Too much folate: A risk factor for cancer and cardiovascular disease?

Current Opinion in Clinical Nutrition and Metabolic Care

Volumn 12, Issue 1, 2009, Pages 30-36

  Sauer, Julia ^a   Mason, Joel B ^a   Choi, Sang Woon ^a  

^a TUFTS UNIVERSITY   (United States)

Author keywords

Cardiovascular disease; Colorectal cancer; Folate; Folic acid fortification

Indexed keywords

ACETYLSALICYLIC ACID; CYANOCOBALAMIN; FOLIC ACID; HOMOCYSTEINE; PLACEBO; PYRIDOXINE; UNSPECIFIC MONOOXYGENASE;

CANCER RISK; CARCINOGENESIS; CARDIOVASCULAR DISEASE; CARDIOVASCULAR RISK; CLINICAL TRIAL; COLORECTAL ADENOMA; CORONARY ARTERY DISEASE; DIET SUPPLEMENTATION; DIET THERAPY; DIETARY INTAKE; HOMEOSTASIS; HUMAN; NEURAL TUBE DEFECT; NONHUMAN; POLYP; REVIEW; RISK ASSESSMENT; SIDE EFFECT; VITAMIN SUPPLEMENTATION;

ADENOMA; CARDIOVASCULAR DISEASES; CHRONIC DISEASE; COLORECTAL NEOPLASMS; DIETARY SUPPLEMENTS; DOSE-RESPONSE RELATIONSHIP, DRUG; EPIGENESIS, GENETIC; FOLIC ACID; HOMOCYSTEINE; HUMANS; NEOPLASMS; RISK FACTORS;

EID: 58149138834     PISSN: 13631950     EISSN: 15353885     Source Type: Journal    
DOI: 10.1097/MCO.0b013e32831cec62     Document Type: Review

References (56)

1. Ulrich CM, Potter JD. Folate supplementation: too much of a good thing? Cancer Epidemiol Biomarkers Prev 2006; 15:189-193.
2. Kim YI. Folate and DNA methylation: a mechanistic link between folate deficiency and colorectal cancer? Cancer Epidemiol Biomarkers Prev 2004; 13:511-519.
3. Giovannucci E. Epidemiologic studies of folate and colorectal neoplasia: a review. J Nutr 2002; 132 (8 Suppl):2350S-2355S.
4. Ma J, Stampfer MJ, Giovannucci E, et al. Methylenetetrahydrofolate reductase polymorphism, dietary interactions, and risk of colorectal cancer. Cancer Res 1997; 57:1098-1102.
5. Su LJ, Arab L. Nutritional status of folate and colon cancer risk: evidence from NHANES I epidemiologic follow-up study. Ann Epidemiol 2001; 11:65-72.
6. Sanjoaquin MA, Allen N, Couto E, et al. Folate intake and colorectal cancer risk: a meta-analytical approach. Int J Cancer 2005; 113:825-828.
7. Martinez ME, Giovannucci E, Jiang R, et al. Folate fortification, plasma folate, homocysteine and colorectal adenoma recurrence. Int J Cancer 2006; 119: 1440-1446.
8. McCullough ML, Giovannucci EL. Diet and cancer prevention. Oncogene 2004; 23:6349-6364.
9. Van Guelpen B, Hultdin J, Johansson I, et al. Low folate levels may protect against colorectal cancer. Gut 2006; 55:1461-1466.
10. Lin J, Lee IM, Cook NR, et al. Plasma folate, vitamin B-6, vitamin B-12, and risk of breast cancer in women. Am J Clin Nutr 2008; 87:734-743. This study reports that plasma concentrations of folate were not associated with overall breast cancer risk and confer little or no reduction in overall risk of developing breast cancer.
11. Stolzenberg-Solomon RZ, Chang SC, Leitzmann MF, et al. Folate intake, alcohol use, and postmenopausal breast cancer risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Am J Clin Nutr 2006; 83: 895-904.
12. Homocysteine Lowering Trialists C. Dose-dependent effects of folic acid on blood concentrations of homocysteine: a meta-analysis of the randomized trials. Am J Clin Nutr 2005; 82:806-812.
13. Folsom AR, Nieto FJ, McGovern PG, et al. Prospective study of coronary heart disease incidence in relation to fasting total homocysteine, related genetic polymorphisms, and B vitamins: the Atherosclerosis Risk in Communities (ARIC) Study. Circulation 1998; 98:204-210.
14. Robinson K, Arheart K, Refsum H, et al. Low circulating folate and vitamin B6 concentrations: risk factors for stroke, peripheral vascular disease, and coronary artery disease. Circulation 1998; 97:437-443.
15. Honein MA, Paulozzi U, Mathews TJ, et al. Impact of folic acid fortification of the US food supply on the occurrence of neural tube defects. JAMA 2001; 285:2981-2986.
16. Jacques PF, Selhub J, Bostom AG, et al. The effect of folic acid fortification on plasma folate and total homocysteine concentrations. N Engl J Med 1999; 340:1449-1454.
17. Ray JG. Folic acid food fortification in Canada. Nutr Rev 2004; 62 (6 Pt 2): S35-S39.
18. Mason JB, Dickstein A, Jacques PF, et al. A temporal association between folic acid fortification and an increase in colorectal cancer rates may be illuminating important biological principles: a hypothesis. Cancer Epidemiol Biomarkers Prev 2007; 16:1325-1329. In this article, the authors present the hypothesis that the institution of folic acid fortification may have been responsible for the observed increase in CRC rates in the mid-1990s. Although these observations do not prove causality, the authors encourage, deliberating about the institution of fortification programs.
19. Lieberman DA, Smith FW. Screening for colon malignancy with colonoscopy. Am J Gastroenterol 1991; 86:946-951.
20. Song J, Medline A, Mason JB, et al. Effects of dietary folate on intestinal tumorigenesis in the apcMin mouse. Cancer Res 2000; 60:5434-5440.
21. Song J, Sohn KJ, Medline A, et al. Chemopreventive effects of dietary folate on intestinal polyps in Apc+/-Msh2-/- mice. Cancer Res 2000; 60:3191-3199.
22. Bonaa KH, Njolstad I, Ueland PM, et al. Homocysteine lowering and cardiovascular events after acute myocardial infarction. N Engl J Med 2006; 354:1578-1588.
23. Lonn E, Yusuf S, Arnold MJ, et al. Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med 2006; 354:1567-1577.
24. 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: a randomized trial. JAMA 2008; 299:2027-2036. In this randomized trial, it was tested if a combination of folic acid and other B vitamins lower the risk of CVD among high-risk women. The supplementation did not reduce total cardiovascular events among high-risk women.
25. Cole BF, Baron JA, Sandler RS, et al. Folic acid for the prevention of colorectal adenomas: a randomized clinical trial. JAMA 2007; 297:2351-2359. This is the first double-blind, placebo-controlled, randomized clinical trial showing that folic acid was associated with higher risks of having three or more adenomas and of prostate cancer. The authors conclude that folic acid at 1 mg per day dose does not reduce colorectal adenoma risk.
26. Logan RF, Grainge MJ, Shepherd VC, et al. Aspirin and folic acid for the prevention of recurrent colorectal adenomas. Gastroenterology 2008; 134:29-38. The results of this multicenter, randomized, double-blind trial of folic acid supplements (0.5 mg/day) to prevent colorectal adenoma recurrence show that folate supplementation had no effect on adenoma recurrence.
27. Bazzano LA, Reynolds K, Holder KN, et al. Effect of folic acid supplementation on risk of cardiovascular diseases: a meta-analysis of randomized controlled trials. JAMA 2006; 296:2720-2726.
28. Wang X, Qin X, Demirtas H, et al. Efficacy of folic acid supplementation in stroke prevention: a meta-analysis. Lancet 2007; 369:1876-1882. This meta-analysis assessed the efficacy of folic acid supplementation in the prevention of stroke in relevant randomized trials. This analysis revealed that folic acid supplementation can reduce the risk of stroke in primary prevention.
29. Shirodaria C, Antoniades C, Lee J, et al. Global improvement of vascular function and redox state with low-dose folic acid: implications for folate therapy in patients with coronary artery disease. Circulation 2007; 115: 2262-2270. This study presents that a low-dose folic acid intervention improves vascular function, whereas a high-dose folic acid treatment provides no additional benefit.
30. Rader JI, Weaver CM, Angyal G. Total folate in enriched cereal-grain products in the United States following fortification. Food Chemistry 2000; 70:275-289.
31. Institute of Medicine (U.S.). Standing Committee on the Scientific Evaluation of Dietary Reference Intakes and its Panel on Folate, Other B Vitamins, and Choline and Subcommittee on Upper Reference Levels of Nutrients. Dietary reference intakes for thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12, pantothenic acid, biotin, and choline. Washington, D.C.: National Academy Press; 1998.
32. Shaw S, Jayatilleke E, Herbert V, et al. Cleavage of folates during ethanol metabolism. Role of acetaldehyde/xanthine oxidase-generated superoxide. Biochem J 1989; 257:277-280.
33. Pfeiffer CM, Caudill SP, Gunter EW, et al. Biochemical indicators of B vitamin status in the US population after folic acid fortification: results from the National Health and Nutrition Examination Survey 1999-2000. Am J Clin Nutr 2005; 82:442-450.
34. 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; 7:41. This article shows that a supplementation of 400 μg folic acid per day leads to detectable unmetabolized folic acid in serum.
35. 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; 136:189-194.
36. Achon M, Alonso-Aperte E, Ubeda N, et al. Supranormal dietary folic acid supplementation: effects on methionine metabolism in weanling rats. Br J Nutr 2007; 98:490-496. This rat study presents that a 4-week supplementation of folic acid did not exert adverse effects on one-carbon metabolism under the studied conditions.
37. Ashokkumar B, Mohammed ZM, Vaziri ND, et al. Effect of folate oversupplementation on folate uptake by human intestinal and renal epithelial cells. Am J Clin Nutr 2007; 86:159-166. This in-vitro study examined the effects of oversupplementation of folic acid on intestinal and renal folate uptake processes and showed that these processes are downregulated.
38. Canistro D, Pozzetti L, Sapone A, et al. Perturbation of rat hepatic metabolising enzymes by folic acid supplementation. Mutat Res 2008; 637:16-22. This rat study analyzed the potential of folate to modulate XMEs. These results point at the requirement to clarify the toxicological implications of folic acid for humans.
39. Pellis L, Dommels Y, Venema D, et al. High folic acid increases cell turnover and lowers differentiation and iron content in human HT29 colon cancer cells. Br J Nutr 2008; 99:703-708. The results of this study using human colon cancer cells with high folic acid supplementation corroborate the promoting effect of folic acid supplementation on transformed cells.
40. van den Donk M, van Engeland M, Pellis L, et al. Dietary folate intake in combination with MTHFR C677T genotype and promoter methylation of tumor suppressor and DNA repair genes in sporadic colorectal adenomas. Cancer Epidemiol Biomarkers Prev 2007; 16:327-333.
41. van den Donk M, Pellis L, Crott JW, et al. Folic acid and vitamin B-12 supplementation does not favorably influence uracil incorporation and promoter methylation in rectal mucosa DNA of subjects with previous colorectal adenomas. J Nutr 2007; 137:2114-2120. In this study, a supplementation of high doses of folic acid and vitamin B12 did not favorably influence biomarkers of normal DNA synthesis and methylation pattern.
42. Keyes MK, Jang H, Mason JB, et al. Older age and dietary folate are determinants of genomic and p16-specific DNA methylation in mouse colon. J Nutr 2007; 137:1713-1717. In this mice study, it was shown that the epigenetic determinants, genomic DNA methylation and promoter methylation, which are associated with carcinogenesis, are dependent on the level of dietary folate.
43. Piyathilake CJ, Celedonio JE, Macaluso M, et al. Mandatory fortification with folic acid in the United States is associated with increased expression of DNA methyltransferase-1 in the cervix. Nutrition 2008; 24:94-99. This study analyzed archived cervical neoplasia specimens before (1990-1992) and after (2000-2002) mandatory folic acid fortification and showed an increased expression of DNA methyltransferase-1, an enzyme that controls normal DNA methylation.
44. Larsson SC, Giovannucci E, Wolk A. Folate intake, MTHFR polymorphisms, and risk of esophageal, gastric, and pancreatic cancer: a meta-analysis. Gastroenterology 2006; 131:1271-1283.
45. Skinner HG, Michaud DS, Giovannucci EL, et al. A prospective study of folate intake and the risk of pancreatic cancer in men and women. Am J Epidemiol 2004; 160:248-258.
46. Ericson U, Sonestedt E, Gullberg B, et al. High folate intake is associated with lower breast cancer incidence in postmenopausal women in the Malmo Diet and Cancer cohort. Am J Clin Nutr 2007; 86:434-443.
47. Choi SW, Mason JB. Folate carcinogenesis: an integrated scheme. J Nutr 2000; 130:129-132.
48. Choi SW, Mason JB. Folate status: effects on pathways of colorectal carcinogenesis. J Nutr 2002; 132 (8 Suppl):2413S-2418S.
49. Duthie SJ, Narayanan S, Blum S, et al. 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.
50. Duthie SJ, Grant G, Narayanan S. Increased uracil misincorporation in lymphocytes from folate-deficient rats. Br J Cancer 2000; 83:1532-1537.
51. Fuks F. DNA methylation and histone modifications: teaming up to silence genes. Curr Opin Genet Dev 2005; 15:490-495.
52. Dong C, Yoon W, Goldschmidt-Clermont PJ. DNA methylation and atherosclerosis. J Nutr 2002; 132 (8 Suppl):2406S-2409S.
53. Friso S, Choi SW. Gene-nutrient interactions and DNA methylation. J Nutr 2002; 132 (8 Suppl):2382S-2387S.
54. Choi SW, Friso S, Keyes MK, Mason JB. Folate supplementation increases genomic DNA methylation in the liver of elder rats. Br J Nutr 2005; 93:31-35.
55. Kono S, Chen K. Genetic polymorphisms of methylenetetrahydrofolate reductase and colorectal cancer and adenoma. Cancer Sci 2005; 96:535-542.
56. Friso S, Choi SW. Gene-nutrient interactions in one-carbon metabolism. Curr Drug Metab 2005; 6:37-46.