Supplement riboflavin to fix the MTHFR polymorphism

I finished recording a podcast on riboflavin over the weekend with Chris Masterjohn, which I’ll link to here when it is published.

UPDATE: Here is a link to the podcast.

During my research for the podcast, I came across the fascinating discovery that people with the 677C→T (A222V) polymorphism for the methylenetetrahydrofolate reductase (MTHFR) enzyme may simply need some extra riboflavin to make the enzyme work like normal.

People who have a mutation in MTHFR have reduced enzyme activity that affects their ability to use folate in the methionine cycle. Specifically, they are unable to convert 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate (5-methyl THF), the primary circulatory form of folate utilized in homocysteine remethylation to methionine.

The 677C→T (A222V) variant has been particularly noteworthy since it has become recognized as the most common genetic cause of elevated homocysteine levels. 1

Most people, myself included, simply circumvent the issue by supplementing with 5-methyl THF, thereby supplying what the body has difficulty making.

But another option may simply be to take some riboflavin to make the enzyme work properly again. The 677C→T MTHFR mutation causes the enzyme to have a reduced binding affinity for the riboflavin-containing molecule flavin adenine dinucleotide (FAD). 2,3

Supplementing riboflavin can saturate the mutated enzyme with FAD, compensating for its reduced ability to bind to FAD.

As shown in the image below, people with the 677C→T MTHFR mutation have elevated homocysteine levels only when riboflavin status (measured by the EGRAC) is inadequate (>1.2). 4

We also have at least one intervention that I’m aware of showing that supplementing 1.6 mg of riboflavin per day for 12 weeks reduces homocysteine in MTHFR 677C→T carriers, although statistical significance is achieved only in the TT genotype.5 All the participants had an EGRAC > 1.3 at baseline (average of 1.44).

This effect, however, was driven entirely by people with the TT MTHFR genotype and poor riboflavin status at baseline (EGRAC > 1.4), with homocysteine declining by 40% (22 → 13.2 umol/L).5

Importantly, supplementation improved riboflavin status by only 8–12% among all the participants, meaning that average EGRAC levels declined to a minimum of about 1.27.5 It is possible that effects in both CT and TT genotypes would have been more pronounced with a greater dose of riboflavin and greater improvement in riboflavin status.


Summing up

If you have the MTHFR 677C→T mutation, then consider supplementing with 2–5 mg of riboflavin per day, which appears to have a consistent effect on riboflavin status that we can see in as little as two weeks.6 If you want to use higher doses, riboflavin absorption is pretty solid up to about 27 mg in a single bolus,7 with no known upper limit for toxicity.

Improving riboflavin status may make MTHFR work like it should, since the 677C→T mutation simply reduces its ability to bind with its riboflavin-dependent cofactor (FAD). It’s literally addressing the cause (making MTHFR work like normal) rather than the symptom (supplementing with 5-methyl THF because you make less of it).


References

  1. 1.
    Leclerc D, Sibani S, Rozen R. Molecular Biology of Methylenetetrahydrofolate Reductase (MTHFR) and Overview of Mutations/Polymorphisms – Madame Curie Bioscience Database. NCBI Bookshelf. https://www.ncbi.nlm.nih.gov/books/NBK6561/.
  2. 2.
    Guenther B, Sheppard C, Tran P, Rozen R, Matthews R, Ludwig M. The structure and properties of methylenetetrahydrofolate reductase from Escherichia coli suggest how folate ameliorates human hyperhomocysteinemia. Nat Struct Biol. 1999;6(4):359-365. https://www.ncbi.nlm.nih.gov/pubmed/10201405.
  3. 3.
    Yamada K, Chen Z, Rozen R, Matthews R. Effects of common polymorphisms on the properties of recombinant human methylenetetrahydrofolate reductase. Proc Natl Acad Sci U S A. 2001;98(26):14853-14858. https://www.ncbi.nlm.nih.gov/pubmed/11742092.
  4. 4.
    García-Minguillán C, Fernandez-Ballart J, Ceruelo S, et al. Riboflavin status modifies the effects of methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) polymorphisms on homocysteine. Genes Nutr. 2014;9(6):435. https://www.ncbi.nlm.nih.gov/pubmed/25322900.
  5. 5.
    McNulty H, Dowey le, Strain J, et al. Riboflavin lowers homocysteine in individuals homozygous for the MTHFR 677C->T polymorphism. Circulation. 2006;113(1):74-80. https://www.ncbi.nlm.nih.gov/pubmed/16380544.
  6. 6.
    Hoey L, McNulty H, Strain J. Studies of biomarker responses to intervention with riboflavin: a systematic review. Am J Clin Nutr. 2009;89(6):1960S-1980S. https://www.ncbi.nlm.nih.gov/pubmed/19403631.
  7. 7.
    Zempleni J, Galloway J, McCormick D. Pharmacokinetics of orally and intravenously administered riboflavin in healthy humans. Am J Clin Nutr. 1996;63(1):54-66. https://www.ncbi.nlm.nih.gov/pubmed/8604671.