Skip to main content

Hyperhomocysteinemia and Cancer: The Role of Natural Products and Nutritional Interventions

  • Chapter
  • First Online:
Nutritional Management and Metabolic Aspects of Hyperhomocysteinemia

Abstract

Dietary proteins metabolism involves the production of homocysteine which result from methionine as a sulfur-containing amino acid. Elevated levels of plasma homocysteine are associated with high risk of cardiovascular diseases. However, Previous studies indicate that plasma homocysteine can be used as a tumor marker and can be considered as a risk factor for cancer. The levels of homocysteine in the plasma is highly controlled by diet and several strategies were suggested for lowering plasma homocysteine. In this chapter, homocysteine biosynthesis and metabolism were explained. Diseases associated with hyperhomocysteinemia were discussed with special emphasis on cancer. Various natural products and dietary interventions were evaluated for their anticancer effects through lowering plasma homocysteine. This chapter will provide a solid ground for researchers to understand the link between hyperhomocysteinemia and cancer and the possible role of diet and natural product in lowering plasma homocysteine.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

eBook
USD 16.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  1. Mcdonald L, Bary C, Field C, Love F, Davies B (1964) Homocystinuria, thrombosis, and the blood-platelets. Lancet 1:745–746

    Article  CAS  PubMed  Google Scholar 

  2. Sharma GS, Kumar T, Dar TA, Singh LR (2015) Protein N-homocysteinylation: from cellular toxicity to neurodegeneration. Biochim Biophys Acta 1850:2239–2245

    Article  CAS  PubMed  Google Scholar 

  3. Azzini E, Ruggeri S, Polito A (2020) Homocysteine: its possible emerging role in at-risk population groups. Int J Mol Sci 21(4):1421

    Article  CAS  PubMed Central  Google Scholar 

  4. Hasan T, Arora R, Bansal AK, Bhattacharya R, Sharma GS, Singh LR (2019) Disturbed homocysteine metabolism is associated with cancer. Exp Mol Med 51(2):1–13

    Article  PubMed  CAS  Google Scholar 

  5. Wu LL, Wu JT (2002) Hyperhomocysteinemia is a risk factor for cancer and a new potential tumor marker. Clin Chim Acta 322:21–28

    Article  CAS  PubMed  Google Scholar 

  6. Kumar A et al (2017) The metabolism and significance of homocysteine in nutrition and health. Nutr Metab 14(1):78

    Article  CAS  Google Scholar 

  7. Selhub J (1999) Homocysteine metabolism. Annu Rev Nutr 19(1):217–246

    Article  CAS  PubMed  Google Scholar 

  8. Škovierová H et al (2016) The molecular and cellular effect of homocysteine metabolism imbalance on human health. Int J Mol Sci 17(10):1733

    Article  PubMed Central  CAS  Google Scholar 

  9. Mudd SH, Cantoni G (1958) Activation of methionine for transmethylation III. The methionine-activating enzyme of bakers’ yeast. J Biol Chem 231(1):481–492

    Article  CAS  PubMed  Google Scholar 

  10. McCully KS (2001) The biomedical significance of homocysteine. J Sci Explor 15(1):5–20

    Google Scholar 

  11. 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(1):75–81

    Article  CAS  PubMed  Google Scholar 

  12. Cantoni G, Chiang P (1980) Natural sulfur compounds, in novel biochemical and structural aspects. Plenum Publishing Co, New York, pp 67–80

    Book  Google Scholar 

  13. Mandaviya PR, Stolk L, Heil SG (2014) Homocysteine and DNA methylation: a review of animal and human literature. Mol Genet Metab 113(4):243–252

    Article  CAS  PubMed  Google Scholar 

  14. Esse R et al (2013) Protein arginine methylation is more prone to inhibition by S-adenosylhomocysteine than DNA methylation in vascular endothelial cells. PLoS One 8(2):e55483

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Jung M, Pfeifer GP (2015) Aging and DNA methylation. BMC Biol 13(1):7

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Champe PC, Harvey RA, Ferrier DR (2005) Biochemistry. Lippincott Williams & Wilkins, Philadelphia

    Google Scholar 

  17. Li YN et al (1996) Cloning, mapping and RNA analysis of the human methionine synthase gene. Hum Mol Genet 5(12):1851–1858

    Article  CAS  PubMed  Google Scholar 

  18. Castro R et al (2006) Homocysteine metabolism, hyperhomocysteinaemia and vascular disease: an overview. J Inherit Metab Dis 29(1):3–20

    Article  CAS  PubMed  Google Scholar 

  19. Pajares MA, Pérez-Sala D (2006) Betaine homocysteine S-methyltransferase: just a regulator of homocysteine metabolism? Cell Mol Life Sci 63(23):2792–2803

    Article  CAS  PubMed  Google Scholar 

  20. Teng Y-W, Cerdena I, Zeisel SH (2012) Homocysteinemia in mice with genetic betaine homocysteine S-methyltransferase deficiency is independent of dietary folate intake. J Nutr 142(11):1964–1967

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Lu SC (2013) Glutathione synthesis. Biochim Biophys Acta Gen Subj 1830(5):3143–3153

    Article  CAS  Google Scholar 

  22. Vitvitsky V et al (2003) Redox regulation of homocysteine-dependent glutathione synthesis. Redox Rep 8(1):57–63

    Article  CAS  PubMed  Google Scholar 

  23. Chiku T et al (2009) H2S biogenesis by human cystathionine γ-lyase leads to the novel sulfur metabolites lanthionine and homolanthionine and is responsive to the grade of hyperhomocysteinemia. J Biol Chem 284(17):11601–11612

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Yang Q, He G-W (2019) Imbalance of homocysteine and H2S: significance, mechanisms, and therapeutic promise in vascular injury. Oxidative Med Cell Longev 2019:7629673

    Article  Google Scholar 

  25. Barroso M, Handy DE, Castro R (2017) The link between hyperhomocysteinemia and hypomethylation: implications for cardiovascular disease. J Inborn Errors Metab Screen 5:2326409817698994

    Article  CAS  Google Scholar 

  26. Sunden SL et al (1997) Betaine–homocysteine methyltransferase expression in porcine and human tissues and chromosomal localization of the human gene. Arch Biochem Biophys 345(1):171–174

    Article  CAS  PubMed  Google Scholar 

  27. Maron BA, Loscalzo J (2009) The treatment of hyperhomocysteinemia. Annu Rev Med 60:39–54

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Feligioni M et al (2019) Hyperhomocysteinemia as a risk factor and potential nutraceutical target for certain pathologies. Front Nutr 6:49

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Jakubowski H (2002) Homocysteine is a protein amino acid in humans implications for homocysteine-linked disease. J Biol Chem 277(34):30425–30428

    Article  CAS  PubMed  Google Scholar 

  30. Manolescu BN et al (2010) Homocysteine and vitamin therapy in stroke prevention and treatment: a review. Acta Biochim Pol 57(4):467–477

    Article  CAS  PubMed  Google Scholar 

  31. Kim J et al (2018) Causes of hyperhomocysteinemia and its pathological significance. Arch Pharm Res 41(4):372–383

    Article  CAS  PubMed  Google Scholar 

  32. Fowler B (2005) Homocystein – an independent risk factor for cardiovascular and thrombotic diseases. Ther Umsch Revue Ther 62(9):641–646

    Google Scholar 

  33. Asfar S, Safar H (2007) Homocysteine levels and peripheral arterial occlusive disease: a prospective cohort study and review of the literature. J Cardiovasc Surg 48(5):601

    CAS  Google Scholar 

  34. Wierzbicki AS (2007) Homocysteine and cardiovascular disease: a review of the evidence. Diab Vasc Dis Res 4(2):143–149

    Article  PubMed  Google Scholar 

  35. Morris AA et al (2017) Guidelines for the diagnosis and management of cystathionine beta-synthase deficiency. J Inherit Metab Dis 40(1):49–74

    Article  CAS  PubMed  Google Scholar 

  36. Dutta S et al (2005) Cystathionine β-synthase T833C/844INS68 polymorphism: a family-based study on mentally retarded children. Behav Brain Funct 1(1):25

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Kruger WD et al (2000) Polymorphisms in the CBS gene associated with decreased risk of coronary artery disease and increased responsiveness to total homocysteine lowering by folic acid. Mol Genet Metab 70(1):53–60

    Article  CAS  PubMed  Google Scholar 

  38. Yakub M et al (2012) Polymorphisms in MTHFR, MS and CBS genes and homocysteine levels in a Pakistani population. PLoS One 7(3):e33222

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Fischer JD, Holliday GL, Thornton JM (2010) The CoFactor database: organic cofactors in enzyme catalysis. Bioinformatics 26(19):2496–2497

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Miller JW et al (1994) Vitamin B− 6 deficiency vs folate deficiency: comparison of responses to methionine loading in rats. Am J Clin Nutr 59(5):1033–1039

    Article  CAS  PubMed  Google Scholar 

  41. Markišić M, Pavlović AM, Pavlović DM (2017) The impact of homocysteine, vitamin b12, and vitamin d levels on functional outcome after first-ever ischaemic stroke. Biomed Res Int 2017:5489057

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Miller AL (2003) The methionine-homocysteine cycle and its effects on cognitive diseases. (Homocysteine & cognitive). Altern Med Rev 8(1):7–20

    PubMed  Google Scholar 

  43. Guney T, Yikilmaz AS, Dilek I (2016) Epidemiology of vitamin B12 deficiency. Epidemiol Commun Non-Commun Dis Attrib Lifestyle Nat Humankind 2016:103

    Google Scholar 

  44. Brown MJ, Beier K (2018) Vitamin B6 deficiency (pyridoxine). In: StatPearls [Internet]. StatPearls Publishing

    Google Scholar 

  45. Collaboration, H.L.T (1998) Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials. BMJ 316(7135):894–898

    Article  Google Scholar 

  46. De Bree A et al (2004) Evidence for a protective (synergistic?) effect of B-vitamins and omega-3 fatty acids on cardiovascular diseases. Eur J Clin Nutr 58(5):732–744

    Article  PubMed  CAS  Google Scholar 

  47. Miodownik C et al (2007) High-dose vitamin B6 decreases homocysteine serum levels in patients with schizophrenia and schizoaffective disorders: a preliminary study. Clin Neuropharmacol 30(1):13–17

    Article  CAS  PubMed  Google Scholar 

  48. Garlick PJ (2006) Toxicity of methionine in humans. J Nutr 136(6):1722S–1725S

    Article  CAS  PubMed  Google Scholar 

  49. Chwatko G et al (2007) Mutations in methylenetetrahydrofolate reductase or cystathionine β-syntase gene, or a high-methionine diet, increase homocysteine thiolactone levels in humans and mice. FASEB J 21(8):1707–1713

    Article  CAS  PubMed  Google Scholar 

  50. van Guldener C (2006) Why is homocysteine elevated in renal failure and what can be expected from homocysteine-lowering? Nephrol Dial Transplant 21(5):1161–1166

    Article  PubMed  Google Scholar 

  51. Van guldener C, Robinson K (2000) Homocysteine and renal disease. In: Seminars in thrombosis and hemostasis. Copyright© 2000 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New …

    Google Scholar 

  52. Veldman B et al (2005) Reduced plasma total homocysteine concentrations in Type 1 diabetes mellitus is determined by increased renal clearance. Diabet Med 22(3):301–305

    Article  CAS  PubMed  Google Scholar 

  53. Foundation, N.K (2018) Estimated glomerular filtration rate (eGFR) [cited 2020 May 26]. Available from: https://www.kidney.org/atoz/content/gfr

  54. Long Y, Nie J (2016) Homocysteine in renal injury. Kidney Dis 2(2):80–87

    Article  Google Scholar 

  55. Van Guldener C, Stam F, Stehouwer CD (2001) Homocysteine metabolism in renal failure. Kidney Int 59:S234–S237

    Article  Google Scholar 

  56. Laidlaw SA et al (1994) Patterns of fasting plasma amino acid levels in chronic renal insufficiency: results from the feasibility phase of the Modification of Diet in Renal Disease Study. Am J Kidney Dis 23(4):504–513

    Article  CAS  PubMed  Google Scholar 

  57. Loehrer F et al (1998) Evidence for disturbed S-adenosylmethionine: S-adenosylhomocysteine ratio in patients with end-stage renal failure: a cause for disturbed methylation reactions? Nephrol Dial Transplant 13(3):656–661

    Article  CAS  PubMed  Google Scholar 

  58. Ducloux D et al (2002) Hyperhomocysteinaemia therapy in haemodialysis patients: folinic versus folic acid in combination with vitamin B6 and B12. Nephrol Dial Transplant 17(5):865–870

    Article  CAS  PubMed  Google Scholar 

  59. Suliman M et al (1997) Total, free, and protein-bound sulphur amino acids in uraemic patients. Nephrol Dial Transplant 12(11):2332–2338

    Article  CAS  PubMed  Google Scholar 

  60. Yildirim I et al (2019) Serum sulphate levels in hemodialysis patients. Int J Nephrol 2019:1063514

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Nakanishi T et al (2002) Association of hyperhomocysteinemia with plasma sulfate and urine sulfate excretion in patients with progressive renal disease. Am J Kidney Dis 40(5):909–915

    Article  CAS  PubMed  Google Scholar 

  62. Lien EA et al (2001) Total plasma homocysteine in hypo-and hyperthyroidism: covariations and causality. J Clin Endocrinol Metab 86(4):1846–1846

    Article  CAS  Google Scholar 

  63. Bamashmoos SA et al (2013) Relationship between total homocysteine, total cholesterol and creatinine levels in overt hypothyroid patients. Springerplus 2(1):423

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Morris MS et al (2001) Hyperhomocysteinemia and hypercholesterolemia associated with hypothyroidism in the third US National Health and Nutrition Examination Survey. Atherosclerosis 155(1):195–200

    Article  CAS  PubMed  Google Scholar 

  65. Mincer Dl Fau, Jialal I (2020) Hashimoto thyroiditis. BTI – StatPearls

    Google Scholar 

  66. Cicone F et al (2018) Hyperhomocysteinemia in acute iatrogenic hypothyroidism: the relevance of thyroid autoimmunity. J Endocrinol Investig 41(7):831–837

    Article  CAS  Google Scholar 

  67. Demirbas B et al (2004) Plasma homocysteine levels in hyperthyroid patients. Endocr J 51(1):121–125

    Article  CAS  PubMed  Google Scholar 

  68. Orzechowska-Pawilojc A et al (2009) Homocysteine, folate, and cobalamin levels in hyperthyroid women before and after treatment. Endokrynol Pol 60(6):443–448

    CAS  PubMed  Google Scholar 

  69. Catargi B et al (1999) Homocysteine, hypothyroidism, and effect of thyroid hormone replacement. Thyroid 9(12):1163–1166

    Article  CAS  PubMed  Google Scholar 

  70. de Benoist B (2008) Conclusions of a WHO technical consultation on folate and vitamin B12 deficiencies. Food Nutr Bull 29(2_Suppl 1):S238–S244

    Article  PubMed  Google Scholar 

  71. Hariz A, Bhattacharya PT (2020) Megaloblastic anemia. In: StatPearls [Internet]. StatPearls Publishing

    Google Scholar 

  72. Lowenthal EA et al (2000) Homocysteine elevation in sickle cell disease. J Am Coll Nutr 19(5):608–612

    Article  CAS  PubMed  Google Scholar 

  73. Nozari E, Ghavamzadeh S, Razazian N (2019) The effect of vitamin B12 and folic acid supplementation on serum homocysteine, anemia status and quality of life of patients with multiple sclerosis. Clin Nutr Res 8(1):36–45

    Article  PubMed  PubMed Central  Google Scholar 

  74. Lin J et al (2010) Plasma homocysteine and cysteine and risk of breast cancer in women. Cancer Res 70(6):2397–2405

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Zhang D et al (2015) Elevated homocysteine level and folate deficiency associated with increased overall risk of carcinogenesis: meta-analysis of 83 case-control studies involving 35,758 individuals. PLoS One 10(5):e0123423

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  76. Wu LL, Wu JT (2002) Hyperhomocysteinemia is a risk factor for cancer and a new potential tumor marker. Clin Chim Acta 322(1–2):21–28

    Article  CAS  PubMed  Google Scholar 

  77. Hasan T et al (2019) Disturbed homocysteine metabolism is associated with cancer. Exp Mol Med 51(2):1–13

    Article  PubMed  CAS  Google Scholar 

  78. Sun C-F et al (2002) Serum total homocysteine increases with the rapid proliferation rate of tumor cells and decline upon cell death: a potential new tumor marker. Clin Chim Acta 321(1–2):55–62

    Article  CAS  PubMed  Google Scholar 

  79. Desouza C et al (2002) Drugs affecting homocysteine metabolism. Drugs 62(4):605–616

    Article  CAS  PubMed  Google Scholar 

  80. Fallah S et al (2012) Influence of oral contraceptive pills on homocysteine and nitric oxide levels: as risk factors for cardiovascular disease. J Clin Lab Anal 26(2):120–123

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Norouzi V et al (2011) Effect of oral contraceptive therapy on homocysteine and C-reactive protein levels in women: an observational study. Anatol J Cardiol/Anadolu Kardiyol Derg 11(8):698–702

    Google Scholar 

  82. Giovannucci E et al (1995) Alcohol, low-methionine – low-folate diets, and risk of colon cancer in men. J Natl Cancer Inst 87:265–273

    Google Scholar 

  83. Kato I et al (1999) Serum folate, homocysteine and colorectal cancer risk in women: a nested case–control study. Br J Cancer 79:1917–1921

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Ma J et al (1999) A polymorphism of the methionine synthase gene: association with plasma folate, vitamin B12, homocyst(e)ine, and colorectal cancer risk. Cancer Epidemiol Biomark Prev 8:825–829

    CAS  Google Scholar 

  85. Bravatà V (2015) Controversial roles of methylenetetrahydrofolate reductase polymorphisms and folate in breast cancer disease. Int J Food Sci Nutr 66:43–49

    Article  PubMed  CAS  Google Scholar 

  86. Montfort WR et al (1990) Structure, multiple site binding, and segmental accommodation in thymidylate synthase on binding dUMP and an antifolate. Biochemistry 29:6964–6977

    Article  CAS  PubMed  Google Scholar 

  87. Blount BC et al (1997) Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: implications for cancer and neuronal damage. Proc Natl Acad Sci U S A 94:3290–3295

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Crider KS, Yang TP, Berry RJ, Bailey LB (2012) Folate and DNA methylation: a review of molecular mechanisms and the evidence for Folate’s role. Adv Nutr 3:21–38

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Hall LE, Mitchell SE, O’Neill RJ (2012) Pericentric and centromeric transcription: a perfect balance required. Chromosom Res 20:535–546

    Article  CAS  Google Scholar 

  90. Ehrlich M (2002) DNA methylation in cancer: too much, but also too little. Oncogene 21:5400–5413

    Article  CAS  PubMed  Google Scholar 

  91. Refsum H et al (2006) The Hordaland Homocysteine Study: a community-based study of homocysteine, its determinants, and associations with disease. J Nutr 136:1731S–1740S

    Article  CAS  PubMed  Google Scholar 

  92. Rickles FR, Levine M, Edwards RL (1992) Hemostatic alterations in cancer patients. Cancer Metastasis Rev 11:237–248

    Article  CAS  PubMed  Google Scholar 

  93. GATT A et al (2007) Hyperhomocysteinemia in women with advanced breast cancer. Int J Lab Hematol 29:421–425

    Article  CAS  PubMed  Google Scholar 

  94. Welch GN, Loscalzo J (1998) Homocysteine and atherothrombosis. N Engl J Med 338:1042–1050

    Article  CAS  PubMed  Google Scholar 

  95. Sharma GS, Kumar T, Singh LR (2014) N-homocysteinylation induces different structural and functional consequences on acidic and basic proteins. PLoS One 9:e116386

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Lentz SR et al (1996) Vascular dysfunction in monkeys with diet-induced hyperhomocyst (e) inemia. J Clin Invest 98:24–29

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. FitzGerald GA (2003) Parsing an enigma: the pharmacodynamics of aspirin resistance. Lancet 361:542–544

    Article  PubMed  Google Scholar 

  98. Talib WH (2017) Consumption of garlic and lemon aqueous extracts combination reduces tumor burden by angiogenesis inhibition, apoptosis induction, and immune system modulation. Nutrition 43:89–97

    Article  PubMed  CAS  Google Scholar 

  99. Talib WH (2017) Regressions of breast carcinoma syngraft following treatment with piperine in combination with thymoquinone. Sci Pharm 85(3):27

    Article  PubMed Central  Google Scholar 

  100. Talib WH, Al-hadid SA, Ali MBW, Al-Yasari IH, Ali MRA (2018) Role of curcumin in regulating p53 in breast cancer: an overview of the mechanism of action. Breast Cancer Target Ther 10:207

    Article  CAS  Google Scholar 

  101. Talib WH, Al Kury LT (2018) Parthenolide inhibits tumor-promoting effects of nicotine in lung cancer by inducing P53-dependent apoptosis and inhibiting VEGF expression. Biomed Pharmacother 107:1488–1495

    Article  CAS  PubMed  Google Scholar 

  102. Al Obaydi MF, Hamed WM, Al Kury LT, Talib WH (2020) Terfezia boudieri: a desert truffle with anticancer and immunomodulatory activities. Front Nutr 7:38

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Kim J et al (2018) Causes of hyperhomocysteinemia and its pathological significance. Arch Pharm Res 41(4):372–383

    Article  CAS  PubMed  Google Scholar 

  104. Craig SA (2004) Betaine in human nutrition. Am J Clin Nutr 80(3):539–549

    Article  CAS  PubMed  Google Scholar 

  105. Kumar A et al (2017) The metabolism and significance of homocysteine in nutrition and health. Nutr Metab (Lond) 14:78

    Article  CAS  Google Scholar 

  106. Malinow MR, Bostom AG, Krauss RM (1999) Homocyst(e)ine, diet, and cardiovascular diseases: a statement for healthcare professionals from the Nutrition Committee, American Heart Association. Circulation 99(1):178–182

    Article  CAS  PubMed  Google Scholar 

  107. Robinson K et al (1998) Low circulating folate and vitamin B6 concentrations: risk factors for stroke, peripheral vascular disease, and coronary artery disease. Eur COMAC Group Circ 97(5):437–443

    CAS  Google Scholar 

  108. Kang SS, Wong PW, Norusis M (1987) Homocysteinemia due to folate deficiency. Metabolism 36(5):458–462

    Article  CAS  PubMed  Google Scholar 

  109. Selhub J et al (1993) Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. JAMA 270(22):2693–2698

    Article  CAS  PubMed  Google Scholar 

  110. Tinelli C et al (2019) Hyperhomocysteinemia as a risk factor and potential nutraceutical target for certain pathologies. Front Nutr 6:49

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  111. Khan KM, Jialal I (2020) Folic acid (folate) deficiency. In: StatPearls. StatPearls Publishing Copyright ©, StatPearls Publishing LLC, Treasure Island

    Google Scholar 

  112. Rasmussen K et al (1996) Age- and gender-specific reference intervals for total homocysteine and methylmalonic acid in plasma before and after vitamin supplementation. Clin Chem 42(4):630–636

    Article  CAS  PubMed  Google Scholar 

  113. Institute of Medicine Standing Committee on the Scientific Evaluation of Dietary Reference, I., O.B.V. Its Panel on Folate, and Choline (1998) The national academies collection: reports funded by National Institutes of Health. In: Dietary reference intakes for thiamin, riboflavin, niacin, vitamin B(6), folate, vitamin B(12), pantothenic acid, biotin, and dholine. National Academies Press (US) Copyright ©, National Academy of Sciences, Washington, DC

    Google Scholar 

  114. Homocysteine Lowering Trialists’ Collaboration (2005) Dose-dependent effects of folic acid on blood concentrations of homocysteine: a meta-analysis of the randomized trials. Am J Clin Nutr 82(4):806–812

    Article  Google Scholar 

  115. van Oort FV et al (2003) Folic acid and reduction of plasma homocysteine concentrations in older adults: a dose-response study. Am J Clin Nutr 77(5):1318–1323

    Article  PubMed  Google Scholar 

  116. Assanelli D et al (2004) Folic acid and vitamin E supplementation effects on homocysteinemia, endothelial function and plasma antioxidant capacity in young myocardial-infarction patients. Pharmacol Res 49(1):79–84

    Article  CAS  PubMed  Google Scholar 

  117. Mitu O et al (2020) The effect of vitamin supplementation on subclinical atherosclerosis in patients without manifest cardiovascular diseases: never-ending hope or underestimated effect? Molecules (Basel, Switz) 25(7):1717

    Article  CAS  Google Scholar 

  118. Boushey CJ et al (1995) A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes. JAMA 274(13):1049–1057

    Article  CAS  PubMed  Google Scholar 

  119. den Heijer M et al (1998) Vitamin supplementation reduces blood homocysteine levels: a controlled trial in patients with venous thrombosis and healthy volunteers. Arterioscler Thromb Vasc Biol 18(3):356–361

    Article  Google Scholar 

  120. Brouwer IA et al (1999) Dietary folate from vegetables and citrus fruit decreases plasma homocysteine concentrations in humans in a dietary controlled trial. J Nutr 129(6):1135–1139

    Article  CAS  PubMed  Google Scholar 

  121. Alfthan G et al (2003) Folate intake, plasma folate and homocysteine status in a random Finnish population. Eur J Clin Nutr 57(1):81–88

    Article  CAS  PubMed  Google Scholar 

  122. Brouwer IA et al (1999) Low-dose folic acid supplementation decreases plasma homocysteine concentrations: a randomized trial. Am J Clin Nutr 69(1):99–104

    Article  CAS  PubMed  Google Scholar 

  123. Appel LJ et al (2000) Effect of dietary patterns on serum homocysteine: results of a randomized, controlled feeding study. Circulation 102(8):852–857

    Article  CAS  PubMed  Google Scholar 

  124. Riddell LJ et al (2000) Dietary strategies for lowering homocysteine concentrations. Am J Clin Nutr 71(6):1448–1454

    Article  CAS  PubMed  Google Scholar 

  125. Tucker KL et al (1996) Dietary intake pattern relates to plasma folate and homocysteine concentrations in the Framingham Heart Study. J Nutr 126(12):3025–3031

    Article  CAS  PubMed  Google Scholar 

  126. Teixeira JA et al (2020) Prudent dietary pattern influences homocysteine level more than folate, vitamin B12, and docosahexaenoic acid: a structural equation model approach. Eur J Nutr 59(1):81–91

    Article  CAS  PubMed  Google Scholar 

  127. Pintó X et al (2005) A folate-rich diet is as effective as folic acid from supplements in decreasing plasma homocysteine concentrations. Int J Med Sci 2(2):58–63

    Article  PubMed  PubMed Central  Google Scholar 

  128. Ray JG, Cole DE, Boss SC (2000) An Ontario-wide study of vitamin B12, serum folate, and red cell folate levels in relation to plasma homocysteine: is a preventable public health issue on the rise? Clin Biochem 33(5):337–343

    Article  CAS  PubMed  Google Scholar 

  129. Gonin JM et al (2003) Controlled trials of very high dose folic acid, vitamins B12 and B6, intravenous folinic acid and serine for treatment of hyperhomocysteinemia in ESRD. J Nephrol 16(4):522–534

    CAS  PubMed  Google Scholar 

  130. Ubbink JB et al (1993) Hyperhomocysteinemia and the response to vitamin supplementation. Clin Investig 71(12):993–998

    Article  CAS  PubMed  Google Scholar 

  131. MacKenzie KE et al (2006) Folate and vitamin B6 rapidly normalize endothelial dysfunction in children with type 1 diabetes mellitus. Pediatrics 118(1):242–253

    Article  PubMed  Google Scholar 

  132. Papandreou D et al (2010) Oral supplementation of folic acid for two months reduces total serum homocysteine levels in hyperhomocysteinemic Greek children. Hippokratia 14(2):105–108

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Collaboration, H.L.T (1998) Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials. Homocysteine Lowering Trialists’ Collaboration. BMJ 316(7135):894–898

    Article  Google Scholar 

  134. Bostom AG et al (1997) Treatment of hyperhomocysteinemia in renal transplant recipients. A randomized, placebo-controlled trial. Ann Intern Med 127(12):1089–1092

    Article  CAS  PubMed  Google Scholar 

  135. Ford TC et al (2018) The effect of a high-dose vitamin B multivitamin supplement on the relationship between brain metabolism and blood biomarkers of oxidative stress: a randomized control trial. Nutrients 10(12):1860

    Article  PubMed Central  CAS  Google Scholar 

  136. Woodside JV et al (1998) Effect of B-group vitamins and antioxidant vitamins on hyperhomocysteinemia: a double-blind, randomized, factorial-design, controlled trial. Am J Clin Nutr 67(5):858–866

    Article  CAS  PubMed  Google Scholar 

  137. Tucker KL et al (2004) Breakfast cereal fortified with folic acid, vitamin B-6, and vitamin B-12 increases vitamin concentrations and reduces homocysteine concentrations: a randomized trial. Am J Clin Nutr 79(5):805–811

    Article  CAS  PubMed  Google Scholar 

  138. Powers HJ (2003) Riboflavin (vitamin B-2) and health. Am J Clin Nutr 77(6):1352–1360

    Article  CAS  PubMed  Google Scholar 

  139. Shimakawa T et al (1997) Vitamin intake: a possible determinant of plasma homocyst(e)ine among middle-aged adults. Ann Epidemiol 7(4):285–293

    Article  CAS  PubMed  Google Scholar 

  140. Jacques PF et al (2001) Determinants of plasma total homocysteine concentration in the Framingham Offspring cohort. Am J Clin Nutr 73(3):613–621

    Article  CAS  PubMed  Google Scholar 

  141. Hustad S et al (2000) Riboflavin as a determinant of plasma total homocysteine: effect modification by the methylenetetrahydrofolate reductase C677T polymorphism. Clin Chem 46(8 Pt 1):1065–1071

    Article  CAS  PubMed  Google Scholar 

  142. Morgan KJ, Zabik ME, Leveille GA (1981) The role of breakfast in nutrient intake of 5- to 12-year-old children. Am J Clin Nutr 34(7):1418–1427

    Article  CAS  PubMed  Google Scholar 

  143. Morgan KJ, Zabik ME (1984) The influence of ready-to-eat cereal consumption at breakfast on nutrient intakes of individuals 62 years and older. J Am Coll Nutr 3(1):27–44

    Article  CAS  PubMed  Google Scholar 

  144. Preziosi P et al (1999) Breakfast type, daily nutrient intakes and vitamin and mineral status of French children, adolescents, and adults. J Am Coll Nutr 18(2):171–178

    Article  PubMed  Google Scholar 

  145. Moat SJ et al (2003) Effect of riboflavin status on the homocysteine-lowering effect of folate in relation to the MTHFR (C677T) genotype. Clin Chem 49(2):295–302

    Article  CAS  PubMed  Google Scholar 

  146. Krishnaswamy K (1971) Erythrocyte glutamic oxaloacetic transaminase activity in patients with oral lesions. Int J Vitam Nutr Res 41(2):247–252

    CAS  PubMed  Google Scholar 

  147. Lakshmi AV, Bamji MS (1974) Tissue pyridoxal phosphate concentration and pyridoxaminephosphate oxidase activity in riboflavin deficiency in rats and man. Br J Nutr 32(2):249–255

    Article  CAS  PubMed  Google Scholar 

  148. McGregor DO et al (2002) Betaine supplementation decreases post-methionine hyperhomocysteinemia in chronic renal failure. Kidney Int 61(3):1040–1046

    Article  CAS  PubMed  Google Scholar 

  149. Brouwer IA, Verhoef P, Urgert R (2000) Betaine supplementation and plasma homocysteine in healthy volunteers. Arch Intern Med 160(16):2546–2547

    Article  CAS  PubMed  Google Scholar 

  150. Wilcken DE, Dudman NP, Tyrrell PA (1985) Homocystinuria due to cystathionine beta-synthase deficiency – the effects of betaine treatment in pyridoxine-responsive patients. Metabolism 34(12):1115–1121

    Google Scholar 

  151. Carmel R et al (1988) Hereditary defect of cobalamin metabolism (cblG mutation) presenting as a neurologic disorder in adulthood. N Engl J Med 318(26):1738–1741

    Article  CAS  PubMed  Google Scholar 

  152. Schwab U et al (2002) Betaine supplementation decreases plasma homocysteine concentrations but does not affect body weight, body composition, or resting energy expenditure in human subjects. Am J Clin Nutr 76(5):961–967

    Article  CAS  PubMed  Google Scholar 

  153. Steenge GR, Verhoef P, Katan MB (2003) Betaine supplementation lowers plasma homocysteine in healthy men and women. J Nutr 133(5):1291–1295

    Article  CAS  PubMed  Google Scholar 

  154. Melse-Boonstra A et al (2005) Betaine concentration as a determinant of fasting total homocysteine concentrations and the effect of folic acid supplementation on betaine concentrations. Am J Clin Nutr 81(6):1378–1382

    Article  CAS  PubMed  Google Scholar 

  155. Holm PI et al (2005) Betaine and folate status as cooperative determinants of plasma homocysteine in humans. Arterioscler Thromb Vasc Biol 25(2):379–385

    Article  CAS  PubMed  Google Scholar 

  156. Zeisel SH et al (2003) Concentrations of choline-containing compounds and betaine in common foods. J Nutr 133(5):1302–1307

    Article  CAS  PubMed  Google Scholar 

  157. Chiuve SE et al (2007) The association between betaine and choline intakes and the plasma concentrations of homocysteine in women. Am J Clin Nutr 86(4):1073–1081

    Article  CAS  PubMed  Google Scholar 

  158. Lee JE et al (2010) Are dietary choline and betaine intakes determinants of total homocysteine concentration? Am J Clin Nutr 91(5):1303–1310

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Olthof MR et al (2005) Choline supplemented as phosphatidylcholine decreases fasting and postmethionine-loading plasma homocysteine concentrations in healthy men. Am J Clin Nutr 82(1):111–117

    Article  CAS  PubMed  Google Scholar 

  160. Mahmoud AM, Ali MM (2019) Methyl donor micronutrients that modify DNA methylation and cancer outcome. Nutrients 11(3):608

    Article  CAS  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Wamidh H. Talib .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2021 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Talib, W.H., Barakat, M., Al Kury, L.T. (2021). Hyperhomocysteinemia and Cancer: The Role of Natural Products and Nutritional Interventions. In: Waly, M.I. (eds) Nutritional Management and Metabolic Aspects of Hyperhomocysteinemia. Springer, Cham. https://doi.org/10.1007/978-3-030-57839-8_2

Download citation

  • DOI: https://doi.org/10.1007/978-3-030-57839-8_2

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-030-57838-1

  • Online ISBN: 978-3-030-57839-8

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics