How to get rid of unmetabolized folic acid?
Folate or folic acid is referred to as vitamin B9, a key cofactor in one-carbon metabolism. Folate is the common terminology used for a group of molecules including folic acid, folinic acid or 5-formyltetrahydrofolate (5-FTHF), 5-methyltetrahydrofolate (5-MTHF) or L-methylfolate, 10-formyl-tetrahydrofolate (10-formyl-THF), 5,10-methylene-THF and unsubstituted tetrahydrofolate (THF).
Supplementation of folate is required to maintain adequate levels in mammals. Folic acid, folinic acid and 5-MTHF are different forms of folate that can be found in folate supplements1. The main differences between folate and folic acid is all about the forms in which they exist, folate is a reduced form while folic acid is an oxidized form. The reduced forms of vitamin B9 such as dihydrofolate and tetrahydrofolate are less stable biochemically, whereas the oxidized form, folic acid in supplements and fortified foods stays stable for a longer period of time2. Folic acid is a synthetic (man-made) water-soluble compound that does not exist in nature. It is comprised of a pteroyl group which is connected to a glutamic acid part and shows greater stability than the folates which are in reduced forms. In addition, folic acid depends upon 4 different conversion processes that need to happen within the body before it can become the 5-MTHF which your body can then directly absorb and use.
In contrast, Folate is a naturally occurring and comprised of polyglutamines in their tails. As compared to folate, folinic acid is also a naturally occurring compound in food, however, it is readily converted to THF even in the absence of dihydrofolate reductase (DHFR). Consequently, the effects of folinic acid are not affected by the drug compounds, for instance, methotrexate, which inhibits DHFR.
5-MTHF, naturally available, has metabolic advantages over folic acid and folinic acid. One advantage is that changes in the pH of the gastrointestinal tract do not affect the absorption of 5-MTHF. And the other is that the bioavailability of 5-MTHF is not interrupted by metabolic issues related to genetics or any metabolic-related diseases. So the supplementation of 5-MTHF rather than folic acid is advised to reduce the possibilities of masking hematological symptoms that occur with a deficiency of vitamin B12. Also, 5-MTHF is believed to reduce the probable adverse effects caused by unmetabolized folic acid in the human body. Several notions such as disruption in folate metabolism due to genetic shortcomings like methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms or any drug interactions, malabsorption syndromes such as celiac and Crohn’s disease, long-term medications (folate antagonists, antacids), alcoholism, poor absorption of ingested folate and low dietary intake, have been considered for folate deficiency in the human population. Folate deficiency has been treated by recommending folic acid supplements and fortified foods – even though this may be an inferior way to address the deficiency. Supplementing with the active form of folate, L-5-Methylfolate, is now preferred for obtaining optimal health benefits.
The food sources of folate are green leafy vegetables, sprouts, brewer’s yeast, beans, peanuts, sunflower seeds, cruciferous vegetables, fruits, whole grains, liver, seafood, and eggs.. Folate is necessary for DNA and RNA synthesis, metabolism of amino acids, regulated cell division, activation of B12, reduction of homocysteine levels, supporting the production of s-adenosyl methionine (SAMe) and reducing the of risk of neural tube defects in the pregnant women. Besides these above-mentioned functions, folate is a key methyl donor and involved in the synthesis of neurotransmitters such as dopamine, serotonin, melatonin, epinephrine and norepinephrine. Cancer, cardiovascular disease, neural tube defects and cognitive impairment are the possible consequences of folate deficiency. As per the Food and Agriculture Organization of the United Nations and World Health Organization (FAO/WHO) Expert Consultation report made in 1988, three states of folate nutrition were defined:
- folate adequacy
- impending folate deficiency and
- overt folate deficiency
Improvement in folate status for folate adequacy is not required and an increase in folate intake would not have any benefits. On the contrary, increasing folate intake levels would be mandatory to the people with impending folate and overt folate deficiencies. In the FAO/WHO report, folate levels greater than 150 mg/L in a red blood cell and greater than 7.5 mg/L in the liver was recommended.
The red blood cell folate levels has been considered to be the golden standard for folate status, whereas the folate levels in the liver was thought to be of less relevance to a person’s true folate status.
Because of the remarkable fluctuation in the plasma folate levels, it is rarely used in the identification of folate status. Hematological pathogenesis indicators including mean corpuscular volume, hypersegmentation of neutrophils and early stages of anemia are important indicators for the reduced folate status. Furthermore, plasma homocysteine is a very sensitive biomarker of folate status. An estimated average requirement as well as an estimation of the recommended dietary allowance of folic acid was suggested by FAO/WHO consultation experts as shown in the table below.
It’s worth noting that these recommendations were made long before the Human Genome Project came along which gave us new information on folate metabolism through genetic polymorphisms found in the body like MTHFR.
Estimated average requirement (mg/day)
Recommended nutrient intake (mg/day)
Folate acts as a catalyst in one-carbon metabolism, its notable biological reactions are:
- synthesis of purine and pyrimidine bases of nucleic acids
- production of methylating agents that are required for gene regulation and
- metabolism of amino acids including methionine, serine, glycine and histidine.
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L-methylfolate has several advantages over folic acid including:
- this active form crosses the BBB easily
- the requirement of a 4-step conversion process pathway from folic acid to the active form gets bypassed
- less chance of masking a vitamin B12 deficiency
- the bioavailability is 7 times better than folic acid11.
FAO/WHO expert consultation on human vitamin and mineral requirements. Vitamin B12. Chapter-5; 53-64 (http://www.fao.org/3/a-y2809e.pdf).
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