from E.coli suggests how folate ameliorates human hyperhomocysteinemia. 1999. Nat Struct Biol; 6: 355-365.
22. D’Angelo, A., et al. The role of vitamin B12 in fasting hyperhomocysteinemia and its interaction with the homozygous C677T mutation of the MTHF reductase gene: A case control study of patients with early onset thrombotic events. 2000. Thromb Haemostat; 13: 563-570.
23. Guttormsen, A., et al. Determinants and vitamin responsiveness of intermediate hyperhomocysteinemia (>40µmol/L2): the Hordaland homocysteine study. 2000. J Clin Invest; 98: 2174-2183.
24. Ueland, P., et al. Determinants of plasma homocysteine. 2000. In homocysteine and vascular disease (Robinson, K., ed): 59-84, Kluwer Academic publishers.
25. Stern, L., et al. Genomic DNA hypomethylation, a characteristic of most cancers, is present in peripheral leukocytes of individuals who are homozygous for the C677T polymorphism in the methylenetetrahydrofolate reductase gene. 2000. Cancer Epidemiol Biomarker Prev; 9: 849-853.
26. Kim, Y-I. Folate and carcinogenesis: evidence, mechanisms and implications. 1999. J Nutr: Biochem; 10:66-88.
27. Levine, A., et al. The methylenetetra-hydrofolate reductase C677->T polymorphism and distal colorectal adenoma risk. 2000. Cancer Epidemiol Biomarker Prev; 9: 657-663.
28. Slattery, M., et al. methylenetetrahydrofolate reductase, diet and risk of colon cancer. Cancer Epidemiol Biomarker Prev; 8: 513-518.
29. Ulrich, C., et al. Colorectal adenoma and the C677T-MTHfR polymorphism: evidence for gene-environment interaction. 1999. Cancer Epidemiol Biomarker Prev; 8: 659-668.
30. Chen, J., et al. MTHFR polymorphism, methyl-replete diets and the risk of colorectal carcinoma and adenoma among U.S. men and women: an example of gene-environment interactions in colorectal tumorigenesis. 1999. J Nutr; 129:560S-564S.
31. Ulvik, A., et al. Smoking, folate and methylenetetrahydrofolate reductase status as interactive determinants of adenomatous and hyperplastic polyps of the colorectum. Am J Med Genetics (in press).
32. Aspirin-folate prevention of large bowel polyps. Clinical trials.gov. NCT00272324.
33. Ureland, P., Hustad, S., Schneede, J., et al. Biological and clinical implications of the MTHFR C677T polymorphism. 2001. Trends in Pharm Sci; 22(4):195-201.
34. Jablonski, N., Chaplin, G. Colloquium paper: human skin pigmentation as an adaption to UV radiation 2010. Proc Natl Acad Sci USA; 107:8962-8969.
35. Jablonski, N., Chaplin, G. The evolution of human skin colouration. 2000. J Hum Evol; 39:57-106.
36. Jablonski, N. The evolution of human skin and skin colour. 2004. Annu Rev Anthropol; 33: 585-623.
37. Lao, O., de Gruijter, J., van Duijin, K., et al. Signature of positive selection in genes associated with human skin pigmentation as revealed from analysis of single nucleotide polymorphism. 2007. Ann Hum Genet; 71: 354-369.
38. Rees, J. The genetics of sun sensitivity in humans. 2004. Am J Hum Genet; 75: 739-751.
39. Graf, J., Hodgson, R., Van Daal, A. Single nucleotide polymorphism in the MATP gene are associated with normal human pigmentation variation. 2005. Hum Mutat;25: 278-284.
40. Tornaletti, S., Hanawalt, P. Effect of DNA lesions on transcription elongation. 1999. Biochimie; 81:139-146.
41. Ludock, M. Folic acid: nutritional biochemistry, molecular biology and role in disese processes. 2000. Mol Genet Metab; 71: 121-138.
42. Fox, J., Shin, W., Caudill, M., et al. A UV-responsive internal ribosome entry site enhances serine hydroxymethyl transferase 1 expression for DNA damage repair. 2009. J Biol Chem; 284: 31097-31108.
43. Ludock, M., Yates, Z., Glandville, T., et al. A critical role of B-vitamin nutrition in human development and evolutionary biology. 2003 Nutr Res; 23: 1463-1475.
44. Juzeniene, A., Thu Tam, T., Iani, V., et al. methyltetrahydrofolate can be photodregraded by endogenous photosensitisers. 2009. Free Radic Biol Med; 47: 1199-1204.
45. Lowell, W., Davis, G. The light of life: evidence that the sun modulates human life-span. 2008. Med Hypotheses; 70: 501-507.
46. Gavrilov, L, Gavrilova, N. Season of birth and human longevity. 1999. J Anti-aging Med; 2: 365-366.
47. Marzullo, G., Fraser, F. Similar rhythms of seasonal conception in neural tube defects and schizophrenia: a hypothesis of oxidative stress and the photoperiod. 2005. Birth Defects Res; 73: 1-5.
48. Foster, R., Roenreberg, T. Human responses to the geo-physical daily, annual and lunar cycles. 2008. Curr Biol; 18: R784-794.
49. Ludock,M., Glanville, t., Ovadia, L., et al. Photoperiod at conception predicts C677T-MTHFR genotype: a novel gene-environment interaction. 2000. Am J Hum Biol; 22: 484-489.
50. Ludock, M., Yates, Z. Folic acid fortification: a double-edged sword. 2009. Curr Opin Clin Nutr Metab Care; 12: 555-564.
51. Gluckman, P., Hanson, M., Cooper, C., et al. Effect of in utero and early-life conditions on adult health and disease. 2008. N Engl J Med;359-61-73.
52. Bailey, S., Ayling, J. The extent of slow and variable activity of dihydrofolate reductase in human liver and its implications for high folic acid intake. 2009. Proc Natl Acad Sci USA; 106: 15424-15429.
53. Pfeiffer, C., Caudill, S., Gunter, E., et al. Biochemical indicators of B vitamin status in a US population after folic acid fortification: results from the national health and nutrition examination survey 1999-2000. 2005. Am J Clin Nutr; 82: 442-4450.
54. Reynolds, E. Vitamin B12, floic acid and the nervous system. 2006. Lancet Neurol; 5: 949-960.
55. Morris, M., Jacques, P., Rosenberg, I., et al. Folate and vitamin B12 status in relation to anaemia, macrocytosis and cognitive impairment among older Americans in the age of folic acid fortification. 20007; 85:193-200.
56. Troan, A., Mitchell, B., Sorensen, B., et al. Evidence of unmetabolised folic acid in plasma is associated with decrease natural killer cell cytotoxicity among post-menopausal women. 2006. J Nutr; 136:189-194.
57. Haggarty, P., McCallum, H., McBain, H., et al. Effect of B vitamins and genetics on success of in-vitro fertilisation: prospective cohort study. 2006. Lancet; 367: 1513-1519.
58. Reyes-Engel, A., Munoz, E., Gaitan, m., et al. Implications on human fertility of the 677C->T and 1298A->C polymorphism of the MTHFR gene: consequences of possible genetic selection. 2002. Mol Hum Reprod; 8: 952-957.
2. Bailey, L., Gregory III, J. Folate metabolism and requirements. 1999. J Nutr. 129:779-782.
3. Kim, Y. MTHFR polymorphism, folate and cancer risk: a paradigm of gene-nutrition interaction in carcinogenesis. 2000. Nutr Review; 58: 205-217.
4. Hubner, R., Houston, R. Folate and colorectal cancer prevention. 2009. Br J Cancer; 100: 233-239.
5. Choi, S-W., Mason, J. Folate status: effects on pathways of colorectal carcinogenesis. 2002. J Nutr; 132 2413S-2418S.
6. Blout, B., Mack, M., Wehr, C., et al. Folate deficiency causes uracil misincorporation into human DNA and chromosome breakages; implications for cancer and neuronal damage.1997. Pro Natl Acad Sci USA; 94: 3290-3295.
7. Kelly, P., McPartlin, J., Goggins, M., et al. Unmetabolised folic acid in serum: acute studies in subjects consuming fortified foods and supplements. 1997. Am J Clin Nutr; 65:1790-1795.
8. Roger, L., Pfeiffer, C., Bailey, L., et al. A dual-label stable-isotope protocol is suitable for determination of folate bioavaiability: evaluation of urinary excretion and plasma folate kinetics of intravenous and oral doses of [13C5] and [2H2] folic acid. 1997. J nutr; 127: 2321-2327.
9. Gregory, J. Case study: folate bioavailability. 2001. J Nutr; 131: 1376S-1382S.
10. Steinberg, S., Campbell, C., Hillman, R. Kinetics of the normal folate enterohepatic cycle. !979. J Clin invest; 64: 83-88.
11. Melikian, V., Paton, A., Leeming, R., et al. Site of reduction and methylation of folic acid in man. 1971. Lancet; 2: 955-957.
12. Shane, B. Folylpolyglutamate synthesis and role in the regulation of one-carbon metabolism. 1989. Vitamins & hormones; 45:263-335.
13. Trippett, T., Garcia, S., Monova, K., et al. Localisation of a human reduced folate carrier protein in the mitochondrial as well as cell membrane of leukaemia cells. 2001. Cancer Res; 61: 1941-1947.
14. Tibbetts, A. Appling, D. Compartmentalisation of mammalian folate-related one-carbon metabolism.2010. Annu Res Nutr; 30: 57-81.
15. Frosst, P., et al. Identification of a candidate genetic risk factor for vascular disease: a common mutation at the methylenetetrahydrofolate reductase locus. 1995. Nat Genet; 10: 111-113.
16. Brattstrom, L., et al. common methylenetetrahydrofolate reductase gene mutation leads to hyperhomocysteinemia but not to vascular disease. 1998. Circulation; 98: 2520-2526.
17. Botto, L., Yang, Q. 5,10-methylenetetrahydorfolate reductase gene variants and congenital abnormalities: a HuGE review. 2000. Am J Epideiomiol; 151: 862-877.
18. Malinow, M., et al. The effects of folic acid supplementation on total homocysteinemia are modified by multivitamin use and methylenetetrahydrofolate reductase genotypes. 1997. Arterioscler. Thromb vasc Biol; 17: 1157-1162.
19. Nelen, W., et al. methylenetetrahydrofolate reductase polymorphism affects the change in homocysteine and folate concentrations resulting from low dose folic acid supplementation in women with unexplained recurrent miscarriages. 1998. J Nutr;128:1336-1341.
20. Hustad, B., et al. Riboflavin as a determinant of plasma total homocysteine: effect modified by methylenetetrahydrofolate reductase C677T polymorphism. 2000. Clin Chem ; 46:1065-1071.
21. Guenther, B., et al. The structure and properties of methylenetetrahydrofolate reductase from E.coli suggests how folate ameliorates human hyperhomocysteinemia. 1999. Nat Struct Biol; 6: 355-365.
22. D’Angelo, A., et al. The role of vitamin B12 in fasting hyperhomocysteinemia and its interaction with the homozygous C677T mutation of the MTHF reductase gene: A case control study of patients with early onset thrombotic events. 2000. Thromb Haemostat; 13: 563-570.
23. Guttormsen, A., et al. Determinants and vitamin responsiveness of intermediate hyperhomocysteinemia (>40µmol/L2): the Hordaland homocysteine study. 2000. J Clin Invest; 98: 2174-2183.
24. Ueland, P., et al. Determinants of plasma homocysteine. 2000. In homocysteine and vascular disease (Robinson, K., ed): 59-84, Kluwer Academic publishers.
25. Stern, L., et al. Genomic DNA hypomethylation, a characteristic of most cancers, is present in peripheral leukocytes of individuals who are homozygous for the C677T polymorphism in the methylenetetrahydrofolate reductase gene. 2000. Cancer Epidemiol Biomarker Prev; 9: 849-853.
26. Kim, Y-I. Folate and carcinogenesis: evidence, mechanisms and implications. 1999. J Nutr: Biochem; 10:66-88.
27. Levine, A., et al. The methylenetetra-hydrofolate reductase C677->T polymorphism and distal colorectal adenoma risk. 2000. Cancer Epidemiol Biomarker Prev; 9: 657-663.
28. Slattery, M., et al. methylenetetrahydrofolate reductase, diet and risk of colon cancer. Cancer Epidemiol Biomarker Prev; 8: 513-518.
29. Ulrich, C., et al. Colorectal adenoma and the C677T-MTHfR polymorphism: evidence for gene-environment interaction. 1999. Cancer Epidemiol Biomarker Prev; 8: 659-668.
30. Chen, J., et al. MTHFR polymorphism, methyl-replete diets and the risk of colorectal carcinoma and adenoma among U.S. men and women: an example of gene-environment interactions in colorectal tumorigenesis. 1999. J Nutr; 129:560S-564S.
31. Ulvik, A., et al. Smoking, folate and methylenetetrahydrofolate reductase status as interactive determinants of adenomatous and hyperplastic polyps of the colorectum. Am J Med Genetics (in press).
32. Aspirin-folate prevention of large bowel polyps. Clinical trials.gov. NCT00272324.
33. Ureland, P., Hustad, S., Schneede, J., et al. Biological and clinical implications of the MTHFR C677T polymorphism. 2001. Trends in Pharm Sci; 22(4):195-201.
34. Jablonski, N., Chaplin, G. Colloquium paper: human skin pigmentation as an adaption to UV radiation 2010. Proc Natl Acad Sci USA; 107:8962-8969.
35. Jablonski, N., Chaplin, G. The evolution of human skin colouration. 2000. J Hum Evol; 39:57-106.
36. Jablonski, N. The evolution of human skin and skin colour. 2004. Annu Rev Anthropol; 33: 585-623.
37. Lao, O., de Gruijter, J., van Duijin, K., et al. Signature of positive selection in genes associated with human skin pigmentation as revealed from analysis of single nucleotide polymorphism. 2007. Ann Hum Genet; 71: 354-369.
38. Rees, J. The genetics of sun sensitivity in humans. 2004. Am J Hum Genet; 75: 739-751.
39. Graf, J., Hodgson, R., Van Daal, A. Single nucleotide polymorphism in the MATP gene are associated with normal human pigmentation variation. 2005. Hum Mutat;25: 278-284.
40. Tornaletti, S., Hanawalt, P. Effect of DNA lesions on transcription elongation. 1999. Biochimie; 81:139-146.
41. Ludock, M. Folic acid: nutritional biochemistry, molecular biology and role in disese processes. 2000. Mol Genet Metab; 71: 121-138.
42. Fox, J., Shin, W., Caudill, M., et al. A UV-responsive internal ribosome entry site enhances serine hydroxymethyl transferase 1 expression for DNA damage repair. 2009. J Biol Chem; 284: 31097-31108.
43. Ludock, M., Yates, Z., Glandville, T., et al. A critical role of B-vitamin nutrition in human development and evolutionary biology. 2003 Nutr Res; 23: 1463-1475.
44. Juzeniene, A., Thu Tam, T., Iani, V., et al. methyltetrahydrofolate can be photodregraded by endogenous photosensitisers. 2009. Free Radic Biol Med; 47: 1199-1204.
45. Lowell, W., Davis, G. The light of life: evidence that the sun modulates human life-span. 2008. Med Hypotheses; 70: 501-507.
46. Gavrilov, L, Gavrilova, N. Season of birth and human longevity. 1999. J Anti-aging Med; 2: 365-366.
47. Marzullo, G., Fraser, F. Similar rhythms of seasonal conception in neural tube defects and schizophrenia: a hypothesis of oxidative stress and the photoperiod. 2005. Birth Defects Res; 73: 1-5.
48. Foster, R., Roenreberg, T. Human responses to the geo-physical daily, annual and lunar cycles. 2008. Curr Biol; 18: R784-794.
49. Ludock,M., Glanville, t., Ovadia, L., et al. Photoperiod at conception predicts C677T-MTHFR genotype: a novel gene-environment interaction. 2000. Am J Hum Biol; 22: 484-489.
50. Ludock, M., Yates, Z. Folic acid fortification: a double-edged sword. 2009. Curr Opin Clin Nutr Metab Care; 12: 555-564.
51. Gluckman, P., Hanson, M., Cooper, C., et al. Effect of in utero and early-life conditions on adult health and disease. 2008. N Engl J Med;359-61-73.
52. Bailey, S., Ayling, J. The extent of slow and variable activity of dihydrofolate reductase in human liver and its implications for high folic acid intake. 2009. Proc Natl Acad Sci USA; 106: 15424-15429.
53. Pfeiffer, C., Caudill, S., Gunter, E., et al. Biochemical indicators of B vitamin status in a US population after folic acid fortification: results from the national health and nutrition examination survey 1999-2000. 2005. Am J Clin Nutr; 82: 442-4450.
54. Reynolds, E. Vitamin B12, floic acid and the nervous system. 2006. Lancet Neurol; 5: 949-960.
55. Morris, M., Jacques, P., Rosenberg, I., et al. Folate and vitamin B12 status in relation to anaemia, macrocytosis and cognitive impairment among older Americans in the age of folic acid fortification. 20007; 85:193-200.
56. Troan, A., Mitchell, B., Sorensen, B., et al. Evidence of unmetabolised folic acid in plasma is associated with decrease natural killer cell cytotoxicity among post-menopausal women. 2006. J Nutr; 136:189-194.
57. Haggarty, P., McCallum, H., McBain, H., et al. Effect of B vitamins and genetics on success of in-vitro fertilisation: prospective cohort study. 2006. Lancet; 367: 1513-1519.
58. Reyes-Engel, A., Munoz, E., Gaitan, m., et al. Implications on human fertility of the 677C->T and 1298A->C polymorphism of the MTHFR gene: consequences of possible genetic selection. 2002. Mol Hum Reprod; 8: 952-957.