Folic Acid & MTHFR
Food fortification and numerous supplements utilize folic acid as the form of folate. It’s synthetic and different to the natural forms of folate in food.
The body employs the folates present in food as coenzymes and regulatory molecules. The most bioactive form of folate is methylfolate which issued for methylation processes.
Evidence suggests that the consumption of folic acid can be harmful and can’t fix a folate deficiency due to an MTHFR mutation.
Folic Acid Inhibits Folate Receptors
Folate receptors have a high affinity for folic acid. This means that the folate receptors will bind to folic acid over natural folates causing a reduction in methylfolate available for methylation.
Folic Acid blocks the uptake of methylfolate to the brain
Only methylfolate, among the various forms of folate, can traverse the blood-brain barrier and participate in the synthesis of crucial mood-regulating neurotransmitters such as dopamine and serotonin.
Folic acid blocks the uptake of methylfolate into the brain via inhibition of folate receptors.
Folic Acid Inhibits DHFR enzyme
Until the DHFR enzyme converts it into dihydrofolate and tetrahydrofolate, folic acid does not exert any beneficial physiological effects on the body.
Research indicates that the DHFR enzyme can only convert 200mcg of folic acid into dihydrofolate. Given its presence in supplements, fortified wheat products, and numerous commercial breakfast cereals, consuming 200mcg of folic acid per day is easily achievable.
As a consequence, unmetabolized folic acid accumulates, causing a decrease in the quantity of available folate for methylfolate synthesis. This occurs because the DHFR enzyme not only converts folate from food into tetrahydrofolate but also facilitates its subsequent transformation into methylfolate through MTHFR.
Unmetabolized folic acid disrupts immune function
When the conversion of folic acid into dihydrofolate is hindered by DHFR, unmetabolized folic acid accumulates in the bloodstream.
Research has demonstrated that unmetabolized folic acid can lead to immune dysfunction, including a decrease in the activity of Natural Killer cells. Natural Killer cells are important in fighting viral infections and can also kill cancer cells.
Unmetabolized folic acid, cognitive impairment and anemias
Population studies in the USA of elderly people with high levels of unmetabolized folic acid and low vitamin B12 status have a higher risk of cognitive impairment than those with normal folate status.
They also have a higher risk of “folate or B12” deficiency anemia which causes the body to produce abnormally large red blood cells that don’t function properly.
Folic acid causes Pseudo MTHFR deficiency
In the USA, a recent case report involved testing a pregnant woman who had infertility problems for MTHFR and homocysteine levels. Her results were wild type (ie no mutation) on MTHFR and her homocysteine was high at 17.2 umol/L. Homocysteine at this level is higher than expected for someone with no mutation on MTHFR.
Questioning of this patient identified she had been taking 5mg of folic acid per day. Her high homocysteine level indicates she has unmetabolised folic acid which is blocking the uptake of her natural folates via a reduction in folate receptor and DHFR activity. The net result of this is high homocysteine.
High homocysteine is an infertility and miscarriage risk factor in both women and men.
What this suggests is that by simply consuming too much folic acid, you will have a reduction in the functioning of MTHFR whether you have a gene mutation or not. If however, you do have an MTHFR mutation, this effect could be even more problematic.
What about MTHFR and methylfolate?
Individuals with an MTHFR gene mutation should steer clear of folic acid, as its conversion into methylfolate necessitates the involvement of multiple genes, enzymes, and cofactors. It’s therefore unlikely to fix the methylfolate deficiency in those with MTHFR.
Methylfolate furnishes the necessary bioavailable form of folate essential for methylation processes, effectively bypassing a genetic mutation on MTHFR.
- Bailey SW et al 2009 ‘The extremely slow and variable activity of dihydrofolate reductase in human liver and its implications for high folic acid intake’, Proceedings of the National Academy of Sciences of the USA, vol. 106, no.36, pp 15424-15429. PMID: 19706381
- Clovis P et al 2017, ‘A daily dose of 5 mg of folic acid for 90 days is associated with increased serum unmetabolized folic acid and reduced natural killer cell cytotoxicity in healthy Brazilian adults’, Journal of Nutrition, vol 147, no.9, pp.1677-1685. PMID: 28724658
- Cornet D et al 2019, ‘High doses of folic acid induce a pseudo-methylenetetrahydrofolate syndrome’, SAGE Open Medical Case Reports, Vol 7, pp 1-4. PMID: 31205715
- Smith DA et al, 2008 ‘Is folic acid good for everyone?, American Journal of Clinical Nutrition, vol. 87, pp. 517-533. PMID: 18326588
- Troen AM et al 2006, Unmetabolized folic acid in plasma is associated with reduced natural killer cell cytotoxicity among postmenopausal women’, The Journal of Nutrition, vol. 136, no. 1, pp189-194. PMID: 16365081