Histamine is a compound involved in diverse physiological processes. The body regulates this molecule through a balance of production, use, and degradation, known as histamine metabolism. This system ensures histamine performs its functions without accumulating to levels that cause adverse effects.
Histamine Production and Bodily Storage
Histamine synthesis begins with L-histidine, an amino acid from dietary protein. The enzyme L-histidine decarboxylase (HDC) converts L-histidine into histamine. This process occurs within specific cells designed to produce and store the molecule.
Histamine-producing cells are located throughout the body. Primary sources include mast cells in connective tissues and basophils, a type of white blood cell, which are involved in immune responses. In the stomach, enterochromaffin-like (ECL) cells produce histamine to regulate gastric acid. Histaminergic neurons in the central nervous system also synthesize histamine, where it acts as a neurotransmitter.
Once synthesized, histamine is stored inside cellular compartments called granules. This keeps the histamine inert and contained, preventing it from acting on tissues until a specific trigger prompts its release. This controlled deployment ensures histamine is used only when and where it is needed.
The Two Primary Routes of Histamine Breakdown
The body uses two main enzymatic pathways to degrade histamine in different locations. The primary pathway for breaking down histamine from external sources, like food, is managed by the enzyme diamine oxidase (DAO). DAO is mainly located in the cells lining the small intestine, kidneys, placenta, and thymus. It works by converting histamine into an inactive compound that is then further processed.
For histamine inside cells, breakdown is handled by histamine N-methyltransferase (HNMT). HNMT is widely distributed in body tissues, with high concentrations in the liver and central nervous system. It inactivates histamine by transferring a methyl group to it, transforming it into an inactive compound that is metabolized further.
DAO and HNMT do not overlap in function due to their different locations. DAO clears histamine entering from the gut, while HNMT manages histamine levels within tissues and the brain. The efficiency of these pathways depends on nutrient cofactors. DAO requires vitamin B6, vitamin C, and copper, while HNMT relies on S-adenosylmethionine (SAMe).
Influences on Histamine Metabolic Balance
Several factors can influence histamine metabolism. Genetic variations in the genes that code for breakdown enzymes can impact their efficiency. Variations in the AOC1 gene, which produces DAO, can reduce the ability to process histamine from external sources. Similarly, genetic differences in the HNMT gene can alter the breakdown of histamine within cells.
Diet affects the body’s histamine load. Some foods are naturally high in histamine, such as aged cheeses, fermented products, and processed meats. Other foods act as “histamine liberators,” triggering the release of histamine from the body’s mast cells. Alcohol and certain medications can also inhibit the DAO enzyme, hindering the breakdown of ingested histamine.
Gastrointestinal health is closely linked to histamine metabolism. The small intestine is the main site of DAO production, so conditions like inflammatory bowel disease (IBD) or small intestinal bacterial overgrowth (SIBO) can impair DAO synthesis. An imbalance in gut bacteria can also contribute to higher histamine levels, as some bacterial species produce histamine.
Consequences of Impaired Histamine Processing
When the body cannot break down histamine fast enough, it accumulates, leading to a condition called histamine intolerance. This is not a true allergy but a metabolic imbalance where degradation pathways cannot keep up with the histamine load. The resulting excess of histamine can provoke a wide array of symptoms.
The symptoms of histamine intolerance are diverse because histamine receptors are present in nearly every organ system. Common manifestations include:
- Dermatological issues, including hives, itching, and flushing.
- Gastrointestinal problems, such as bloating, abdominal pain, and diarrhea.
- Neurological symptoms, including headaches, migraines, and dizziness.
- Respiratory symptoms, such as nasal congestion and sneezing.
- Cardiovascular symptoms, including heart palpitations or low blood pressure.
Impaired histamine processing can worsen other conditions. For example, in individuals with mast cell activation syndrome (MCAS), a reduced ability to degrade histamine can increase the overall symptom burden. Although distinct from a classic allergy, the symptoms of histamine intolerance can mimic an allergic reaction.