Histamine is an organic compound involved in local immune system, as well as regulating Physiology 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 (Autacoid) because it is produced without involvement of the classic endocrine ; 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 and by found in nearby connective tissues. Histamine increases the permeability of the capillaries to white blood cells and some , to allow them to engage in the Infection tissues. It consists of an imidazole ring attached to an ethylamine chain; under physiological conditions, the amino group of the side-chain is protonated.
Histamine has two basic centres, namely the aliphatic amino group and whichever nitrogen atom of the imidazole ring does not already have a hydrogen. Under physiological conditions, the aliphatic amino group (having a p Ka around 9.4) will be protonated, whereas the second nitrogen of the imidazole ring (p Ka ≈ 5.8) will not be protonated. Thus, histamine is normally protonated to a singly charged cation. Since human blood is slightly basic (with a normal pH range of 7.35 to 7.45) therefore the predominant form of histamine present in human blood is monoprotic at the aliphatic nitrogen. Histamine is a monoamine neurotransmitter.
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 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; contain it in the 2–10 mg/L range.
The most important pathophysiologic mechanism of mast cell and basophil histamine release is immune system. These cells, if sensitized by IgE antibody attached to their cell membrane, degranulation when exposed to the appropriate antigen. Certain and , including such drugs as morphine, and curare alkaloids, can displace histamine in granules and cause its release. 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.
DAO is typically expressed in Epithelium 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 , 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. Zygosity recessive genotypes at the rs2052129, rs2268999, rs10156191 and rs1049742 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 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 (ASD). 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 and maintaining homeostasis in the Gut microbiota. 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 entering the body. People who suffer from widespread sensitivities and allergic reactions may have mast cell activation syndrome (MCAS), in which excessive amounts of histamine are released from , 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.
+ Biological targets of histamine in the human body | ||||
receptor | CNS: Expressed on the 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| style="vertical-align:top" | '''CNS''': [[Sleep-wake cycle]] (promotes wakefulness), [[body temperature]], [[nociception]], [[endocrine homeostasisendocrine system]], regulates [[appetite]], involved in cognitionPeriphery: Causes bronchoconstriction, bronchial smooth muscle contraction, urinary bladder contractions, vasodilation, promotes hypernociception (visceral hypersensitivity), involved in itch and urticaria. | ||
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| style="vertical-align:top" | 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.
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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 and in the bone marrow. It is also expressed in the thymus, small intestine, spleen, and colon. | |||
Putatively: CNS (hypothalamus, thalamus) and intestinal epithelium | Brain: Produces fast inhibitory postsynaptic potentials Intestinal epithelium: chloride secretion (associated with secretory diarrhea) |
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 Alertness can occur from the inhibition of histamine biosynthesis or the loss (i.e., degeneration or destruction) of histamine-releasing neurons in the TMN.
Histamine intolerance is a presumed set of adverse reactions (such as flush, itching, rhinitis, etc.) to ingested histamine in food. The mainstream theory accepts that there may exist adverse reactions to ingested histamine, but does not recognize histamine intolerance as a separate condition that can be diagnosed.
The role of histamine in health and disease is an area of ongoing research. For example, histamine is researched in its potential link with migraine episodes, when there is a noted elevation in the plasma concentrations of both histamine and calcitonin gene-related peptide (CGRP). These two substances are potent vasodilators, and have been demonstrated to mutually stimulate each other's release within the trigeminovascular system, a mechanism that could potentially instigate the onset of migraines. In patients with a deficiency in histamine degradation due to variants in the AOC1 gene that encodes diamine oxidase enzyme, a diet high in histamine has been observed to trigger migraines, that suggests a potential functional relationship between exogenous histamine and CGRP, which could be instrumental in understanding the genesis of diet-induced migraines, so that the role of histamine, particularly in relation to CGRP, is a promising area of research for elucidating the mechanisms underlying migraine development and aggravation, especially relevant in the context of dietary triggers and genetic predispositions related to histamine metabolism.
As a solution for the rapid metabolism of histamine, the measurement of histamine and its metabolites, particularly the 1,4-methyl-imidazolacetic acid, in a 24-hour urine sample, provides an efficient alternative to histamine measurement because the values of these metabolites remain elevated for a much longer period than the histamine itself.
Commercial laboratories provide a 24-hour urine sample test for 1,4-methyl-imidazolacetic acid, the metabolite of histamine. This test is a valuable tool in assessing the metabolism of histamine in the body, as direct measurement of histamine in the serum has low diagnostic value due to the specificities of histamine metabolism.
The urine test involves collecting all urine produced in a 24-hour period, which is then analyzed for the presence of 1,4-methyl-imidazolacetic acid. This comprehensive approach ensures a more accurate reflection of histamine metabolism over an extended period; as such, the 1,4-methyl-imidazolacetic acid urine test offered by commercial labs is currently the most reliable method to determine the rate of histamine metabolism, which may be helpful for the health care practitioners to assess individual’s health status, such as to diagnose interstitial cystitis.
"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.
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