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Normal histamine metabolism in healthy people

Chemical characteristics of histamine

Histamine (combining the Greek "histos" = tissue and "amin" = nitrogenous compound) is a natural substance, which fulfils important regulatory and mediatory functions in animal organisms, and is also frequently found in bacteria and in the plant kingdoms. Biochemically, histamine belongs to the group of biogenic amines. In its purest form, histamine is a white solid material with a molar mass of 111.15 g/mol. Histamine is easily soluble in water and ethanol, but badly dissolved in diethyl ether, which indicates that it has also bad solubility in fat.

Molecular formula: C₅H₉N₃

Structural formula:

Synonyms: 2-(1H-imidazol-4-yl)ethanamine

CAS number: 51-45-6

Functions of histamine

In the human organism, histamine fulfils various functions as tissue hormone, neurotransmitter and messenger substance (biochemical signal transduction), which have only been insufficiently studied so far. At a molecular level, histamine exerts its actions via an activation of histamine receptors H1, H2, H3 and H4, which are part of the family of G protein-coupled receptors (GPCR). Histamine acts by binding to target receptors according to the lock and key model and modulating intracellular signal cascades (signal transduction chains).

An activation of H1 receptors is primarily responsible for the allergy symptoms triggered by histamine. These include itching and pain, contractions of smooth muscle tissue in the bronchial tubes and large blood vessels (diameter of more than 80 µm) as well as dilation of smaller blood vessels with hives and flush. In the central nervous system, histamine is involved in triggering vomiting and the regulation of the sleep-wake cycle via an activation of H1 receptors. H1 receptors also play a part in regulating the release of hormones such as adrenaline. Histamine is a messenger substance active in inflammatory processes and burns, and furthermore boosts the release of additional inflammatory mediators. Besides, it seems to play a part in the regulation of body temperature, the central control of blood pressure and pain perception. [Wikipedia: Histamine]

H2 receptors are involved in the regulation of gastric acid production and bowel movements (motility, peristalsis). An increase of gastric acid production may be interpreted as a component of histamine-induced immune reaction. An accelerated onward transport of the intestinal contents leads to diarrhea and may also be seen as an immune response. A stimulation of H2 receptors also leads to an accelerated or stronger heart beat as well as dilation of smaller blood vessels.

In the human body the H3 receptors are primarily found presynaptically on cells of the central and peripheral nervous systems. As autoreceptors they play a role when negative feedback prevents additional histamine release. Via presynaptic receptors (in particular H2 receptors), histamine has a regulatory influence on noradrenergic, serotoninergic, cholinergic, dopaminergic and glutaminergic neurons by blocking the release of neurotransmitters in the central and peripheral nervous systems. Thus it inhibits the release of the neurotransmitters acetylcholine, noradrenalin and serotonin as heteroreceptor. In this way, histamine influences indirectly the activity of these neurotransmitters. Through these mechanisms, the H3 receptors play a role in the central regulation of hunger and thirst, the circadian rhythm, body temperature and blood pressure. Furthermore, these receptors are said to be directly or indirectly implicated in the pathophysiology of neurological pain, schizophrenia, Parkinson's disease and ADHS.

H4 receptors are involved in the targeted migration of immune cells such as eosinophil granulocytes, T lymphocytes and monocytes to sources of histamine. This is why it is assumed that these receptors play an important role in the recruitment of leukocytes during immune responses, in particular in allergic reactions.

Monoamine transporters regulate cytological processes
Unlike previously believed, water-soluble hormones such as serotonin, histamine and catecholamine do not only act via receptors on the cell's surface but also through monoamine transporters (MATs) within the cells. Similar to phosphorylation, monoamine transporters have profound effects on various cytological processes, which still need further clarification [Vowinckel 2012; Walther; Stahlberg and Vowinckel 2011; Walther 2007; Scinexx 2009]. With antihistamines - which are only really ever specific to a single type of receptor - such cytological modifications cannot be prevented.

Histamine and other water-soluble monoamines cannot pass the cell membrane by diffusion. A considerable part of their effects are triggered by numerous membranous monoamine receptors (histamine receptors). Specific monoamine transporters, however, accumulate histamine and other hormones in the cytoplasm, where the monoamines constitutively activate signal proteins through transglutaminase (TGase) by monoamine transporters. This leads to longer lasting hormone activity similar to those observed in thrombocytes and in muscle cells of blood vessels. [Walther 2007]

Biosynthesis of histamine

Histamine is derived from the decarboxylation of the amino acid histidine, a reaction catalyzed by the enzyme L-histidine decarboxylase.

The ability to synthesize histamine is very common in microorganisms such as bacteria or yeast, as well as in the animal and plant kingdoms.

Occurrence of histamine

Endogenous histamine (=produced naturally in the body)

Storage

Histamine is a substance produced by the organism itself and stored in blood and tissue cells. The storage takes place by binding to heparin in so-called vesicles. These are small organelles, separated by membranes, inside the cell. Enclosed in these vesicles, histamine is immobilized and cannot do any harm, but it is always able to be immediately released if required. Histamine is particularly synthesized and stored in the following cell types:

• Mast cells [Jarisch 2004]
• Basophile granulocytes [Jarisch 2004]
• Neurons and other nerve cells, such as cerebrovascular endothelial cells [Hough 1999]

The basophile granulocytes are blood cells. Mast cells are found in tissue, in particular in epidermal cells of the skin, in histamine-storing cells of the mucous membranes, in bronchial tubes, the gastro-intestinal system (i.e. gastric mucosa) and the brain. The highest histamine concentrations can be measured in the hypothalamus [Jarisch 2004; Hough 1999; Wikipedia: Histamine].

Release of histamine

Histamine is released from the vesicles during IgE-induced immediate-type (type I) allergic reactions or through complement factors such as for example an endotoxin-induced shock. In addition to tissue hormones, medications such as opiates, muscle relaxants, plasma expanders and radiocontrast agents, may trigger the release of histamine (please refer to Liste unverträglicher Medikamente). Other important storage sites of histamine are the ECL cells of the gastric mucosa, which can release histamine induced by hormones and tissue hormones such as gastrin, acetylcholine and pituitary adenylate cyclase activating polypeptide (PACAP).
A release of histamine in the synaptic cleft of histaminergic neurons is inhibited by acetylcholine, noradrenalin, and histamine via the presynaptic receptors.

Exogenous histamine (ingested by food)

For histamine intolerance, exogenous (=coming from the outside) histamine is probably even more relevant than histamine produced by the body itself. Histamine is a component that can be found in most foods in varying concentrations. It occurs when food perishes, particularly products that are fermented, matured or have been stored over a long period of time. An additional, but less important source of exogenous histamine is the gut flora. Many kinds of microorganisms found in the intestines are able to produce histamine.
Histamine ingested with food or produced in the gut must not get into the body, because an increased histamine level (histamine poisoning) may disrupt the body's own histamine degradation, leading to numerous histamine-induced symptoms. Healthy people have two effective enzymatic barriers (please refer to "degradation of histamine").

Histamine in animals and plants

In a little digression, it should be mentioned that histamine is produced and stored in some plants and animals as defense substance. The common nettle for example stores histamine (alongside other substances) in its urticating hairs (trichomes) and injects these upon contact, causing a painful sting. When in danger, the grasshopper, Poekilocerus bufonius (Pyrgomorphidae), secrets a substance, which in addition to cardenolides contains about 1% of histamine. Histamine is also secreted by the cutaneous glands in the skin of some Leptodactylidae frogs. Furthermore, animals and plant antigens such as the mast-cell degranulating peptide (MCD peptide) in the bumblebee venom may release histamine from the mast cells of higher animals and trigger an inflammatory response.

Degradation of histamine

Histamine may be metabolized through four mechanisms, whereby the first two mentioned constitute the primary degradation pathways:

1. Oxidative deamination through diamine oxidase (DAO, histaminase).
   Chemical equation: Histamine + H₂O + O₂ => (imidazole-4-yl)acetaldehyde + NH₃ + H₂O₂
2. Cyclical methylation through histamine N-methyltransferase (HNMT).
   The product resulting from the reaction is N-methylhistamine (NMH).
3. Acetylation into acetylhistamine.
   (This degradation pathway is primarily important in microbial degradation)
4. Hydroxylase into hydantoin propionic acid.
   (Vitamin C could be a cofactor in hydroxylase reactions, which convert histamine into hydantoin propionic acid - analogous to histidine degradation into hydantoin propionate. Presumably, this degradation mechanism is less significant in terms of quantity)

The two primary degradation pathways of histamine [Source: Wikipedia].

All four known, respectively postulated degradation methods of histamine [Bielenberg 2005].

DAO is excreted by the cells as secretory protein and is responsible for breaking down histamine outside the cells (extracellular), while HNMT only degrades histamine as cytosolic protein within the cells (intracellular), for example in the liver or in the brain.

DAO is primarily synthesized in the cells of the bowel mucosa and excreted into the intestinal lumen, where the DAO mixes with the bolus and breaks down most of the present histamine. This way, DAO creates a first barrier against the entry of histamine into the body.
Histamine, which is absorbed into the body via the intestinal mucosa, reaches the bloodstream and is transported towards the liver. In the liver, the primary detoxifying organ of the body, the degradation takes place with the aid of HNMT.

Histamine released into the cells from vesicles within the body is broken down by HNMT intracellularly.

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