Folate is a B vitamin found in dark green leafy vegetables such as spinach, romaine lettuce, turnip greens, mustard greens, collard greens, as well as broccoli, beets and lentils. The word folate in Latin is folium, meaning leaf. Many people confuse folate with folic acid. Folic acid is an oxidized synthetic compound found in dietary supplements and fortified foods.

The bioactive form of folate that enters into the folate metabolic cycle is tetrahydrofolate (THF).(1) Folic acid begins its reduction and conversion into THF in the liver.



This process requires dihydrofolate reductase. The naturally low activity of this enzyme may result in high levels of unmetabolized folic acid entering the blood stream. Several studies have reported the presence of unmetabolized folic acid in the blood following the intake of folic acid supplements or fortified foods.(2)

Naturally occurring folate from fruits and vegetables is metabolized into THF in the mucosa of the small intestines. Naturally occurring folate functions as a coenzyme for the synthesis of DNA, to repair DNA, and acts as a cofactor in certain biological reactions. It is important in assisting rapid cell division and growth, particularly in developing embryos and in infancy. Folate aids in the development of red blood cells, prevents anemia, supports nervous system function, prevents neural tube defects in newborns. A lack of dietary folate can lead to many health problems, including macrocytic anemia with weakness or shortness of breath, weakness and limb numbness, pregnancy complications, mental confusion, forgetfulness, cognitive declines, depression, sore or swollen tongue, headaches, heart palpitations, irritability, and behavioral disorders.

Food fortification of folic acid was mandated in the United States in 1998. While the incidence of neural tube defects (NTD) has been significantly reduced since folic acid fortification, there has been increased concern about the safety of high intake of folic acid.(3) For example, the increase of colon cancer in the United States, Canada, and Chile was associated with the institution of folic acid fortification programs.(4) (5) (6) Additionally, a randomized control trial associated the daily supplementation of folic acid with an increased risk of prostate cancer.(7) Researchers hypothesize that excess folic acid may stimulate the growth of established neoplasm. The presence of unmetabolized folic acid in the blood is also associated with decreased natural killer cell cytotoxicity, which weakens their ability to destroy tumor cells.(8)

Another important role played by folate is in the conversion of homocysteine to the amino acid methionine found in meat, milk, cheese, eggs, white flour, and other heavy protein foods that we love. A deficiency of folate derived 5-methyl-THF prevents the conversion of homocysteine to methionine. This convertion also requires adequate levels of vitamin B6 (the active form P5P), vitamin B12 (methylcobalamin or methylB12), and niacin. The enzyme methionine synthase (MS) is responsible for the regeneration of methionine from homocysteine. MS relies on vitamin B-12 (methylcobalamin) and niacin dependent methionine synthase reductase (MSR) in order to convert 5-methyl-THF to THF. In the process, MS transfers a methyl group to homocysteine to form Methionine.

Elevated homocysteine levels may cause irritation to the blood vessels, thereby increasing the risk for hardening of the arteries, blood clots, heart attack, and/or stroke. High levels of homocysteine is also implicated in non-insulin-dependent diabetes. People with high homocysteine levels are also seen in people with kidney disease, low levels of thyroid hormones, psoriasis, and in those taking certain medications such as trimethoprim, pyrimethamine, methotrexate and the class of sulfonamides.(9)

It has been recognized that some people with high levels of homocysteine also have a common genetic variant that impairs their ability to convert THF to 5-methl-THF through the enzyme methylenetetrahydrofolate reductase, abbreviated MTHFR. More on this in Part 2 of this article.

Most people should be able to get plenty of folate through the consumption of adequate vegetables, particularly the dark green leafy variety. Women planning on becoming pregnant should consume between 800 and 1200 mcg of folate per day for several months before the start of pregnancy.

We suggest supplementing with the active form of folate 5-MTHF. Also consider the role the intestines play in the formation of THF, which may include optimizing the intestinal flora and treating candida.

Bio-active folate and vitamin B-12:





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