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Methylation and The Histamine and Mast Cell Connection

Updated: Mar 10

Methylation is one of the most important chemical processes in the body. It supports histamine breakdown and clearance.

Last week we finished off by talking about Histamine N-methyl Transferase (HNMT), one of the main enzymes responsible for histamine clearance. While it is the main enzyme, there are others that are also part of the methylation pathway.

After HNMT has acted on histamine, then Monoamine oxidase B (MAO B) finishes the job. These enzymes are part of the liver’s methylation pathway. There are several other genes involved in methylation that help metabolize histamine so that it can be removed from your body. These include:

  • COMT – Catechol-O-Methyltransferase

  • MTHFR – Methylenetetrahydrofolate Reductase

  • MTR – Methionine Synthase

  • MTRR – Methionine Synthase Reductase

If you aren’t methylating adequately, then you can’t break down histamine adequately.

If you have variations of these genes that impair or slow down histamine clearance, then supporting this liver pathway is especially important for you.

Genetic Variations Impacting Phase 2

Methylation doesn’t just break down histamine. It is also needed for clearance of other catecholamines such as dopamine, norepinephrine and epinephrine, catechol estrogens, homocysteine, heavy metals, plastics, mold, alcohol, smoke, and some drugs. It’s important to reduce environmental exposure to these compounds as much as possible as a first step.

Methylation detoxifies all these different compounds.

Let’s say you have mold exposure. Maybe there was a leak under your sink and unbeknownst, mold started growing under the cabinet. Besides wreaking complete havoc on your nervous system and mast cells, now your methylation pathway must work even harder: it must clear both excess histamine and mold.

But it only has a limited capacity. It can’t clear as much histamine as in the past because it’s also trying to clear mold. So now your histamine load is higher than usual, plus you are dealing with all the mold symptoms.

That’s why limiting exposure to toxins is so important. Not only can they trigger mast cells to release histamine and other chemical mediators, but they share your liver’s detox pathways.

Just like a highway, those liver pathways have a limited capacity. Too many cars on a highway and you have a traffic jam. Too many toxins being filtered by your liver, and toxins get backed up and impact your health.

Supporting Methylation

In scientific terms, methylation involves the addition of a methyl group to a molecule. Let’s break that down into layman’s language.

Folate enters your cells. Folate is also known as vitamin B9. You get it from eating leafy green foods.

Once inside your cells, it undergoes many transformations that require both enzymes and cofactors to happen. First it is converted to DHF (dihydrofolate) and THF (tetrahydrofolate) with the help of vitamin B3 (a cofactor) and enzymes like DHFR (dihydrofolate reductase).

After that, different enzymes and cofactors are utilized.

For example, find the green MTHFR on the methylation diagram below. MTHFR is the enzyme Methylenetetrahydrofolate Reductase. Ahead of MTHFR in the cycle is 5, 10-methyleneTHF. To become 5-methylTHF, both the enzyme MTHFR and the cofactors vitamin B2 and magnesium (Mg) are needed for that conversion to happen.

The enzymes (in green) are genetically determined, but the cofactors (in red) are nutrients that you consume. That’s great news because it means that ensuring you have adequate amounts of these important nutrients will mean you can influence your liver’s ability to methylate histamine and toxins! Let’s have a look at some of those nutrients.

Nutrients to Support Methylation

Riboflavin (B2)

Niacin (B3)


Folate (methylfolate)

B12 (methylcobalamin)





Ready to start working in these important nutrients into your daily meals, all while keeping the histamine or mast cell piece of the picture in mind?

Check out part two of this blog - Show Your Liver Some Love.

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