Serving Size: 1 Vegetarian Capsule
Product Contains: Vitamin B1 (as Thiamine HCl) 100 mg; Vitamin B2 50 mg; (as Riboflavin HCl 35 mg; Riboflavin-5-Phosphate 15 mg) Vitamin B3 50 mg; (as Niacinamide 25 mg; Niacin 25 mg) Vitamin B6 50 mg; (as Pyridoxine HCl 40 mg; Pyridoxyl-5-Phosphate 10 mg) Folates (NatureFolateTM blend) 200 mcg: Vitamin B12 (as Methylcobalamin) 250 mcg; Biotin (as d-Biotin) 2 mg; Vitamin B5 (as Pantothenic Acid) 100 mg; Choline 200 mg; Trimethylglycine 200 mg;
Other Ingredients: Microcrystalline cellulose, magnesium stearate.
Recommended Use: As a dietary supplement, take one capsule per day with meals or as directed by your health care practitioner.
This product does not contain: wheat, yeast, soy , gluten, eggs, dairy, corn, artificial colors, flavors, sugars, or preservatives.
Rationale for Replacing Folic Acid with NatureFolate™
THIS INFORMATION IS PROVIDED FOR THE USE OF PHYSICIANS AND OTHER LICENSED HEALTH CARE PRACTITIONERS ONLY. THIS INFORMATION IS INTENDED FOR PHYSICIANS AND OTHER LICENSED HEALTH CARE PROVIDERS TO USE AS A BASIS FOR DETERMINING WHETHER OR NOT TO RECOMMEND THESE PRODUCTS TO THEIR PATIENTS. THIS MEDICAL AND SCIENTIFIC INFORMATION IS NOT FOR USE BY CONSUMERS. THE DIETARY SUPPLEMENT PRODUCTS OFFERED BY DESIGNS FOR HEALTH ARE NOT INTENDED FOR USE BY CONSUMERS AS A MEANS TO CURE, TREAT, PREVENT, DIAGNOSE, OR MITIGATE ANY DISEASE OR OTHER MEDICAL CONDITION.
Introduction
Folate is a generic term for a group of water soluble b-vitamins that includes folic acid and naturally occurring folates in food. The terms "folic acid" and "folate" are often used interchangeably, but more appropriately, folic acid refers to the fully oxidized synthetic compound (pteroylmonoglutamic acid) used in dietary supplements and in food fortification while folate refers to the various tetrahydrofolate derivatives naturally present in foods.1, 2 Folic acid got its name from folium, the Latin word for leaf when it was isolated from spinach in 1941.(1)
Humans are unable to make their own folate, making it an essential nutrient that is typically obtained from the diet.3 Important sources of folate
are leafy green vegetables, fruits, legumes, liver, eggs, dairy products, and orange juice. Food folates are mainly pteroylpolyglutamate forms of tetrahydofolate, 5-methyl-tetrahydrofolate (5-MTHF), 10-formyltetrahydrofolate and 5-formyltetrahydrofolate.(4, 5) Folic acid, which is again, the fully oxidized synthetic compound (pteroylmonoglutamic acid), is obtained in the diet mainly from folic acid-fortified grain products and folic acidcontaining supplements. Unlike any of the natural folates in foods that are in reduced forms, folic acid is a fully oxidized compound. Human exposure to this form was non-existent until its chemical synthesis (1943) and use in food fortification (1998) and dietary supplements.(6) The small amount of folic acid that can be isolated from cells occurs through the in vitro oxidation of natural tetrahydrofolates.(7)
There are three forms of folate currently used in dietary supplements: (1) folic acid, a fully oxidized synthetic chemical compound; (2) folinic acid, also known as 5-formyl- tetrahydrofolic acid, leucovorin calcium and calcium folinate, and 3) methyl folate, also known as the calcium salt of 5-methyltetrahydrofolic acid.(8, 9) Folic acid is the most commonly used form in dietary supplements since its synthesis, due to its stability and lower cost.1, 7 Folinic acid has been the standard adjunct to anti-cancer drugs such as methotrexate and 5-fluorouracil.(10, 11) Following the development of the stable form of folinic acid, calcium folinate, it has found use in dietary supplements.(8) More recently 5-MTHF has become available for use in dietary supplements.(7, 9) A manufacturer that holds rights to several patents covering the use of 5-MTHF in foods has imposed stringent restrictions such as specifying what formulas and dosages can be used, consequently preventing the general use of 5-MTHF in dietary supplements.
Health Concerns with Folic Acid
Folates are essential cofactors in one carbon metabolism and their deficiency is associated with health risks such as neural tube defects, cancers and hyperhomocysteinemia.(2, 12, 13) Following the discovery and synthesis of folic acid, it has been demonstrated that folic acid supplementation can greatly reduce the incidence and recurrence of neural tube defects.(14, 15) This led to the mandatory fortification of cereal-grain products with folic acid in the USA and Canada.(16, 17) Since then, studies reported many health benefits of folic acid fortification.(18-20) However, there were also studies that raised
concern over the safety of chronically high intake of folic acid from fortified foods, beverages and dietary supplements.(6, 21, 22) It has been shown that many breakfast cereals are over-fortified with folic acid, that when consumed with other folic acid-containing beverages and dietary supplements, could result in intakes that greatly exceed recommended daily doses.(21, 23-25)
The risk of higher than desired folic acid intake is compounded by concerns over the appearance of unmetabolized (unaltered) folic acid (pteroylmonoglutamic
acid) in the blood circulatory system.(22, 26) It has been demonstrated that even a modest intake of less than 400 micrograms per day of folic acid from fortified foods or supplements may lead to the appearance of umetabolized folic acid in the bloodstream.(27-29) Unlike the natural folates (e.g., 5-methyltetrahydrofolate and 5-formyltetrahydrofolate), folic acid is not a normal metabolite and must be reduced to dihydrofolate and then to tetrahydrofolate, the form that can enter the folate cycle.(7, 26) The low dihydrofolate reductase activity in human liver, where folic acid is first metabolized, could be saturated following even a modest or repeated dietary intake of folic acid, resulting in unmetabolized folic acid entering the systemic circulation.(22, 26)
The health outcomes of chronic exposure to unmetabolized folic acid have not been evaluated and several papers recommend that long term studies on the safety of folic acid be conducted.(6, 21, 30) There are several studies that seem to indicate potential risk of folic acid intake.(31-36) One study showed an apparent increase in the incidence of colorectal cancer after the mandatory fortification of folic acid in both the USA and Canada.(35) There is a growing body of evidence that seems to suggest the dual role of folates in carcinogenesis. High folate status prevents cancer development in the absence of preneoplastic lesions, but folic acid supplementation promotes the growth and development of existing preneoplastic lesions.(30, 37, 38)
Another concern with folic acid intake is associated with accelerated cognitive decline in older persons. One paper reported that persons who consumed folic acid in excess of 400 micrograms per day had a significantly faster rate of cognitive decline than supplement non-users, possibly due to masking of unrecognized B12 deficiency.(31) The elderly are known to often have compromised B12 status and consequently could be at greater risk for cognitive decline.(36)
NatureFolate™
Researchers at Designs for Health thoroughly reviewed hundreds of papers on folic acid and have decided that the fully oxidized, synthetic form is not the ideal choice for nutritional supplement formulations. DFH is replacing folic acid with a natural folate blend called NatureFolate™. NatureFolate™ is made from a concentrated vegetable juice powder containing a blend of natural folates, including 5-methyltetrahydrofolate (5-MTHF) and 5-formyltetrahydrofolate with additional fortified 5-formyltetrahydrofolate as calcium folinate.
References
1. Hoffbrand AV, Weir DG. The history of folic acid. Br J Haematol. 2001 Jun;113(3):579-89.
2. Bender DA. Nutritional biochemistry of the vitamins. Cambridge (UK): Cambridge University Press; 2003.
3. Grooper SS, Smith JL, Groff JL. Advanced nutrition and human metabolism. Belmont (CA): Thomson Wadsworth; 2005.
4. O'Broin JD, Temperley IJ, Brown JP, et al. Nutritional stability of various naturally occurring monoglutamate derivatives of folic acid. Am J Clin Nutr. 1975 May;28(5):438-44.
5. Gregory JF 3rd, Bhandari SD, Bailey LB, et al. Relative bioavailability of deuterium-labeled monoglutamyl tetrahydrofolates and folic acid in human subjects. Am J Clin Nutr. 1992
Jun;55(6):1147-53.
6. Solomons NW. Food fortification with folic acid: has the other shoe dropped? Nutr Rev. 2007 Nov;65(11):512-5.
7. Scott J. Methyltetrahydrofolate: The superior alternative to folic acid. In: Kramer K, Hoppe PP, Packer L, editors. Nutraceuticals in health and disease prevention. New York: Marcer Decker;
2001. p. 75-90.
8. Kelly GS. Folates: supplemental forms and therapeutic applications. Altern Med Rev. 1998 Jun;3(3):208-20
9. Wallin H. Calcium L-5-Methyltetrahydrofolate (L-5-MTHF-Ca). Chemical and Technical Assessment 65th JECFA ftp://ftp.fao.org/es/esn/jecfa/cta_65_l-5-mthf.pdf
10. Straw JA, Szapary D, Wynn WT. Pharmacokinetics of the diastereoisomers of leucovorin after intravenous and oral administration to normal subjects. Cancer Res. 1984 Jul;44(7):3114-9
11. Boarman DM, Allegra CJ. Intracellular metabolism of 5-formyl tetrahydrofolate in human breast and colon cell lines. Cancer Res. 1992 Jan 1;52(1):36-44
12. Brody T. Nutritional biochemistry. San Diego: Academic Press 1999.
13. Lucock M. Is folic acid the ultimate functional food component for disease prevention? BMJ. 2004 Jan 24;328(7433):211-4.
14. Center for Disease Control and Prevention. Spina Bifida and Anencephaly Before and After Folic Acid Mandate --- United States, 1995--1996 and 1999-2000. MMWR Weekly, May 7, 2004 53(17):362-365 http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5317a3.htm
15. Williams LJ, Mai CT, Edmonds LD, et al. Prevalence of spina bifida and anencephaly during the transition to mandatory folic acid fortification in the United States. Teratology. 2002Jul;66(1):33-9.
16. Rader JI. Folic acid fortification, folate status and plasma homocysteine. J Nutr. 2002 Aug;132(8 Suppl):2466S-2470S.
17. 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 Jul 12;357(2):135-42.
18. 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 May 13;340(19):1449-54.
19. Choumenkovitch SF, Jacques PF, Nadeau MR, et al. Folic acid fortification increases red blood cell folate concentrations in the Framingham study. J Nutr. 2001 Dec;131(12):3277-80.
20. 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 Aug;82(2):442-50.
21. Ulrich CM, Potter JD. Folate supplementation: too much of a good thing? Cancer Epidemiol Biomarkers Prev. 2006 Feb;15(2):189-93.
22. Wright AJ, Dainty JR, Finglas PM. 2007. Folic acid metabolism in human subjects revisited: potential implications for proposed mandatory folic acid fortification in the UK. British Journal of Nutrition 98:667-675.
23. Lewis CJ, Crane NT, Wilson DB, et al. Estimated folate intakes: data updated to reflect food fortification, increased bioavailability, and dietary supplement use. Am J Clin Nutr. 1999 Aug;70(2):198-207.
24. Quinlivan EP, Gregory JF 3rd. Effect of food fortification on folic acid intake in the United States. Am J Clin Nutr. 2003 Jan;77(1):221-5.
25. Whittaker P, Tufaro PR, Rader JI. Iron and folate in fortified cereals. J Am Coll Nutr. 2001 Jun;20(3):247-54.
26. Powers HJ. Folic acid under scrutiny. Br J Nutr. 2007 Oct;98(4):665-6. Epub 2007
27. Kelly P, McPartlin J, Goggins M, et al. Unmetabolized folic acid in serum: acute studies in subjects consuming fortified food and supplements. Am J Clin Nutr. 1997 Jun;65(6):1790-5.
28. Sweeney MR, McPartlin J, Weir DG, et al. Postprandial serum folic acid response to multiple doses of folic acid in fortified bread. Br J Nutr. 2006 Jan;95(1):145-51.
29. 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 Mar 22;7(147):41.
30. Smith AD, Kim YI, Refsum H. Is folic acid good for everyone? Am J Clin Nutr. 2008 Mar;87(3):517-33.
31. Morris MC, Evans DA, Bienias JL, et al. Dietary folate and vitamin B12 intake and cognitive decline among community-dwelling older persons. Arch Neurol. 2005 Apr;62(4):641-5.
32. Kim YI. Does a high folate intake increase the risk of breast cancer? Nutr Rev. 2006 Oct;64(10 Pt 1):468-75.
33. 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 Apr;83(4):895-904.
34. Cole BF, Baron JA, Sandler RS, et. al. Folic acid for the prevention of colorectal adenomas: a randomized clinical trial. JAMA. 2007 Jun 6;297(21):2351-9.
35. 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 Jul;16(7):1325-9.
36. Morris MS, Jacques PF, Rosenberg IH, et al. Folate and vitamin B-12 status in relation to anemia, macrocytosis, and cognitive impairment in older Americans in the age of folic acid fortification. Am J Clin Nutr. 2007 Jan;85(1):193-200.
37. Kim YI. Folic acid fortification and supplementation--good for some but not so good for others. Nutr Rev. 2007 Nov;65(11):504-11.
38. Ulrich CM. Folate and cancer prevention: a closer look at a complex picture. Am J Clin Nutr. 2007 Aug;86(2):271-3.
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