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| Names | |
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| IUPAC name
2-(1H-Imidazol-4-yl)ethanamine
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| Identifiers | |
3D model (JSmol)
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| ChEBI | |
| ChEMBL | |
| ChemSpider | |
| ECHA InfoCard | 100.000.092 |
| KEGG | |
| MeSH | Histamine |
PubChem CID
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| UNII | |
CompTox Dashboard (EPA)
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| Properties | |
| C5H9N3 | |
| Molar mass | 111.148 g·mol−1 |
| Melting point | 83.5 °C (182.3 °F; 356.6 K) |
| Boiling point | 209.5 °C (409.1 °F; 482.6 K) |
| Easily soluble in cold water, hot water | |
| Solubility in other solvents | Easily soluble in methanol. Very slightly soluble in diethyl ether. Easily soluble in ethanol. |
| log P | −0.7 |
| Acidity (pKa) | Imidazole: 6.04 Terminal NH2: 9.75 |
| Pharmacology | |
| L03AX14 (WHO) V04CG03 (WHO) (phosphate) | |
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Histamine is an organic nitrogenous compound involved in local immune responses, as well as regulating physiological function in the gut and acting as a neurotransmitter for the brain, spinal cord, and uterus. Histamine is involved in the inflammatory response and has a central role as a mediator of itching. As part of an immune response to foreign pathogens, histamine is produced by basophils and by mast cells found in nearby connective tissues. Histamine increases the permeability of the capillaries to white blood cells and some proteins, to allow them to engage pathogens in the infected tissues. It consists of an imidazole ring attached to an ethylamine chain; under physiological conditions, the amino group of the side-chain is protonated.
Properties
Histamine base, obtained as a mineral oil mull, melts at 83–84 °C. Hydrochloride and phosphorus salts form white hygroscopic crystals and are easily dissolved in water or ethanol, but not in ether. In aqueous solution, the imidazole ring of histamine exists in two tautomeric
forms, identified by which of the two nitrogen atoms is protonated. The
nitrogen farther away from the side chain is the 'tele' nitrogen and is
denoted by a lowercase tau sign and the nitrogen closer to the side
chain is the 'pros' nitrogen and is denoted by the pi sign. The tele
tautomer, Nτ-H-histamine, is preferred in solution as compared to the pros tautomer, Nπ-H-histamine.
The tele tautomer (Nτ-H-histamine), on the left is more stable than the pros tautomer (Nπ-H-histamine) on the right.
Histamine has two basic centres, namely the aliphatic amino group and whichever nitrogen atom of the imidazole ring does not already have a proton. Under physiological conditions, the aliphatic amino group (having a pKa around 9.4) will be protonated, whereas the second nitrogen of the imidazole ring (pKa ≈ 5.8) will not be protonated.
Thus, histamine is normally protonated to a singly charged cation. Histamine is a monoamine neurotransmitter.
Synthesis and metabolism
Histamine is derived from the decarboxylation of the amino acid histidine, a reaction catalyzed by the enzyme L-histidine decarboxylase. It is a hydrophilic vasoactive amine.
Conversion of histidine to histamine by histidine decarboxylase
Once formed, histamine is either stored or rapidly inactivated by its primary degradative enzymes, histamine-N-methyltransferase or diamine oxidase. In the central nervous system, histamine released into the synapses is primarily broken down by histamine-N-methyltransferase, while in other tissues both enzymes may play a role. Several other enzymes, including MAO-B and ALDH2, further process the immediate metabolites of histamine for excretion or recycling.
Bacteria also are capable of producing histamine using histidine
decarboxylase enzymes unrelated to those found in animals. A
non-infectious form of foodborne disease, scombroid poisoning,
is due to histamine production by bacteria in spoiled food,
particularly fish. Fermented foods and beverages naturally contain
small quantities of histamine due to a similar conversion performed by
fermenting bacteria or yeasts. Sake contains histamine in the 20–40 mg/L range; wines contain it in the 2–10 mg/L range.
Storage and release
Mast cells.
Most histamine in the body is generated in granules in mast cells and in white blood cells (leukocytes) called basophils.
Mast cells are especially numerous at sites of potential injury — the
nose, mouth, and feet, internal body surfaces, and blood vessels.
Non-mast cell histamine is found in several tissues, including the brain, where it functions as a neurotransmitter. Another important site of histamine storage and release is the enterochromaffin-like (ECL) cell of the stomach.
The most important pathophysiologic mechanism of mast cell and basophil histamine release is immunologic. These cells, if sensitized by IgE antibodies attached to their membranes, degranulate when exposed to the appropriate antigen. Certain amines and alkaloids, including such drugs as morphine, and curare alkaloids, can displace histamine in granules and cause its release. Antibiotics like polymyxin are also found to stimulate histamine release.
Histamine release occurs when allergens bind to mast-cell-bound
IgE antibodies. Reduction of IgE overproduction may lower the likelihood
of allergens finding sufficient free IgE to trigger a mast-cell-release
of histamine.
Mechanism of action
In humans, histamine exerts its effects primarily by binding to G protein-coupled histamine receptors, designated H1 through H4. As of 2015, histamine is believed to activate ligand-gated chloride channels in the brain and intestinal epithelium.
| G-protein coupled receptor | Location | Function |
|---|---|---|
| Histamine H1 receptor |
• CNS: Expressed on the dendrites of the output neurons of the histaminergic tuberomammillary nucleus, which projects to the dorsal raphe, locus coeruleus, and additional structures. • Periphery: Smooth muscle, endothelium, sensory nerves |
• CNS: Sleep-wake cycle (promotes wakefulness), body temperature, nociception, endocrine homeostasis, regulates appetite, involved in cognition • Periphery: Causes bronchoconstriction, bronchial smooth muscle contraction, urinary bladder contractions, vasodilation, promotes hypernociception (visceral hypersensitivity), involved in itch perception and urticaria. |
| Histamine H2 receptor |
• CNS: Dorsal striatum (caudate nucleus and putamen), cerebral cortex (external layers), hippocampal formation, dentate nucleus of the cerebellum • Periphery: Located on parietal cells, vascular smooth muscle cells, neutrophils, mast cells, as well as on cells in the heart and uterus |
• CNS: Not established (note: most known H2 receptor ligands are unable to cross the blood–brain barrier in sufficient concentrations to allow for neuropsychological and behavioral testing) • Periphery: Primarily involved in vasodilation and stimulation of gastric acid secretion. Urinary bladder relaxation. Modulates gastrointestinal function. |
| Histamine H3 receptor | Located in the central nervous system and to a lesser extent peripheral nervous system tissue | Autoreceptor and heteroreceptor functions: decreased neurotransmitter release of histamine, acetylcholine, norepinephrine, serotonin. Modulates nociception, gastric acid secretion, and food intake. |
| Histamine H4 receptor | Located primarily on basophils and in the bone marrow. It is also expressed in the thymus, small intestine, spleen, and colon. | Plays a role in mast cell chemotaxis, itch perception, cytokine production and secretion, and visceral hypersensitivity. Other putative functions (e.g., inflammation, allergy, cognition, etc.) have not been fully characterized. |
| Histamine-gated chloride channel | Putatively: CNS (hypothalamus, thalamus) and intestinal epithelium | Brain: Produces fast inhibitory postsynaptic potentials Intestinal epithelium: chloride secretion (associated with secretory diarrhea) |
Roles in the body
Although
histamine is small compared to other biological molecules (containing
only 17 atoms), it plays an important role in the body. It is known to
be involved in 23 different physiological functions. Histamine is known
to be involved in many physiological functions because of its chemical
properties that allow it to be versatile in binding. It is Coulombic
(able to carry a charge), conformational, and flexible. This allows it
to interact and bind more easily.
Vasodilation and fall in blood pressure
It
has been known for more than one hundred years that an intravenous
injection of histamine causes a fall in the blood pressure.
The underlying mechanism concerns both vascular hyperpermeability and
vasodilation. Histamine binding to endothelial cells causes them to
contract, thus increasing vascular leak. It also stimulates synthesis
and release of various vascular smooth muscle cell relaxants, such as nitric oxide, endothelium-derived hyperpolarizing factors and other compounds, resulting in blood vessel dilation. These two mechanisms play a key role in the pathophysiology of anaphylaxis.
Effects on nasal mucous membrane
Increased
vascular permeability causes fluid to escape from capillaries into the
tissues, which leads to the classic symptoms of an allergic reaction: a
runny nose and watery eyes. Allergens can bind to IgE-loaded mast cells in the nasal cavity's mucous membranes. This can lead to three clinical responses:
- sneezing due to histamine-associated sensory neural stimulation
- hyper-secretion from glandular tissue
- nasal congestion due to vascular engorgement associated with vasodilation and increased capillary permeability
Sleep-wake regulation
Histamine is a neurotransmitter that is released from histaminergic neurons which project out of the mammalian hypothalamus. The cell bodies of these neurons are located in a portion of the posterior hypothalamus known as the tuberomammillary nucleus (TMN). The histamine neurons in this region comprise the brain's histamine system, which projects widely throughout the brain and includes axonal projections to the cortex, medial forebrain bundle, and elsewhere. The histamine neurons in the TMN are involved in regulating the sleep-wake cycle and promote arousal when activated. The neural firing rate of histamine neurons in the TMN is strongly positively correlated
with an individual's state of arousal. These neurons fire rapidly
during periods of wakefulness, fire more slowly during periods of
relaxation/tiredness, and stop firing altogether during REM and NREM (non-REM) sleep.
First-generation H1 antihistamines (i.e., antagonists of histamine receptor H1) are capable of crossing the blood–brain barrier and produce drowsiness by antagonizing histamine H1 receptors in the tuberomammillary nucleus. The newer class of second-generation H1 antihistamines
do not readily permeate the blood–brain barrier and thus are less
likely to cause sedation, although individual reactions, concomitant
medications and dosage may increase the likelihood of a sedating effect.
In contrast, histamine H3 receptor antagonists increase wakefulness. Similar to the sedative effect of first-generation H1 antihistamines, an inability to maintain vigilance
can occur from the inhibition of histamine biosynthesis or the loss
(i.e., degeneration or destruction) of histamine-releasing neurons in
the TMN.
Gastric acid release
Enterochromaffin-like cells, located within the gastric glands of the stomach, release histamine that stimulates nearby parietal cells by binding to the apical H2
receptor. Stimulation of the parietal cell induces the uptake of carbon
dioxide and water from the blood, which is then converted to carbonic
acid by the enzyme carbonic anhydrase. Inside the cytoplasm of the
parietal cell, the carbonic acid readily dissociates into hydrogen and
bicarbonate ions. The bicarbonate ions diffuse back through the basilar
membrane and into the bloodstream, while the hydrogen ions are pumped
into the lumen of the stomach via a K+/H+ ATPase pump. Histamine release is halted when the pH of the stomach starts to decrease. Antagonist molecules, like ranitidine, block the H2 receptor and prevent histamine from binding, causing decreased hydrogen ion secretion.
Protective effects
While histamine has stimulatory effects upon neurons, it also has suppressive ones that protect against the susceptibility to convulsion, drug sensitization, denervation supersensitivity, ischemic lesions and stress. It has also been suggested that histamine controls the mechanisms by which memories and learning are forgotten.
Erection and sexual function
Libido loss and erectile failure can occur during treatment with histamine H2 receptor antagonists such as cimetidine, ranitidine, and risperidone. The injection of histamine into the corpus cavernosum in men with psychogenic impotence produces full or partial erections in 74% of them. It has been suggested that H2 antagonists may cause sexual difficulties by reducing the functional binding of testosterone to its endogenous receptors.
Schizophrenia
Metabolites of histamine are increased in the cerebrospinal fluid of people with schizophrenia, while the efficiency of H1 receptor binding sites is decreased. Many atypical antipsychotic
medications have the effect of increasing histamine production, because
histamine levels seem to be imbalanced in people with that disorder.
Multiple sclerosis
Histamine therapy for treatment of multiple sclerosis
is currently being studied. The different H receptors have been known
to have different effects on the treatment of this disease. The H1 and H4 receptors, in one study, have been shown to be counterproductive in the treatment of MS. The H1 and H4
receptors are thought to increase permeability in the blood-brain
barrier, thus increasing infiltration of unwanted cells in the central
nervous system. This can cause inflammation, and MS symptom worsening.
The H2 and H3 receptors are thought to be helpful
when treating MS patients. Histamine has been shown to help with T-cell
differentiation. This is important because in MS, the body's immune
system attacks its own myelin sheaths on nerve cells (which causes loss
of signaling function and eventual nerve degeneration). By helping T
cells to differentiate, the T cells will be less likely to attack the
body's own cells, and instead attack invaders.
Disorders
As an integral part of the immune system, histamine may be involved in immune system disorders and allergies. Mastocytosis is a rare disease in which there is a proliferation of mast cells that produce excess histamine.
History
The properties of histamine, then called β-iminazolylethylamine, were first described in 1910 by the British scientists Henry H. Dale and P.P. Laidlaw. By 1913 the name histamine was in use, using combining forms of histo- + amine, yielding "tissue amine".
"H substance" or "substance H" are occasionally used in medical
literature for histamine or a hypothetical histamine-like diffusible
substance released in allergic reactions of skin and in the responses of
tissue to inflammation.
On the TV Show, Impractical Jokers, before having to be a part of Australia's Thunder from Down Under, one of the guys, Murr was injected with histamines as punishment.
