Histamine

Histamine is an organic nitrogenous compound involved in local immune responses communication, as well as regulating physiological functions in the gut and acting as a neurotransmitter for the brain, spinal cord, and uterus. Discovered in 1910, histamine has been considered a local hormone because it is produced without involvement of the classic endocrine glands; however, in recent years, histamine has been recognized as a central neurotransmitter. 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. 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, N^τ-H-histamine, is preferred in solution as compared to the pros tautomer, N^π-H-histamine.
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 will be protonated, whereas the second nitrogen of the imidazole ring will not be protonated.
Thus, histamine is normally protonated to a singly charged cation. Since human blood is slightly basic therefore the predominant form of histamine present in human blood is monoprotic at the aliphatic nitrogen. 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 -histidine decarboxylase. It is a hydrophilic vasoactive amine.
Image:Histidine decarboxylase.svg|thumb|center|433px|class=skin-invert-image|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

Most histamine in the body is generated in granules in mast cells and in white blood cells 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 hypothalamus region of the brain, where it functions as a neurotransmitter. Another important site of histamine storage and release is the enterochromaffin-like 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.

Degradation

Histamine is released by mast cells as an immune response and is later degraded primarily by two enzymes: diamine oxidase, coded by AOC1 genes, and histamine-N-methyltransferase, coded by the HNMT gene. The presence of single nucleotide polymorphisms at these genes are associated with a wide variety of disorders, from ulcerative colitis to autism spectrum disorder. Histamine degradation is crucial to the prevention of allergic reactions to otherwise harmless substances.
DAO is typically expressed in epithelial cells at the tip of the villus of the small intestine mucosa. Reduced DAO activity is associated with gastrointestinal disorders and widespread food intolerances. This is due to an increase in histamine absorption through enterocytes, which increases histamine concentration in the bloodstream. One study found that migraine patients with gluten sensitivity were positively correlated with having lower DAO serum levels. Low DAO activity can have more severe consequences as mutations in the ABP1 alleles of the AOC1 gene have been associated with ulcerative colitis. Heterozygous or homozygous recessive genotypes at the rs2052129, rs2268999, rs10156191 and rs1049742 alleles increased the risk for reduced DAO activity. People with genotypes for reduced DAO activity can avoid foods high in histamine, such as alcohol, fermented foods, and aged foods, to attenuate any allergic reactions. Additionally, they should be aware whether any probiotics they are taking contain any histamine-producing strains and consult with their doctor to receive proper support.
HNMT is expressed in the central nervous system, where deficiencies have been shown to lead to aggressive behavior and abnormal sleep-wake cycles in mice. Since brain histamine as a neurotransmitter regulates a number of neurophysiological functions, emphasis has been placed on the development of drugs to target histamine regulation. Yoshikawa et al. explores how the C314T, A939G, G179A, and T632C polymorphisms all impact HNMT enzymatic activity and the pathogenesis of various neurological disorders. These mutations can have either a positive or negative impact. Some patients with ADHD have been shown to exhibit exacerbated symptoms in response to food additives and preservatives, due in part to histamine release. In a double-blind placebo-controlled crossover trial, children with ADHD who responded with aggravated symptoms after consuming a challenge beverage were more likely to have HNMT polymorphisms at T939C and Thr105Ile. Histamine's role in neuroinflammation and cognition has made it a target of study for many neurological disorders, including autism spectrum disorder. De novo deletions in the HNMT gene have also been associated with ASD.
Mast cells serve an important immunological role by defending the body from antigens and maintaining homeostasis in the gut microbiome. They act as an alarm to trigger inflammatory responses by the immune system. Their presence in the digestive system enables them to serve as an early barrier to pathogens entering the body. People who suffer from widespread sensitivities and allergic reactions may have mast cell activation syndrome, in which excessive amounts of histamine are released from mast cells, and cannot be properly degraded. The abnormal release of histamine can be caused by either dysfunctional internal signals from defective mast cells or by the development of clonal mast cell populations through mutations occurring in the tyrosine kinase Kit. In such cases, the body may not be able to produce sufficient degradative enzymes to properly eliminate the excess histamine. Since MCAS is symptomatically characterized as such a broad disorder, it is difficult to diagnose and can be mislabeled as a variety of diseases, including irritable bowel syndrome and fibromyalgia.
Histamine is often explored as a potential cause for diseases related to hyper-responsiveness of the immune system. In patients with asthma, abnormal histamine receptor activation in the lungs is associated with bronchospasm, airway obstruction, and production of excess mucus. Mutations in histamine degradation are more common in patients with a combination of asthma and allergen hypersensitivity than in those with just asthma. The HNMT-464 TT and HNMT-1639 TT polymorphisms are significantly more common among children with allergic asthma, the latter of which is overrepresented in African-American children.

Mechanism of action

In humans, histamine exerts its effects primarily by binding to G protein-coupled histamine receptors, designated H₁ through H₄., histamine is believed to activate ligand-gated chloride channels in the brain and intestinal epithelium.

	Location	Function	Sources
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, mast cells, sensory nerves	CNS: Sleep-wake cycle, body temperature, nociception, endocrine homeostasis, regulates appetite, involved in cognition Periphery: Causes bronchoconstriction, bronchial smooth muscle contraction, urinary bladder contractions, vasodilation, promotes hypernociception, involved in itch perception and urticaria.
receptor	CNS: Dorsal striatum, cerebral cortex, 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 Periphery: Primarily involved in vasodilation and stimulation of gastric acid secretion. Urinary bladder relaxation. Modulates gastrointestinal function.
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.
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 have not been fully characterized.
Ligand-gated ion channel	Location	Function	Sources
	Putatively: CNS and intestinal epithelium	Brain: Produces fast inhibitory postsynaptic potentials Intestinal epithelium: chloride secretion