The Journal of Nutritional Biochemistry
Volume 16, Issue 8 , Pages 467-478 , August 2005

Uracil misincorporation into DNA of leukocytes of young women with positive folate balance depends on plasma vitamin B12 concentrations and methylenetetrahydrofolate reductase polymorphisms. A pilot study

  • Maria Kapiszewska

      Affiliations

    • Department of General Biochemistry, Faculty of Biotechnology, Jagiellonian University, Krakow, 30-387 Poland
    • Corresponding Author InformationCorresponding author.
  • ,
  • Malgorzata Kalemba

      Affiliations

    • Department of General Biochemistry, Faculty of Biotechnology, Jagiellonian University, Krakow, 30-387 Poland
  • ,
  • Urszula Wojciech

      Affiliations

    • Department of General Biochemistry, Faculty of Biotechnology, Jagiellonian University, Krakow, 30-387 Poland
  • ,
  • Tomasz Milewicz

      Affiliations

    • Collegium Medicum, Jagiellonian University, Krakow, 30-387 Poland

Received 5 June 2004 ,Revised 4 October 2004 ,Accepted 5 January 2005.

References 

  1. Hu FB, Willett WC. Optimal diets for prevention of coronary heart disease. JAMA. 2002;288:2569–2578
  2. West SG. Effect of diet on vascular reactivity: an emerging marker for vascular risk. Curr Atheroscler Rep. 2001;3:446–455
  3. Ward M. Homocysteine, folate, and cardiovascular disease. Int J Vitam Nutr Res. 2001;71:173–178
  4. Finglas PM, Wright AJ, Wolfe CA, Hart DJ, Wright DM, Dainty JR. Is there more to folates than neural-tube defects?. Proc Nutr Soc. 2003;62:591–598
  5. Kim YI. Role of folate in colon cancer development and progression. J Nutr. 2003;133:3731S–3739S
  6. Sharp L, Little J, Schofield AC, Pavlidou E, Cotton SC, Miedzybrodzka Z, et al. Folate and breast cancer: the role of polymorphisms in methylenetetrahydrofolate reductase (MTHFR). Cancer Lett. 2002;181:65–71
  7. Prinz-Langenohl R, Fohr I, Pietrzik K. Beneficial role for folate in the prevention of colorectal and breast cancer. Eur J Nutr. 2001;40:98–105
  8. Lucock M. Folic acid: nutritional biochemistry, molecular biology, and role in disease processes. Mol Genet Metab. 2000;71:121–138
  9. Duthie SJ, Narayanan S, Brand GM, Grant G. DNA stability and genomic methylation status in colonocytes isolated from methyl-donor-deficient rats. Eur J Nutr. 2000;39:106–111
  10. Duthie SJ, Narayanan S, Brand GM, Pirie L, Grant G. Impact of folate deficiency on DNA stability. J Nutr. 2002;132:2444S–2449S
  11. Fenech M. Biomarkers of genetic damage for cancer epidemiology. Toxicology. 2002;181–182:411–416
  12. Fenech M, Crott JW. Micronuclei, nucleoplasmic bridges and nuclear buds induced in folic acid deficient human lymphocytes—evidence for breakage–fusion–bridge cycles in the cytokinesis-block micronucleus assay. Mutat Res. 2002;504:131–136
  13. Blount BC, Mack MM, Wehr CM, MacGregor JT, Hiatt RA, Wang G, et al. Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: implications for cancer and neuronal damage. Proc Natl Acad Sci U S A. 1997;94:3290–3295
  14. Blount BC, Ames BN. DNA damage in folate deficiency. Baillieres Clin Haematol. 1995;8:461–478
  15. Scott JM. Folate and vitamin B12. Proc Nutr Soc. 1999;58:441–448
  16. Molloy AM, Daly S, Mills JL, Kirke PN, Whitehead AS, Ramsbottom D, et al. Thermolabile variant of 5,10-methylenetetrahydrofolate reductase associated with low red-cell folates: implications for folate intake recommendations. Lancet. 1997;349:1591–1593
  17. Weisberg I, Tran P, Christensen B, Sibani S, Rozen R. A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity. Mol Genet Metab. 1998;64:169–172
  18. Tice RR, Agurell E, Anderson D, Burlinson B, Hartmann A, Kobayashi H, et al. Single cell gel/comet assay: guidelines for in vitro and in vivo genetic toxicology testing. Environ Mol Mutagen. 2000;35:206–221
  19. Abu-Amero KK, Wyngaard CA, Dzimiri N. Prevalence and role of methylenetetrahydrofolate reductase 677 C→T and 1298 A→C polymorphisms in coronary artery disease in Arabs. Arch Pathol Lab Med. 2003;127:1349–1352
  20. Singh NP, Stephens RE. Microgel electrophoresis: sensitivity, mechanisms, and DNA electrostretching. Mutat Res. 1997;383:167–175
  21. Collins AR, Dusinska M. Oxidation of cellular DNA measured with the comet assay. Methods Mol Biol. 2002;186:147–159
  22. Duthie SJ, Grant G, Narayanan S. Increased uracil misincorporation in lymphocytes from folate-deficient rats. Br J Cancer. 2000;83:1532–1537
  23. Duthie SJ, Johnson W, Dobson VL. The effect of dietary flavonoids on DNA damage (strand breaks and oxidised pyrimidines) and growth in human cells. Mutat Res. 1997;390:141–151
  24. Duthie SJ, McMillan P. Uracil misincorporation in human DNA detected using single cell gel electrophoresis. Carcinogenesis. 1997;18:1709–1714
  25. Duthie SJ, Hawdon A. DNA instability (strand breakage, uracil misincorporation, and defective repair) is increased by folic acid depletion in human lymphocytes in vitro. FASEB J. 1998;12:1491–1497
  26. Palyvoda O, Polanska J, Wygoda A, Rzeszowska-Wolny J. DNA damage and repair in lymphocytes of normal individuals and cancer patients: studies by the comet assay and micronucleus tests. Acta Biochim Pol. 2003;50:181–190
  27. Collins AR, Harrington V, Drew J, Melvin R. Nutritional modulation of DNA repair in a human intervention study. Carcinogenesis. 2003;24:511–515
  28. Icke GC, Dennis M, Sjollema S, Nicol DJ, Eikelboom JW. Red cell N5-methyltetrahydrofolate concentrations and C677T methylenetetrahydrofolate reductase genotype in patients with stroke. J Clin Pathol. 2004;57:54–57
  29. Quere I, Perneger TV, Zittoun J, Bellet H, Gris JC, Daures JP, et al. Red blood cell methylfolate and plasma homocysteine as risk factors for venous thromboembolism: a matched case-control study. Lancet. 2002;359:747–752
  30. Rogalska-Niedzwiedz M, Chabros E, Chwojnowska Z, Wajszczyk B, Charzewska J, Ziemlanski S. The study of folate consumption in a group of women at childbearing age. Zyw Czlow Metab. 2000;XXVII:172–183
  31. Finnell RH, Gould A, Spiegelstein O. Pathobiology and genetics of neural tube defects. Epilepsia. 2003;44(Suppl 3):14–23
  32. Gefrides LA, Bennett GD, Finnell RH. Effects of folate supplementation on the risk of spontaneous and induced neural tube defects in Splotch mice. Teratology. 2002;65:63–69
  33. Shaw GM, Lammer EJ, Zhu H, Baker MW, Neri E, Finnell RH. Maternal periconceptional vitamin use, genetic variation of infant reduced folate carrier (A80G), and risk of spina bifida. Am J Med Genet. 2002;108:1–6
  34. Cortese C, Motti C. MTHFR gene polymorphism, homocysteine and cardiovascular disease. Public Health Nutr. 2001;4:493–497
  35. Jee SH, Beaty TH, Suh I, Yoon Y, Appel LJ. The methylenetetrahydrofolate reductase gene is associated with increased cardiovascular risk in Japan, but not in other populations. Atherosclerosis. 2000;153:161–168
  36. Giovannucci E. Epidemiologic studies of folate and colorectal neoplasia: a review. J Nutr. 2002;132:2350S–2355S
  37. Rock CL, Lampe JW, Patterson RE. Nutrition, genetics, and risks of cancer. Annu Rev Public Health. 2000;21:47–64
  38. Brunaud L, Alberto JM, Ayav A, Gerard P, Namour F, Antunes L, et al. Effects of vitamin B12 and folate deficiencies on DNA methylation and carcinogenesis in rat liver. Clin Chem Lab Med. 2003;41:1012–1019
  39. Milner JA, McDonald SS, Anderson DE, Greenwald P. Molecular targets for nutrients involved with cancer prevention. Nutr Cancer. 2001;41:1–16
  40. Jennings E. Folic acid as a cancer-preventing agent. Med Hypotheses. 1995;45:297–303
  41. Miao XP, Lin DX. Folate and cancer. Ai Zheng. 2003;22:668–671
  42. Yates Z, Lucock M. Interaction between common folate polymorphisms and B-vitamin nutritional status modulates homocysteine and risk for a thrombotic event. Mol Genet Metab. 2003;79:201–213
  43. MacGregor JT. Dietary factors affecting spontaneous chromosomal damage in man. Prog Clin Biol Res. 1990;347:139–153
  44. Chango A, Potier De Courcy G, Boisson F, Guilland JC, Barbe F, Perrin MO, et al. 5,10-Methylenetetrahydrofolate reductase common mutations, folate status and plasma homocysteine in healthy French adults of the Supplementation en Vitamines et Mineraux Antioxydants (SUVI.MAX) cohort. Br J Nutr. 2000;84:891–896
  45. D'Angelo A, Coppola A, Madonna P, Fermo I, Pagano A, Mazzola G, et al. The role of vitamin B12 in fasting hyperhomocysteinemia and its interaction with the homozygous C677T mutation of the methylenetetrahydrofolate reductase (MTHFR) gene. A case-control study of patients with early-onset thrombotic events. Thromb Haemost. 2000;83:563–570
  46. de Bree A, van Dusseldorp M, Brouwer IA, van het Hof KH, Steegers-Theunissen RP. Folate intake in Europe: recommended, actual and desired intake. Eur J Clin Nutr. 1997;51:643–660
  47. Fenech M. The role of folic acid and vitamin B12 in genomic stability of human cells. Mutat Res. 2001;475:57–67
  48. Brouwer IA, van Dusseldorp M, West CE, Meyboom S, Thomas CM, Duran M, et al. Dietary folate from vegetables and citrus fruit decreases plasma homocysteine concentrations in humans in a dietary controlled trial. J Nutr. 1999;129:1135–1139
  49. Hustad S, Ueland PM, Vollset SE, Zhang Y, Bjorke-Monsen AL, Schneede J. Riboflavin as a determinant of plasma total homocysteine: effect modification by the methylenetetrahydrofolate reductase C677T polymorphism. Clin Chem. 2000;46:1065–1071
  50. Fenech MF, Dreosti IE, Rinaldi JR. Folate, vitamin B12, homocysteine status and chromosome damage rate in lymphocytes of older men. Carcinogenesis. 1997;18:1329–1336
  51. Fenech M, Aitken C, Rinaldi J. Folate, vitamin B12, homocysteine status and DNA damage in young Australian adults. Carcinogenesis. 1998;19:1163–1171
  52. Bailey LB, Gregory JF. Polymorphisms of methylenetetrahydrofolate reductase and other enzymes: metabolic significance, risks and impact on folate requirement. J Nutr. 1999;129:919–922
  53. Cravo ML, Albuquerque CM, Salazar de Sousa L, Gloria LM, Chaves P, Dias Pereira A, et al. Microsatellite instability in non-neoplastic mucosa of patients with ulcerative colitis: effect of folate supplementation. Am J Gastroenterol. 1998;93:2060–2064
  54. Fowler B. Genetic defects of folate and cobalamin metabolism. Eur J Pediatr. 1998;157(Suppl 2):S60–S66
  55. Fenech M. Recommended dietary allowances (RDAs) for genomic stability. Mutat Res. 2001;480–481:51–54
  56. Zijno A, Andreoli C, Leopardi P, Marcon F, Rossi S, Caiola S, et al. Folate status, metabolic genotype, and biomarkers of genotoxicity in healthy subjects. Carcinogenesis. 2003;24:1097–1103
  57. Fenech M. Micronutrients and genomic stability: a new paradigm for recommended dietary allowances (RDAs). Food Chem Toxicol. 2002;40:1113–1117
  58. Ames BN. Micronutrient deficiencies. A major cause of DNA damage. Ann N Y Acad Sci. 1999;889:87–106
  59. Ames BN. Micronutrients prevent cancer and delay aging. Toxicol Lett. 1998;102–103:5–18
  60. Molloy AM. Folate bioavailability and health. Int J Vitam Nutr Res. 2002;72:46–52
  61. Tomkins A. Nutrition and maternal morbidity and mortality. Br J Nutr. 2001;85(Suppl 2):S93–S99
  62. Refsum H. Folate, vitamin B12 and homocysteine in relation to birth defects and pregnancy outcome. Br J Nutr. 2001;85(Suppl 2):S109–S113
  63. Lucock M, Daskalakis I, Hinkins M, Yates Z. An examination of polymorphic genes and folate metabolism in mothers affected by a spina bifida pregnancy. Mol Genet Metab. 2001;73:322–332
  64. Erkkola M, Karppinen M, Knip M, Virtanen S. Nutrition during pregnancy—do recommendations and practice meet?. Duodecim. 2001;117:149–155
  65. Blom HJ. Mutated 5,10-methylenetetrahydrofolate reductase and moderate hyperhomocysteinaemia. Eur J Pediatr. 1998;157(Suppl 2):S131–S134
  66. Botto LD, Yang Q. 5,10-Methylenetetrahydrofolate reductase gene variants and congenital anomalies: a HuGE review. Am J Epidemiol. 2000;151:862–877
  67. Gudnason V, Stansbie D, Scott J, Bowron A, Nicaud V, Humphries S. C677T (thermolabile alanine/valine) polymorphism in methylenetetrahydrofolate reductase (MTHFR): its frequency and impact on plasma homocysteine concentration in different European populations. EARS group. Atherosclerosis. 1998;136:347–354
  68. Abbate R, Sardi I, Pepe G, Marcucci R, Brunelli T, Prisco D, et al. The high prevalence of thermolabile 5-10 methylenetetrahydrofolate reductase (MTHFR) in Italians is not associated to an increased risk for coronary artery disease (CAD). Thromb Haemost. 1998;79:727–730
  69. Nizankowska-Mogilnicka E, Adamek L, Grzanka P, Domagala TB, Sanak M, Krzanowski M, et al. Genetic polymorphisms associated with acute pulmonary embolism and deep venous thrombosis. Eur Respir J. 2003;21:25–30
  70. Domagala TB, Adamek L, Nizankowska E, Sanak M, Szczeklik A. Mutations C677T and A1298C of the 5,10-methylenetetrahydrofolate reductase gene and fasting plasma homocysteine levels are not associated with the increased risk of venous thromboembolic disease. Blood Coagul Fibrinolysis. 2002;13:423–431
  71. van der Put NM, Gabreels F, Stevens EM, Smeitink JA, Trijbels FJ, Eskes TK, et al. A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects?. Am J Hum Genet. 1998;62:1044–1051
  72. Matsuo K, Suzuki R, Hamajima N, Ogura M, Kagami Y, Taji H, et al. Association between polymorphisms of folate- and methionine-metabolizing enzymes and susceptibility to malignant lymphoma. Blood. 2001;97:3205–3209
  73. Szczeklik A, Sanak M, Jankowski M, Dropinski J, Czachor R, Musial J, et al. Mutation A1298C of methylenetetrahydrofolate reductase: risk for early coronary disease not associated with hyperhomocysteinemia. Am J Med Genet. 2001;101:36–39
  74. Weisberg IS, Park E, Ballman KV, Berger P, Nunn M, Suh DS, et al. Investigations of a common genetic variant in betaine-homocysteine methyltransferase (BHMT) in coronary artery disease. Atherosclerosis. 2003;167:205–214
  75. Duthie SJ, Narayanan S, Blum S, Pirie L, Brand GM. Folate deficiency in vitro induces uracil misincorporation and DNA hypomethylation and inhibits DNA excision repair in immortalized normal human colon epithelial cells. Nutr Cancer. 2000;37:245–251
  76. James SJ, Miller BJ, Basnakian AG, Pogribny IP, Pogribna M, Muskhelishvili L. Apoptosis and proliferation under conditions of deoxynucleotide pool imbalance in liver of folate/methyl deficient rats. Carcinogenesis. 1997;18:287–293
  77. Melnyk S, Pogribna M, Miller BJ, Basnakian AG, Pogribny IP, James SJ. Uracil misincorporation, DNA strand breaks, and gene amplification are associated with tumorigenic cell transformation in folate deficient/repleted Chinese hamster ovary cells. Cancer Lett. 1999;146:35–44
  78. Bagley PJ, Selhub J. A common mutation in the methylenetetrahydrofolate reductase gene is associated with an accumulation of formylated tertrahydrofolates in red blood cells. Proc Natl Acad Sci U S A. 1998;95:13217–13220
  79. Crott JW, Mashiyama ST, Ames BN, Fenech M. The effect of folic acid deficiency and MTHFR C677T polymorphism on chromosome damage in human lymphocytes in vitro. Cancer Epidemiol Biomarkers Prev. 2001;10:1089–1096
  80. Skibola CF, Smith MT, Kane E, Roman E, Rollinson S, Cartwright RA, et al. Polymorphisms in the methylenetetrahydrofolate reductase gene are associated with susceptibility to acute leukemia in adults. Proc Natl Acad Sci U S A. 1999;96:12810–12815
  81. Krajinovic M, Lamothe S, Labuda D, Lemieux-Blanchard E, Theoret Y, Moghrabi A, et al. Role of MTHFR genetic polymorphisms in the susceptibility to childhood acute lymphoblastic leukemia. Blood. 2004;103:252–257
  82. Franco RF, Simoes B, Tone LG, Gabellini SM, Zago MA, Falcao RP. The methylenetetrahydrofolate reductase C677T gene polymorphism decreases the risk of childhood acute lymphocytic leukemia. Br J Haematol. 2001;115:616–618
  83. Wiemels JL, Smith RN, Taylor GM, Eden OB, Alexander FE, Greaves MF. Methylenetetrahydrofolate reductase (MTHFR) polymorphisms and risk of molecularly defined subtypes of childhood acute leukemia. Proc Natl Acad Sci U S A. 2001;98:4004–4009

PII: S0955-2863(05)00052-5

doi: 10.1016/j.jnutbio.2005.01.018

The Journal of Nutritional Biochemistry
Volume 16, Issue 8 , Pages 467-478 , August 2005