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MTHFR polymorphism– folic acid or 5MTHFR which is best? (Part 1)

Yvonne Gattung B.Soc.Sci, DipMedHerb, MNZAMH, Natural Fertility Specialist

Over the last couple of years, the topic of methylation and especially as related to the polymorphism MTHFR has been discussed at conferences, via webinars, seminars, in our industry supplier information and widely on the internet. There is a staggering amount of research on folic acid and this is an absolutely huge subject, so for the purposes of this article I want to address one question only-

“I have the MTHFR polymorphism C677T, should I use any folic acid in supplements and what dietary advice is best?”

Firstly some revision and definition of terms

Folate is an umbrella term used to describe all members of the Vitamin B9 group including folic acid, folinic acid, 5MTHF and others

Folate is found in foods such as green leafy vegetables (uncooked best), legumes, eggs and some fruits. Most commonly as polyglutamates, folate from food can be easily destroyed by UV rays, preparation and cooking methods and gastric acid leaving about 50%Book-Green-Leafy-Veggetables to be absorbed.

These natural folates readily convert to dihydrofolatereductase (DHFR) which is the next part of its metabolism process.

Folic acid is not found in nature, it is synthesized and added to some foods. Folic acid does not readily become DHFR. It is oxidised which is why it is stable, cheap and ideal for adding to supplements and foods such as commercially produced bread.

To become biologically active in the body, folic acid requires conversion via the dihydrofolatereductase enzyme (DHFR) to tetrahydrofolate (THF) and then to 5-MTHFR with the help of the enzyme methlytetrahydrofolate reductase.

Circulating folic acid that hFolic-Acid1as not been converted to DHFR is referred to as ‘unmetabolised folic acid’ or UMFA.

Folinic acid is the most stable natural form of folate found naturally in some foods. Folinic acid readily converts to THF without causing UMFA. It is not dependent on dihydrofolate reductase (DHFR) and bypasses steps required for the utilization of folic acid

Folinic acid has a greater ability to cross the blood brain barrier, as it is not dependent on specific folinic acid receptors to facilitate transport. Calcium folinate is the form usually used.

5MTHFR is not found naturally in food. It is the most biologically active form of folate and tends to be well absorbed even with alterations in gastrointestinal pH. If taken in supplement form the Methylenetetrahydrofolate reductase gene is not required for its function.

5MTHFR helps make methionine (with Vitamin B12) and starts the methionine-homocysteine cycle. It is required for the synthesis of SAMe, and glutathione.

Folate is necessary to remove and maintain healthy levels of homocysteine, it is required for red blood cell production (without folate we can have macrocytic anaemia due to insufficient numbers of red blood cells or insufficient hemoglobin), it is required for healthy brain chemistry and for cell division. Hence a higher risk of spina bifida, hydrocephalus, limb defects and cervical dysplasia when folate is deficient.

A Zinc deficiency reduces folate absorption, the oral contraceptive pill depletes folate levels and an excess of folate can mask a Vitamin B12 deficiency.

Methylenetrahydrofolate reductase (MTHFR) affects the distribution of folate and maintains a delicate balance between folate for nucleotide synthesis and those for methionine synthesis. People without the MTHFR polymorphism can metabolise folic acid through the pathway described above without much difficulty. However if the MTHFR polymorphism is present, then this process does not happen well. For folates to be absorbed, the active form as 5MTHFR is needed along with methylated B12.The dose required for each individual differs widely and people should not self-medicate.

In the past the recommendation for those with the MTHFR polymorphism has been 5mg of supplemental folic acid because it was thought that more folic acid could help to correct folate metabolism deficiency.

More recent research casts some doubt on this.

  1. Folic Acid inhibits the DHFR gene?

It has been reported that folic acid inhibits dihydrofolate reductase (DHFR) gene from various species,1,2 and that both the natural form in food and folic acid compete for the same binding site on DHFR.

These reports confirm that folic acid does bind to DHFR gene and thus is not a suitable supplement for MTHFR mutations because it will not be able to correct the folate deficiency. In addition, it will build up unmetabolised folic acid.

  1. The human body has a very limited ability to metabolize folic acid especially in high doses.

The Ministry of Health in New Zealand recommends adults consume around 400 micrograms (µg) of folate each day. Daily folate requirements increase substantially for pregnant and breastfeeding women and they are recommended to consume around 600 and 800 µg of folate each day increasing to 5mg if there is a previous history of NTD, the woman is on medications that deplete folate or if there are serious ongoing health problems. There is no differentiation between those with the MTHFR polymorphism. 3

A healthy human being can only metabolise around 400 mcg of folic acid in one hour. The extra folic acid may appear as UMFA. Folic acid may compete with natural folates for their place on folate receptors and folate enzymes. 4,5

Naturally occurring folates are metabolised in the small intestine and since the 1980’s it was assumed folic acid is metabolized in a similar way. However, in a paper published in the British Journal of Nutrition it is suggested that folic acid is metabolised in the liver. The liver is easily saturated, and fortification of folic acid in foods could lead to significant unmetabolised folic acid entering the blood stream, with the potential to cause a number of health problems such as problems for people being treated for leukaemia and arthritis, women being treated for ectopic pregnancies, men with a family history of bowel cancer, people with blocked arteries being treated with a stent and elderly people with poor vitamin B status. For women undergoing in-vitro fertilisation, it can also increase the likelihood of conceiving multiple embryos, with all the associated risks for the mother and babies.

They suggest “It could take 20 years for any potential harmful effects of unmetabolised folic acid to become apparent.” 6

3. Unmetabolised Folic Acid Causes Immune Dysfunction and other issues?

Folic acid, (from foods fortified with it and supplementation) especially in high dose, forms unmetabolised folic acid (UMFA), is this a problem? Conflicting research exists surrounding the impact of UMFA.

The New Zealand Food Standard permits the voluntary addition of Folic acid to bread sold in New Zealand. Bakers can add folic acid, L-methylenetetrahydrofolate or Calcium (L-MTHF) to bread and cereals under this standard. Any fortified bread sold in a package is to include folic acid or L-MTHFR in the ingredients list if added. The maximum allowed is 2.5 mg/Kg. 7

In the U.S., all flour is fortified with 140 mcg / 100 g of folic acid to supply 100 mcg to daily diet. 8.

Yes UMFA is a problem:

As it overwhelms the liver’s metabolic capacity. (see research mentioned above)

Unmetabolised folic acid may reduce immune function. This report shows that exposing to food fortification and vitamin supplement in large populations in the US results in high folic acid intake, which causes reduced NK cell cytotA-healthy-woman-eating-salad-549886oxicity in post-menopausal women who consumed folate rich diet together with folic acid supplements more than 400 mcg per day, but not in those with lower folate of less than 233 mcg per day.9 The consequence is stronger in women of or older than 60 years and in those with higher unmetabolised folic acid in serum.

There is evidence that low levels of folate can cause cancer, but also high levels of UMFA can also cause cancer. There is no long term information about the safety or possible effects of UMFA – or high intakes of folic acid in general.10

NO, UMFA is not a problem;

In this paper, the folic acid status of women of reproductive age in relation to dietary intake and the effect of folic acid supplementation (1.1 mg or 5 mg). Plasma unmetabolized folic acid was not significantly correlated with folate intake estimated by food frequency questionnaire or biomarkers. The proportion of women with detectable levels of unmetabolized folic acid increased from 65% to 100% after twelve weeks of supplementation; however, the increase in concentrations did not reach statistical significance and the effect was not sustained. Moreover, there were no significant differences between the two doses. This suggests that there are mechanisms by which the body adapts to high folic acid intakes to limit exposure to unmetabolized folic acid.11

It is thought the body locks UMFA out of cells.

But what about those with the MTHFR polymorphism? Maybe UMFA is a greater risk factor for ill health generally?

We will continue this discussion in part 2

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