As the most important biogenic amine, histamine regulates sleep, appetite, motivation, learning, and sexual behavior through its four receptors. Read on to discover its function and the genes that affect it.

What is Histamine?

Most people know about histamine because of antihistamines, drugs commonly used to manage allergy symptoms. Too much histamine for too long brings about a long list of unwanted effects: redness, itching, swelling, runny nose, hives, and others.

Anyone looking to overcome their histamine issues has to start with understanding what histamine is and how it functions in the body.

Histamine is not just detrimental, it also has some protective roles. Problems usually arise if it’s not being broken down fast enough or if it’s being produced in excess and targeting the wrong receptors.

Definition

Histamine is a biogenic amine: that is, a compound made in your body that includes an amine group. Other biogenic amines include tyramine, tryptamine, putrescine, cadaverine, spermine, and spermidine; these are produced by bacteria during improper food storage. Most are detrimental, while others (especially spermidine) can be highly beneficial [1, 2, 3, 4].

Histamine was discovered in 1910 by the winner of the 1936 Nobel Prize in Medicine, Sir Henry H. Dale. Its name is derived from the Greek word histos, meaning tissue, as many tissues throughout the body express it [5, 2].

Release

People talk about problems with mast cell activation, allergies, and other conditions of histamine release. But what exactly is going on in the body?

The following cells in your body produce, release, and store histamine [2, 5, 6]:

  • Mast cells and basophils, types of white blood cells responsible for allergic reactions
  • Enterochromaffin-like (ECL) cells in the stomach lining
  • Histamine-releasing (histaminergic) neurons

In people with histamine intolerance, food allergies, IBD, and IBS, histamine loses all control. It builds up and strays from its typical behavior. As it gains momentum, it can shift the balance in immune cells and reduce barrier integrity in the gut. This triggers all the inflammatory symptoms most people recognize all too well [2].

Other cells can also produce histamine, but at much lower levels. These cells cannot store histamine, so they need to release it straight away [2, 6].

An enzyme called histidine decarboxylase (HDC) makes histamine from the amino acid histidine. Certain microbes, including some gut bacteria, also have the HDC enzyme and can produce histamine from histidine. This may sound like a problem, but researchers think specific histamine-producing probiotic bacteria (such as Lactobacillus rhamnosus) could be beneficial [2].

Immune, stomach, and brain cells can all release histamine when the body demands it. If this process shifts out of balance, too much histamine triggers inflammation and allergies.

Breakdown

Two enzymes control histamine breakdown: histamine N-methyltransferase (HNMT) and diamine oxidase or DAO. These enzymes are extremely important. If either one starts malfunctioning, histamine can increase dramatically throughout the body [7, 2].

HNMT

HNMT is the main histamine-degrading enzyme in the brain. It breaks down histamine inside the cells without being released into the bloodstream. The liver, spleen, gut, prostate, ovaries, kidneys, and lungs also contain it [8, 2, 9].

Methylation

HNMT breaks down histamine by methylating it. Based on this, various blogs claim people with high blood histamine are undermethylators and those with low blood histamine overmethylators. While this may be true in part, it’s far from the rule [2].

The trouble here is that over- and undermethylation is unlikely to take place in all tissues and organs across the body at the same time. You may have low gut HNMT and normal brain HNMT. This doesn’t always make someone an over or undermethylator, the effect may be tissue or organ dependent [10, 11].

Additionally, several causes other than low HNMT activity/undermethylation can raise histamine, such as [12]:

  • Reduced DAO activity (the most common cause of histamine intolerance)
  • Higher histamine production, and
  • Increased histamine intake

DAO

DAO is the main histamine-degrading enzyme in the gut, connective tissues, placenta, and kidneys. This enzyme is released into the blood; it can, therefore, break down histamine found outside of the cells [13, 2, 14].

DAO also degrades other biogenic amines such as putrescine and spermidine [14].

Many sources claim DAO deficiency underlies histamine intolerance and sensitivity. This is possible, but it’s only one likely cause. To make matters worse, testing DAO in the blood tells us little about its activity in the gut [10].

DAO and HNMT enzymes break down histamine. A deficiency in either one can trigger a rise in histamine throughout the body or in specific tissues. We can only estimate someone’s HNMT or DAO activity, since no reliable tests yet exist to measure them.

Histamine Function & Receptors Overview

In the nervous system, histamine acts as a messenger molecule or neurotransmitter. It plays key roles in the sleep-wake cycle, appetite, motivation, learning, memory, and sexual behavior [1, 5, 6].

In the stomach, histamine stimulates acid secretion. In the rest of the body, histamine intensifies the immune response, contracts smooth muscles and airways, dilates blood vessels, and activates itch and pain-associated nerve cells. These resemble symptoms common to allergies and other conditions in which histamine is increased [5, 2].

Receptors

On the surface of target cells, histamine binds to four specific histamine receptors – H1R, H2R, H3R, and H4R – which carry out its functions. Histamine often has opposing roles, depending on which receptor it activates [15].

H1R

  • H1R is mainly found in the brain, airways, blood vessels, and white blood cells [2].
  • In the brain, it increases wakefulness, reduces appetite, and increases thirst [2].
  • H1R activity can produce allergy symptoms, such as redness, itching, swelling, runny nose, airway constriction, anaphylaxis, pinkeye (conjunctivitis), and hives [2].

H2R

  • H2R is mostly found in the brain, stomach, white blood cells, heart, and other internal organs (smooth muscles) [2].
  • It relaxes smooth muscles in the blood vessels, uterus, and airways [6].
  • Activated by histamine, H2R inhibits both Th1 and Th2 immune responses, stimulates stomach acid secretion, increases heart rate, and reduces bone density [1, 2, 5].

H3R

  • H3R is found mainly in histamine-releasing nerve cells in the brain and enterochromaffin-like cells in the stomach [1, 15].
  • H3R prevents histamine release and often opposes the activity of other histamine receptors [2].
  • H3R activity promotes sleep and reduces itching [2, 16].
  • In different parts of the brain, it also lowers acetylcholine, dopamine, serotonin, noradrenaline, GABA, and glutamate [1, 6, 17].
  • It promotes alcohol preference; that is, H3R activity may make you want a drink [18].

H4R

  • H4R is found in the bone marrow and white blood cells. It is also present in smaller amounts in the spleen, thymus, lung, small intestine, colon, and heart [6, 1].
  • It activates white blood cells involved in inflammatory responses [6, 1, 19].
  • H4R is also responsible for cytokine release (increases IL-17 and Th2 cytokines IL-4, IL-5, and IL-13) [1].
Some histamine receptors trigger inflammation and allergic symptoms (H1R and H4R) and others increase stomach acid (H2R). One receptor (H3R) opposes them and prevents histamine release.

Genetics

HDC

HDC codes for histidine decarboxylase, the enzyme that produces histamine. Some HDC gene variants increase the risk of developing allergic rhinitis [7].

  1. rs16963486
  2. rs2073440

HNMT

A variant of HNMT doubles the risk of developing eczema in children, while another variant is associated with chronic hives [7].

Food additives can worsen ADHD symptoms and trigger histamine release. The AA genotype at rs1050891 (a variant also called C939T) was linked with more ADHD behavior in children exposed to certain food colorings and additives (sunset yellow, carmoisine, tartrazine, ponceau 4R, quinoline yellow, Allura red AC, and sodium benzoate). Higher histamine may be the culprit [20, 20].

Taking SAM-e should negate this gene, theoretically. S-adenosyl-L-methionine, also known as SAM-e, occurs naturally in your body and donates methyl groups during the methylation processes. Histamine N-methyltransferase (HMNT) inactivates histamine by methylating it; therefore, SAM-e might help HMNT work more efficiently [21, 8].

And if you have AA, don’t despair, as around 56% of the population does as well.

Certain HNMT gene variants may increase the risk of eczema and ADHD behavior in children. SAM-e might reduce these risks by inactivating histamine.

Diamine Oxidase (DAO)

DAO codes for diamine oxidase, the enzyme that breaks down histamine in the gut and tissues. Here are some important DAO gene SNPs you can look into:

  1. rs1005390
  2. rs1049793
  3. rs17173637
  4. rs10156191
  5. rs1049742
  6. rs2052129
  7. rs2071517

In both rs10156191 and rs1049742, the T allele is associated with lower DAO activity, migraines, and sensitivity to NSAID painkillers (aspirin, ibuprofen). Two T alleles are more harmful than one T allele [22, 23, 24].

Certain gene mutations that lower DAO gene activity might make people more prone to histamine issues.

H4R

Variants of the H4R gene are associated with an increased risk of eczema and infection-induced asthma [7, 1].

The number of H4R copies correlates to the incidence of arthritis, proteinuria, and antinuclear antibody abnormalities in systemic lupus erythematosus (SLE) [1].

Here are two SNPs to look into:

  1. rs11662595
  2. rs11665084

MS4A2

The MS4A2 gene codes for a subunit of the IgE-receptor protein that affects allergic responses and is found on the surface of histamine-producing mast cells and [25].

Mutations in this gene are associated with asthma and fibromyalgia, inflammatory conditions with overactive mast cells [26, 27, 28, 29].

  1. rs512555
  2. rs569108
  3. rs983392

More About Histamine

This is the first post in a six-part series on histamine, histamine intolerance, and how to manage it. To learn more, click through the links below.

Takeaway

Histamine is a biogenic amine and a neurotransmitter. An enzyme called histidine decarboxylase produces it, while histamine N-methyltransferase and diamine oxidase (DAO) break it down. Histamine works through 4 receptors in your body: H1R, H2R, H3R, and H4R.

Through these receptors, histamine plays key roles in the sleep-wake cycle, appetite, motivation, learning, memory, and sexual behavior. In excess, it triggers inflammation and allergies.

Genetic variations (in HDC, HNMT, DAO, H4R, and MS4A2 genes) can affect your histamine metabolism and response.

About the Author

Jasmine Foster, BSc, BEd

BS (Animal Biology), BEd (Secondary Education)

Jasmine received her BS from McGill University and her BEd from Vancouver Island University.

Jasmine loves helping people understand their brains and bodies, a passion that grew out of her dual background in biology and education. From the chem lab to the classroom, everyone has the right to learn and make informed decisions about their health.

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