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Histamine

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For the use as an immunostimulant drug, see Histamine dihydrochloride.
Histamine
Names
IUPAC name
2-(1H-Imidazol-4-yl)ethanamine
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.000.092 Edit this at Wikidata
KEGG
MeSH Histamine
UNII
  • InChI=1S/C5H9N3/c6-2-1-5-3-7-4-8-5/h3-4H,1-2,6H2,(H,7,8) checkY
    Key: NTYJJOPFIAHURM-UHFFFAOYSA-N checkY
  • InChI=1/C5H9N3/c6-2-1-5-3-7-4-8-5/h3-4H,1-2,6H2,(H,7,8)
    Key: NTYJJOPFIAHURM-UHFFFAOYAP
  • NCCC1=C[N]C=N1
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[1]
Solubility in other solvents Easily soluble in methanol. Very slightly soluble in diethyl ether.[1] Easily soluble in ethanol.
log P −0.7[2]
Acidity (pKa) Imidazole: 6.04
Terminal NH2: 9.75[2]
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).
checkY verify (what is checkY☒N ?)

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.[3] Histamine is involved in the inflammatory response and has a central role as a mediator of pruritus.[4] 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.[5]

Properties

Histamine base, obtained as a mineral oil mull, melts at 83–84 °C.[6] Hydrochloride[7] and phosphorus[8] salts form white hygroscopic crystals and are easily dissolved in water or ethanol, but not in ether. In aqueous solution, histamine exists in two tautomeric forms: Nπ-H-histamine and Nτ-H-histamine. The imidazole ring has two nitrogens. The nitrogen farthest away from the side chain is the 'tele' nitrogen and is denoted by a lowercase tau sign. The nitrogen closest to the side chain is the 'pros' nitrogen and is denoted by the pi sign. The position of the nitrogen with the hydrogen on it determines how the tautomer is named. If the nitrogen with the hydrogen is in the tele position, then histamine is in the tele-tautomer form. The tele-tautomer is preferred in solution.

Tautomers of 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 (having a pKa around 9.4) will be protonated, whereas the second nitrogen of the imidazole ring (pKa ≈ 5.8) will not be protonated.[9] Thus, histamine is normally protonated to a singly charged cation.

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.[10]

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 and eosinophils. 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.[11] As of 2015, histamine is believed to activate ligand-gated chloride channels in the brain and intestinal epithelium.

Type Location Function Source
Histamine H1 receptor [11][12][13]
Histamine H2 receptor Located on parietal cells and vascular smooth muscle cells Primarily involved in vasodilation and stimulation of gastric acid secretion. Modulates gastrointestinal function. [11][12]
Histamine H3 receptor Found on 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.		 [11]
Histamine H4 receptor Found primarily in the basophils and in the bone marrow. It is also found on thymus, small intestine, spleen, and colon. Plays a role in mast cell chemotaxis, itch perception, cytokine production and secretion, and visceral hypersensitivity. Other functions (inflammation, allergy, cognition, etc.) have not been fully characterized. [11]
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)		 [11][12]

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.[14]

Vasodilation and a fall in blood pressure

When injected intravenously, histamine causes most blood vessels to dilate, and hence causes a fall in the blood pressure.[15] This is a key mechanism in anaphylaxis, and is thought to be caused when histamine releases nitric oxide, endothelium-derived hyperpolarizing factors and other compounds from the endothelial cells.

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:[16]

  1. sneezing due to histamine-associated sensory neural stimulation
  2. hyper-secretion from glandular tissue
  3. nasal congestion due to vascular engorgement associated with vasodilation and increased capillary permeability

Sleep-wake regulation

Histamine is released as a neurotransmitter. The cell bodies of histamine neurons are found in the posterior hypothalamus, in the tuberomammillary nuclei. From here, these neurons project throughout the brain, including to the cortex, through the medial forebrain bundle. Histamine neurons increase wakefulness and prevent sleep.[17] Classically, antihistamines (H1 histamine receptor antagonists) which cross the blood-brain barrier produce drowsiness. Newer antihistamines are designed to not cross into the brain and thus are less likely to cause sedation, although individual reactions, concomitant medications and dosage may increase the sedative effect. Similar to the effect of older antihistamines, destruction of histamine releasing neurons, or inhibition of histamine synthesis leads to an inability to maintain vigilance. Finally, H3 receptor antagonists increase wakefulness.

Histaminergic neurons have a wakefulness-related firing pattern. They fire rapidly during waking, fire more slowly during periods of relaxation/tiredness and completely stop firing during REM and NREM (non-REM) sleep.

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.[18] It has also been suggested that histamine controls the mechanisms by which memories and learning are forgotten.[19]

Erection and sexual function

Libido loss and erectile failure can occur during treatment with histamine H2 receptor antagonists such as cimetidine, ranitidine, and risperidone.[20] The injection of histamine into the corpus cavernosum in men with psychogenic impotence produces full or partial erections in 74% of them.[21] It has been suggested that H2 antagonists may cause sexual difficulties by reducing the uptake[clarification needed] of testosterone.[20]

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 decreasing histamine production (antagonist), because its use seems to be imbalanced in people with that disorder.[22]

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.[23]

Disorders

As an integral part of the immune system, histamine may be involved in immune system disorders[24] and allergies. Mastocytosis is a rare disease in which there is a proliferation of mast cells that produce excess histamine.[25]

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.[26] 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.[citation needed]

See also

References

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  2. ^ a b Vuckovic, Dajana; Pawliszyn, Janusz (15 March 2011). "Systematic Evaluation of Solid-Phase Microextraction Coatings for Untargeted Metabolomic Profiling of Biological Fluids by Liquid Chromatography−Mass Spectrometry". Analytical Chemistry. 83 (6). Supporting Information: 1944–1954. doi:10.1021/ac102614v.
  3. ^ Marieb, E. (2001). Human anatomy & physiology. San Francisco: Benjamin Cummings. p. 414. ISBN 0-8053-4989-8.
  4. ^ Andersen HH, Elberling J, Arendt-Nielsen L (2015). "Human surrogate models of histaminergic and non-histaminergic itch". Acta Dermato-Venereologica. 95: 771–7. doi:10.2340/00015555-2146. PMID 26015312.
  5. ^ Di Giuseppe, M.; et al. (2003). Nelson Biology 12. Toronto: Thomson Canada. p. 473. ISBN 0-17-625987-2.
  6. ^ http://webbook.nist.gov/cgi/cbook.cgi?ID=C51456&Mask=80
  7. ^ http://www.sigmaaldrich.com/catalog/product/sigma/h7250?lang=en&region=US
  8. ^ http://lib.njutcm.edu.cn/yaodian/ep/EP501E/16_monographs/17_monographs_d-k/histamine_phosphate/0144e.pdf
  9. ^ Paiva, T. B.; Tominaga, M.; Paiva, A. C. M. (1970). "Ionization of histamine, N-acetylhistamine, and their iodinated derivatives". Journal of Medicinal Chemistry. 13 (4): 689–692. doi:10.1021/jm00298a025. PMID 5452432.
  10. ^ http://astrobiology.berkeley.edu/PDFs_articles/WineAnalysisAnalChem.pdf
  11. ^ a b c d e f Panula P, Chazot PL, Cowart M, et al. (2015). "International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors". Pharmacol. Rev. 67 (3): 601–55. doi:10.1124/pr.114.010249. PMID 26084539.
  12. ^ a b c Wouters MM, Vicario M, Santos J (2015). "The role of mast cells in functional GI disorders". Gut. 65: 155–168. doi:10.1136/gutjnl-2015-309151. PMID 26194403.
  13. ^ Blandina, Patrizio; Munari, Leonardo; Provensi, Gustavo; Passani, Maria B. (2012). "Histamine neurons in the tuberomamillary nucleus: a whole center or distinct subpopulations?". Frontiers in Systems Neuroscience. 6. doi:10.3389/fnsys.2012.00033.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  14. ^ Noszal, B.; Kraszni, M.; Racz, A. (2004). "Histamine: fundamentals of biological chemistry". In Falus, A.; Grosman, N.; Darvas, Z. (eds.). Histamine: Biology and Medical Aspects. Budapest: SpringMed. pp. 15–28. ISBN 380557715X.
  15. ^ Dale, HH; Laidlaw, PP (31 December 1910). "The physiological action of beta-iminazolylethylamine". The Journal of Physiology. 41 (5): 318–44. doi:10.1113/jphysiol.1910.sp001406. PMC 1512903. PMID 16993030.
  16. ^ Monroe EW, Daly AF, Shalhoub RF (February 1997). "Appraisal of the validity of histamine-induced wheal and flare to predict the clinical efficacy of antihistamines". J. Allergy Clin. Immunol. 99 (2): S798–806. doi:10.1016/s0091-6749(97)70128-3. PMID 9042073.
  17. ^ Brown, RE; Stevens, DR; Haas, HL (2001). "The Physiology of Brain Histamine". Progress in Neurobiology. 63 (6): 637–672. doi:10.1016/s0301-0082(00)00039-3. PMID 11164999.
  18. ^ Yanai, K; Tashiro, M (2007). "The physiological and pathophysiological roles of neuronal histamine: an insight from human positron emission tomography studies". Pharmacology & therapeutics. 113 (1): 1–15. doi:10.1016/j.pharmthera.2006.06.008. PMID 16890992.
  19. ^ Alvarez, EO (2009). "The role of histamine on cognition". Behavioural Brain Research. 199 (2): 183–9. doi:10.1016/j.bbr.2008.12.010. PMID 19126417.
  20. ^ a b White, JM; Rumbold, GR (1988). "Behavioural effects of histamine and its antagonists: a review". Psychopharmacology. 95 (1): 1–14. doi:10.1007/bf00212757. PMID 3133686.
  21. ^ Cará, AM; Lopes-Martins, RA; Antunes, E; Nahoum, CR; De Nucci, G (1995). "The role of histamine in human penile erection". British Journal of Urology. 75 (2): 220–4. doi:10.1111/j.1464-410X.1995.tb07315.x. PMID 7850330.
  22. ^ Ito, C (2004). "The role of the central histaminergic system on schizophrenia". Drug News & Perspectives. 17 (6): 383–7. doi:10.1358/dnp.2004.17.6.829029. PMID 15334189.
  23. ^ Jadidi-Niaragh F, Mirshafiey A (September 2010). "Histamine and histamine receptors in pathogenesis and treatment of multiple sclerosis". Neuropharmacology. 59 (3): 180–9. doi:10.1016/j.neuropharm.2010.05.005. PMID 20493888.
  24. ^ E. Zampeli; E. Tiligada. "The role of histamine H4 receptor in immune and inflammatory disorders". National Center for Biotechnology Information. Department of Pharmacology, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
  25. ^ Valent P, Horny HP, Escribano L, et al. (July 2001). "Diagnostic criteria and classification of mastocytosis: a consensus proposal". Leuk. Res. 25 (7): 603–25. doi:10.1016/S0145-2126(01)00038-8. PMID 11377686.
  26. ^ Dale HH, Laidlaw PP (December 1910). "The physiological action of β-iminazolylethylamine" (PDF). J. Physiol. (Lond.). 41 (5): 318–44. doi:10.1113/jphysiol.1910.sp001406. PMC 1512903. PMID 16993030.
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