Folates and Folic Acid

What are Folates and Folic Acid?

Folate is a general term used to describe the group of water soluble B-vitamins that includes Folic acid among other compounds. Folate and Folic acid are often used interchangeably but they refer to different compounds. Folic acid refers to the compound pteroylmonoglutamic acid, which is a fully oxidized synthetic compound. Folate refers to the many different tetrahydrofolate compound derivatives that are naturally found in foods. A Folic Acid precursor was isolated from spinach in 1941 and receives it’s name from the Latin words, folium, meaning leaf. Folic Acid does not occur naturally. Folic acid is the oxidized form of naturally occurring tetrahydrofolates. Other forms of folate are oxidized into folic acid in the cells of your body.

More about Folate

As mentioned above, Folate refers to all the derivatives of tetrahydrofolate that occur in nature. There are three forms of Folate that are found in supplements: Folic Acid, 5- formyltetrahydrofolic acid, 5-methyltetrahydrofolic acid (methylfolate).

  1. Folic Acid - This is a fully oxidized synthetic chemical compound that is not found in natural foods. This compound was isolated from spinach in 1941. It is the most used form of Folate in dietary supplements due to its stability. Folatefortified foods or Folic Acid-fortified foods contain this compound.
  2. 5-formyltetrahydrofolic acid (Folnic Acid) - This is a standard supplement that is is given to cancer patients that are getting anti-cancer treatments. It is often prescribed as Methotrexate and 5-flurouracil. It is also found in some dietary supplements as calcium folinate.
  3. 5-methyltetrahydrofolic acid (methyl-folate or 5- MTHF) - Recently, this has been available in dietary supplements. Currently, a manufacture has patents on this compound in foods, and thus, it can only be found by certain manufacturers in certain formulas and doses. This is the predominant form of Folate in the blood. It is considered by many physicians to be the best Folate supplement because it is readily absorbed into the body

Why are Folates and Folic Acid important?

Folate deficiency has been reported to be the most common vitamin deficiency in the United States2. Folate deficiency is associated with megaloblastic anemia, neural tube defects, increased risk of certain cancers, and elevated plasma homocysteine. Elevated plasma homocysteine is a risk factor for cardiovascular disease, stroke, and other health conditions. Deficiencies of folate can occur due to inadequate dietary intake, increased requirement (pregnancy), malabsorption, improper liver functioning, increased elimination of folate3,4.

Folate coenzymes play an important role in the methylation of DNA, synthesis of nucleotides (the subunits of human DNA), and gene expression. Folates also help with the biosynthesis of purines and thymidylate which are key compounds in DNA synthesis and replication. DNA synthesis and replication occurs naturally in the body to create new cells to replace old or improperly functioning cells. Folates help interconvert amino acids. For example, the conversion of homocysteine to methionine which serves as huge methionine source for the production of S-adenosylmethionine (SAMe). SAMe is the universal methyl donor required in all methylation processes in the body.

Methylation

Methylation is the addition of a Methyl (-CH3) group to a compound. Methylation is used in the body for the regulation of gene expression and protein function. It is also used in the RNA processing of DNA synthesis. DNA is what tells every cell what to do. It provides the directions for the creation of all compounds in the body. It also tells each cell how to behave. Cells in different parts of the body perform particular functions and methylation allows for the DNA to condense in the areas where those particular directions are not needed for that cell and increases efficiency in protein production and gene expression.

Folate is also necessary for rapid cell division and growth. Thus, it is very important in the first trimester of pregnancy. Neural tube defects are serious birth defects of the spinal cord and brain that can occur in the first trimester. The development of the brain and spinal cord occurs before Day 24, which is before a woman knows she is pregnant5. Thus, it is important for woman of childbearing age to have proper amounts of folic acid in their diet. This is why in 1998, in the United States, the FDA mandated the fortification of cereal-grain to be fortified with 140 micrograms of folic acid per 100 grams of grains.

Megaloblastic Anemia

Megaloblastic anemia is the release of immature and enlarged erythrocytes (red blood cells). Due to the depression of DNA synthesis, a failure of the normal process of red blood cell maturation in the bone marrow occurs5,6. This is not good because the immature and large red blood cells are too big for the smaller blood vessels in the body (capillaries). Also, because the red blood cells are immature, they are not able to carry proper amounts of oxygen in the body.A vitamins B12 deficiency could also result in megaloblastic anemia.

Hyperhomocysteinemia

Homocysteine is a sulfur-containing amino acid which is converted to methionine and cysteine. One reaction uses a vitamin B12- dependent enzyme to convert homocysteine directly to methionine. Another reaction converts homocysteine to cysteine by the use of a B6-dependent enzyme. Both methionine and cysteine are needed in the body to help methylate different chemicals in the body.

The plasma total homocysteine can be elevated for multiple reasons including, low folate, low vitamin B12, low vitamin B6, renal insufficiency, MTHFR gene mutations, and the use of certain medications7-10. High homocysteine levels in the blood plasma are an independent risk factor for coronary heart disease, calcification of arteries, stroke, peripheral vascular disease, and other diseases that can be associated with abnormal blood clotting. High homocysteine levels in the blood plasma are is also linked to depression, osteoporosis, Alzheimer’s disease, multiple sclerosis, rheumatoid arthritis, placental abruption, NTD, renal failure, and type II diabetes11-13. An independent risk factor simply means that high homocysteine levels can lead to those diseases independent of other environmental factors.

Cancer

Studies have begun to show that low folate in the body has been associated with cervical cancer, colorectal cancer, lung cancer, esophageal cancer, brain cancer, pancreatic cancer, breast cancer, leukemia, and neuroblastoma. The reason why low folate can increase the risk of cancer is due to the impairment of DNA repair, abnormal DNA methylation, and genomic instability14-15. Abnormal DNA methylation and genomic instability can influence the expression of cancer-related genes. Studies have also shown that adequate folate in the body can result in a 3 fold decrease in risk of colon cancer16.

Where can I find Folates in my food?

Folate is an essential nutrient. An essential nutrient is one that humans are unable to make on their own. Thus, folate is unable to be produced, from scratch, in the body and must be obtained from food. Folates mainly come from leafy green vegetables, fruits, legumes, eggs, dairy products and orange juice. Folic acid, the fully oxidized synthetic form of Folate is found in folic acid-fortified grain products and dietary supplements containing folic acid.

Why is 5-MTHF better than other Folate supplements?

Dietary intake of Folate is commonly in the form of Folnic acid, which is a polyglutamate. This must be broken down into monoglutamates in the intestine of the human body before 5- MTHF can be made. Often times, individuals with Folate deficiencies lack the ability to convert Folnic acid into 5-MTHF properly, or are unable to make the amount that the body needs. Thus, taking 5-MTHF supplements can be more helpful than Folic Acid or Folnic Acid supplements. Even when Folic acid, the fully oxidized form of Folate, is partially digested before forming 5- MTHF. Folic Acid needs to be partially digested because it is different from the naturally occurring folates. If that digestive process is not working properly, then Folic acid supplements are not the proper supplement choice. There has been research done that has concluded that the ingestion of 5-formylTHF (Folnic Acid) is as good as the ingestion of 5-MTHF1. Many scientists debate this conclusion, however, 5- MTHF supplements are often preferred by physicians due to their ready uptake by the body.

 

References:

1. Whitehead VM, et al. Intestinal conversion of folinic acid to 5- methyltetrahydrofolate in man. Br J Haematol. 1972 Jan;22(1):63-72.

2. Duthie SJ. Folic acid deficiency and cancer: mechanisms of DNA instability. BR Med Bull. 1999; 55(3):578-92.

3. Kim YI. Folic acid fortification and supplementation—good for some but not so good for others. Nutr Rev. 2007 Nov;65(11):504-11.

4. Wright AJ, Dainty JR, Finglas PM. Folic acid metabolism in human subjects revisited: potential implications for proposed mandatory folic acid fortification in the UK. British Journal of Nutrition. 2007;98:667-75.

5. Bender DA. Nutritional biochemistry of the vitamins. Cambridge (UK): Cambridge University Press; 2003.

6. Forssén KM, et al. Folates and dairy products: a critical update. J Am Coll Nutr. 2000 Apr;19(2 Suppl):100S-110S.

7. Selhub J, et al. Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. JAMA. 1993 Dec 8;270(22): 2693-8.

8. Ubbink JB, et al. Vitamin B12, vitamin B6, and folate nutritional status in men with hyperhomocysteinemia. Am J Clin Nutr. 1993 Jan; 57(1):47-53.

9. Pfeiffer CM, et al. Biochemical indications 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.

10. Faeh D, Chiolero A, Paccaud F. Homocysteine as a risk factor for cardiovascular diseaseL should we (still) worry about? Swiss Med Wkly. 2006 Dec 2;136(47-48):745-56.

11. Ueland PM, et al. The controversy over homocysteine and cardiovascular risk. Am J Clin Nutr. 2000 Aug;72(2):324-32.

12.Richter B, et al. Interaction of folate and homocysteine pathway genotypes evaluated in susceptibility to neural tube defects (NTD) in a German population. J Hum Genet. 2001; 46(3):105-9.

13.Dangour, et al. Plasma homocysteine, but not folate or vitamin B12, predicts mortality in older people in the United Kingdom. J Nutr. 2008 June;138(6):1121-8.

14.Giovannucci E. Epidemiologic studies of folate and colorectal neoplasia: a review. J Nutr. 2002 Aug;132(8 Suppl):2350S-2355S.

15.Ulrich CM. Nutrigenetics in cancer research—folate metabolism and colorectal cancer. J Nutr. 2005 Nov;135(11):2698-702.

16.Giovannucci E, et al. Alcohol, low-methionine—low-folate diets, and risk of colon cancer in men. J Natl Cancer Inst. 1995 Feb 15;87(4):265-73.