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Revision as of 11:53, 9 August 2011 editBeetstra (talk | contribs)Edit filter managers, Administrators172,031 edits Script assisted update of identifiers for the Chem/Drugbox validation project (updated: 'ChEBI').← Previous edit		Latest revision as of 22:54, 16 December 2024 edit undoArthurfragoso (talk | contribs)Extended confirmed users1,841 edits Fixes image on dark mode
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			{{Short description|Organic compound involved in immune responses}}
	{{Refimprove|date=January 2008}}
			{{About||the use as an immunostimulant drug|Histamine dihydrochloride}}
	{{chembox		{{chembox
			| Verifiedimages = changed
	| verifiedrevid = 415529072
			| Watchedfields = changed
			| verifiedrevid = 443858090
	| ImageFile_Ref = {{chemboximage|correct|??}}		| ImageFile_Ref = {{chemboximage|correct|??}}
	| ImageFile=Histamin - Histamine.svg		| ImageFile = Histamine.svg
	|ImageSize=		| ImageSize =
			| ImageClass = skin-invert
	|ImageFile2=Histamine3d.png
			| ImageFile2 = Histamine 3D ball.png
	|ImageSize2=200px
			| ImageSize2 =
	|IUPACName=2-(1''H''-imidazol-4-yl)ethanamine
			| IUPACName = 2-(1''H''-Imidazol-4-yl)ethanamine
	|OtherNames=
			| OtherNames =
	|Section1= {{Chembox Identifiers
	| UNII_Ref = {{fdacite|correct|FDA}}
			|Section1 = {{Chembox Identifiers
			| UNII_Ref = {{fdacite|correct|FDA}}
	| UNII = 820484N8I3		| UNII = 820484N8I3
	| KEGG_Ref = {{keggcite|correct|kegg}}		| KEGG_Ref = {{keggcite|correct|kegg}}
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	| StdInChIKey = NTYJJOPFIAHURM-UHFFFAOYSA-N		| StdInChIKey = NTYJJOPFIAHURM-UHFFFAOYSA-N
	| CASNo_Ref = {{cascite|correct|CAS}}		| CASNo_Ref = {{cascite|correct|CAS}}
	| CASNo=51-45-6		| CASNo = 51-45-6
	| PubChem=774		| PubChem = 774
	| IUPHAR_ligand = 1204		| IUPHAR_ligand = 1204
	| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}		| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
	| ChemSpiderID = 753		| ChemSpiderID = 753
			| ChEBI_Ref = {{ebicite|correct|EBI}}
	| ChEBI = 18295
	| SMILES = n1cc(nc1)CCN		| ChEBI = 18295
			| SMILES = NCCc1ccn1
	| MeSHName=Histamine
			| MeSHName=Histamine
			| DrugBank = DB05381
	}}		}}
	|Section2= {{Chembox Properties
			|Section2 = {{Chembox Properties
	| C=5|H=9|N=3
			| C=5 | H=9 | N=3
	| MolarMass=111.145
	| Appearance=		| Appearance=
	| Density=		| Density=
	| MeltingPt= 83.5 °C (182.3 °F)		| MeltingPtC= 83.5
	| BoilingPt= 209.5 °C (409.1 °F)		| BoilingPtC= 209.5
			| LogP = −0.7<ref name=Vuckovic>{{cite journal | vauthors = Vuckovic D, Pawliszyn J | title = Systematic evaluation of solid-phase microextraction coatings for untargeted metabolomic profiling of biological fluids by liquid chromatography-mass spectrometry | journal = Analytical Chemistry | volume = 83 | issue = 6 | pages = 1944–54 | date = March 2011 | pmid = 21332182 | doi = 10.1021/ac102614v }}</ref>
	| pK<sub>imidazole</sub> 6.04
	| pK<sub>NH2</sub> 9.75		| pKa = ]: 6.04 <br> Terminal NH<sub>2</sub>: 9.75<ref name=Vuckovic />
	| Solubility=Easily soluble in cold water, hot water<ref name="sciencelab.com">http://www.sciencelab.com/msds.php?msdsId=9924264</ref>		| Solubility = Easily soluble in cold water, hot water<ref name="sciencelab.com">{{cite tech report |title=Histamine Material Safety Data Sheet |institution=sciencelab.com |date=2013-05-21 |url=http://www.sciencelab.com/msds.php?msdsId=9924264 |url-status=live |archive-url=https://web.archive.org/web/20120324194707/http://www.sciencelab.com/msds.php?msdsId=9924264 |archive-date=2012-03-24 }}</ref>
	| SolubleOther=Easily soluble in methanol. Very slightly soluble in diethyl ether.<ref name="sciencelab.com"/> Easily soluble in ethanol.		| SolubleOther = Easily soluble in methanol. Very slightly soluble in diethyl ether.<ref name="sciencelab.com"/> Easily soluble in ethanol.
			| Solvent = other solvents
	}}		}}
	|Section3= {{Chembox Hazards		|Section6 = {{Chembox Pharmacology
			| ATCCode_prefix = L03
	| MainHazards=
			| ATCCode_suffix = AX14
	| FlashPt=
			| ATC_Supplemental = {{ATC|V04|CG03}} (phosphate)
	| Autoignition=
			}}
			|Section7 = {{Chembox Hazards
			| MainHazards =
			| FlashPt =
			| AutoignitionPt =
	}}		}}
	}}		}}
	'''Histamine''' is an organic nitrogen compound involved in local ] as well as regulating physiological function in the gut and acting as a ].<ref>{{cite book |author=Marieb, E. |title=Human anatomy & physiology |publisher=Benjamin Cummings |location=San Francisco |year=2001 |pages=414 |isbn=0-8053-4989-8 |oclc= |doi=}}</ref> Histamine triggers the ]. As part of an immune response to foreign ], histamine is produced by ]s and by ]s 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.<ref>{{cite book |title=Nelson Biology 12 |author=Di Giuseppe, M., et al. |year=2003 |publisher=Thomson Canada Ltd. |location=Toronto |isbn=0-17-625987-2 |page=473 }}</ref>
			'''Histamine''' is an organic ]ous compound involved in local ], as well as regulating ] in the ] and acting as a ] for the ], ], and ].<ref>{{cite book | vauthors = Marieb E |title=Human anatomy & physiology |url=https://archive.org/details/humananatomyphys00mari |url-access=registration |publisher=Benjamin Cummings |location=San Francisco |year=2001 |pages= |isbn=0-8053-4989-8 }}</ref><ref>{{cite journal | vauthors = Nieto-Alamilla G, Márquez-Gómez R, García-Gálvez AM, Morales-Figueroa GE, Arias-Montaño JA | title = The Histamine H3 Receptor: Structure, Pharmacology, and Function | journal = Molecular Pharmacology | volume = 90 | issue = 5 | pages = 649–673 | date = November 2016 | pmid = 27563055 | doi = 10.1124/mol.116.104752 | doi-access = free }}</ref> Discovered in 1910, histamine has been considered a local ] (]) because it's produced without involvement of the classic ] ]s; however, in recent years, histamine has been recognized as a central ].<ref name="pmid27028114">{{cite journal | vauthors = Keppel Hesselink JM | title = The terms 'autacoid', 'hormone' and 'chalone' and how they have shifted with time | journal = Autonomic & Autacoid Pharmacology | volume = 35 | issue = 4 | pages = 51–8 | date = December 2015 | pmid = 27028114 | doi = 10.1111/aap.12037 | url = }}</ref> Histamine is involved in the ] and has a central role as a mediator of ].<ref name=andersen>{{cite journal | vauthors = Andersen HH, Elberling J, Arendt-Nielsen L | title = Human surrogate models of histaminergic and non-histaminergic itch | journal = Acta Dermato-Venereologica | volume = 95 | issue = 7 | pages = 771–7 | date = September 2015 | pmid = 26015312 | doi = 10.2340/00015555-2146 | doi-access = free | url = https://vbn.aau.dk/files/219083590/4442_9.pdf | access-date = 2024-02-20 | archive-date = 2019-03-30 | archive-url = https://web.archive.org/web/20190330070753/http://vbn.aau.dk/files/219083590/4442_9.pdf | url-status = live }}</ref> As part of an immune response to foreign ], histamine is produced by ]s and by ]s found in nearby ]s. Histamine increases the ] of the ] to ] and some ]s, to allow them to engage ]s in the ] tissues.<ref>{{cite book |title=Nelson Biology 12 |url=https://archive.org/details/nelsonbiology12gius |url-access=limited | vauthors = Di Giuseppe M, Fraser D |year=2003 |publisher=Thomson Canada |location=Toronto |isbn=0-17-625987-2 |page= }}</ref> It consists of an ] ring attached to an ] chain; under ]s, the ] of the side-chain is ].
	==Properties==
			== Properties ==
	Histamine forms colorless ] ]s that melt at 84°C, and are easily dissolved in ] or ], but not in ]. In ] histamine exists in two ]ic forms, ''N<sup>π</sup>-H''-histamine and ''N<sup>τ</sup>-H''-histamine.
			Histamine base, obtained as a mineral oil ], melts at 83–84&nbsp;°C.<ref>{{cite web|url=http://webbook.nist.gov/cgi/cbook.cgi?ID=C51456&Mask=80|title=Histamine|website=webbook.nist.gov|url-status=dead|archive-url=https://web.archive.org/web/20180427205956/https://webbook.nist.gov/cgi/cbook.cgi?ID=C51456&Mask=80|archive-date=2018-04-27|access-date=2015-01-04}}</ref> Hydrochloride<ref>{{cite web|url=http://www.sigmaaldrich.com/catalog/product/sigma/h7250?lang=en&region=US|title=Histamine dihydrochloride H7250|website=Sigma-Aldrich|url-status=live|archive-url=https://web.archive.org/web/20150809131738/http://www.sigmaaldrich.com/catalog/product/sigma/h7250?lang=en&region=US|archive-date=2015-08-09}}</ref> and phosphorus<ref>{{cite book | chapter-url=http://lib.njutcm.edu.cn/yaodian/ep/EP501E/16_monographs/17_monographs_d-k/histamine_phosphate/0144e.pdf | chapter = Histamine phosphate | title = European Pharmacopoeia | edition = 5th | isbn = 9287152810 |access-date=2015-01-04 |url-status=dead |archive-url=https://web.archive.org/web/20150104181128/http://lib.njutcm.edu.cn/yaodian/ep/EP501E/16_monographs/17_monographs_d-k/histamine_phosphate/0144e.pdf |archive-date=2015-01-04 }}</ref> salts form white ] ]s and are easily dissolved in ] or ], but not in ]. In ], the imidazole ring of histamine exists in two ]ic 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<sup>τ</sup>-H''-histamine, is preferred in solution as compared to the pros tautomer, ''N<sup>π</sup>-H''-histamine.
			]
	{|align="left"
	]
			Histamine has two ] centres, namely the ] amino group and whichever ] atom of the imidazole ring does not already have a ]. Under physiological conditions, the aliphatic amino group (having a ]<sub>a</sub> around 9.4) will be ], whereas the second nitrogen of the imidazole ring (p''K''<sub>a</sub> ≈ 5.8) will not be protonated.<ref name="Paiva 1970">{{cite journal | vauthors = Paiva TB, Tominaga M, Paiva AC | title = Ionization of histamine, N-acetylhistamine, and their iodinated derivatives | journal = Journal of Medicinal Chemistry | volume = 13 | issue = 4 | pages = 689–92 | date = July 1970 | pmid = 5452432 | doi = 10.1021/jm00298a025 }}</ref>
	|}
			Thus, histamine is normally protonated to a singly charged ]. Since human ] 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 ].
	Histamine has two ] centres, namely the ] ] and whichever ] atom of the ] ring does not already have a ]. Under physiological conditions, the aliphatic amino group (having a ]<sub>a</sub> around 9.4) will be ], whereas the second nitrogen of the imidazole ring (pK<sub>a</sub> ≈ 5.8) will not be protonated.<ref name="Paiva 1970">{{cite journal | doi = 10.1021/jm00298a025 | last1 = Paiva | first1 = T. B. | last2 = Tominaga | first2 = M. | last3 = Paiva | first3 = A. C. M. | year = 1970 | title = Ionization of histamine, N-acetylhistamine, and their iodinated derivatives | url = | journal = Journal of Medicinal Chemistry | volume = 13 | issue = 4| pages = 689–692 | pmid = 5452432 }}</ref>
	Thus, histamine is normally protonated to a singly charged ].
	==Synthesis and metabolism==		== Synthesis and metabolism ==
	Histamine is derived from the ] of the ] ], a reaction ] by the ] ]. It is a ] ] ].		Histamine is derived from the ] of the ] ], a reaction ] by the ] ]. It is a ] ] ].
	] to histamine by ]]]		] to histamine by ]]]
	Once formed, histamine is either stored or rapidly inactivated by its primary degradative enzymes, ] or ]. In the central nervous system, histamine released into the ]s is primarily broken down by ], while in other tissues both enzymes may play a role. Several other enzymes, including ] and ], further process the immediate metabolites of histamine for excretion or recycling.		Once formed, histamine is either stored or rapidly inactivated by its primary ]s, ] or ]. In the central nervous system, histamine released into the ]s is primarily broken down by histamine-''N''-methyltransferase, while in other tissues both enzymes may play a role. Several other enzymes, including ] and ], 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&nbsp;mg/L range; wines contain it in the 2–10&nbsp;mg/L range.<ref>http://astrobiology.berkeley.edu/PDFs_articles/WineAnalysisAnalChem.pdf</ref>		Bacteria also are capable of producing histamine using ] enzymes unrelated to those found in animals. A non-infectious form of foodborne disease, ], 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. ] contains histamine in the 20–40&nbsp;mg/L range; ]s contain it in the 2–10&nbsp;mg/L range.<ref name="pmid17892274">{{cite journal | vauthors = Jayarajah CN, Skelley AM, Fortner AD, Mathies RA | title = Analysis of neuroactive amines in fermented beverages using a portable microchip capillary electrophoresis system | journal = Analytical Chemistry | volume = 79 | issue = 21 | pages = 8162–9 | date = November 2007 | pmid = 17892274 | doi = 10.1021/ac071306s |url= http://astrobiology.berkeley.edu/PDFs_articles/WineAnalysisAnalChem.pdf |url-status=dead |archive-url=https://web.archive.org/web/20110719142418/http://astrobiology.berkeley.edu/PDFs_articles/WineAnalysisAnalChem.pdf | archive-date = 19 July 2011 }}</ref>
	==Storage and release==		== Storage and release ==
	]		]
	Most histamine in the body is generated in granules in ] or in white blood cells called ]. 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 ], where it functions as a neurotransmitter. Another important site of histamine storage and release is the ] of the ].		Most histamine in the body is generated in granules in ] and in white blood cells (leukocytes) called ]. 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 ] region of the ], where it functions as a neurotransmitter. Another important site of histamine storage and release is the ] of the ].
	The most important pathophysiologic mechanism of mast cell and basophil histamine release is ]. These cells, if sensitized by ] ] attached to their ], ] when exposed to the appropriate ]. Certain ]s and ]s, including such drugs as ], and ]s, can displace histamine in granules and cause its release. ]s like ] are also found to stimulate histamine release.		The most important pathophysiologic mechanism of mast cell and basophil histamine release is ]. These cells, if sensitized by ] ] attached to their ], ] when exposed to the appropriate ]. Certain ]s and ]s, including such drugs as ], and ] alkaloids, can displace histamine in granules and cause its release. ]s like ] are also found to stimulate histamine release.
	Histamine release occurs when allergens bind to mast-cell-bound 1gE antibodies. Reduction of 1gE overproduction may lower the likelihood of allergens finding sufficent free 1gH to trigger a mast-cell-release of histimine.		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 ==
	==Mechanism of action==
			Histamine is released by mast cells as an immune response and is later degraded primarily by two enzymes: ] (DAO), coded by AOC1 genes, and ] (HNMT), coded by the HNMT gene. The presence of ] (SNPs) at these genes are associated with a wide variety of disorders, from ] to ] (ASD).<ref name="Altered expression of histamine sig">{{cite journal | vauthors = Wright C, Shin JH, Rajpurohit A, Deep-Soboslay A, Collado-Torres L, Brandon NJ, Hyde TM, Kleinman JE, Jaffe AE, Cross AJ, Weinberger DR | display-authors = 6 | title = Altered expression of histamine signaling genes in autism spectrum disorder | journal = Translational Psychiatry | volume = 7 | issue = 5 | pages = e1126 | date = May 2017 | pmid = 28485729 | pmc = 5534955 | doi = 10.1038/tp.2017.87 }}</ref> Histamine degradation is crucial to the prevention of allergic reactions to otherwise harmless substances.
	Histamine exerts its actions by combining with specific cellular ]. The four histamine receptors that have been discovered in humans are designated H1 through H4, and are all ]s (GPCR).
	Histamine receptors in insects, like ], are histamine-gated ]s that function in inhibition of neurons.<ref>Hardie RC 1989 A histamine-activated chloride channel involved in neurotransmission at a photoreceptor synapse. Nature</ref> Histamine-gated chloride channels are implicated in neurotransmission of peripheral sensory information in insects, especially in photoreception/vision. Two receptors subtypes have been identified in Drosophila, HClA and HClB.<ref>Pantazis et al. 2008 Distinct Roles for Two Histamine Receptors (hclA and hclB) at the Drosophila Photoreceptor Synapse. Journal of Neuroscience</ref> There are no known GPCRs for histamine in insects.
			DAO is typically expressed in ] at the tip of the ] of the small intestine mucosa.<ref>{{cite journal | vauthors = Thompson JS | title = Significance of the intestinal gradient of diamine oxidase activity | language = english | journal = Digestive Diseases | volume = 8 | issue = 3 | pages = 163–8 | date = 1990 | pmid = 2110876 | doi = 10.1159/000171249 }}</ref> Reduced DAO activity is associated with gastrointestinal disorders and widespread food intolerances. This is due to an increase in histamine absorption through ]s, which increases histamine concentration in the bloodstream.<ref name="Histamine N-Methyltransferase i">{{cite journal | vauthors = Yoshikawa T, Nakamura T, Yanai K | title = Histamine ''N''-Methyltransferase in the Brain | journal = International Journal of Molecular Sciences | volume = 20 | issue = 3 | pages = 737 | date = February 2019 | pmid = 30744146 | pmc = 6386932 | doi = 10.3390/ijms20030737 | doi-access = free }}</ref> One study found that ] patients with ] were positively correlated with having lower DAO serum levels.<ref>{{cite journal | vauthors = Griauzdaitė K, Maselis K, Žvirblienė A, Vaitkus A, Jančiauskas D, Banaitytė-Baleišienė I, Kupčinskas L, Rastenytė D | display-authors = 6 | title = Associations between migraine, celiac disease, non-celiac gluten sensitivity and activity of diamine oxidase | journal = Medical Hypotheses | volume = 142 | pages = 109738 | date = September 2020 | pmid = 32416409 | doi = 10.1016/j.mehy.2020.109738 | s2cid = 216303896 }}</ref> Low DAO activity can have more severe consequences as mutations in the ABP1 alleles of the AOC1 gene have been associated with ulcerative colitis.<ref>{{cite journal | vauthors = García-Martin E, Mendoza JL, Martínez C, Taxonera C, Urcelay E, Ladero JM, de la Concha EG, Díaz-Rubio M, Agúndez JA | display-authors = 6 | title = Severity of ulcerative colitis is associated with a polymorphism at diamine oxidase gene but not at histamine N-methyltransferase gene | journal = World Journal of Gastroenterology | volume = 12 | issue = 4 | pages = 615–20 | date = January 2006 | pmid = 16489678 | pmc = 4066097 | doi = 10.3748/wjg.v12.i4.615 | doi-access = free }}</ref> ] recessive genotypes at the rs2052129, rs2268999, rs10156191 and rs1049742 ]s increased the risk for reduced DAO activity.<ref>{{cite journal | vauthors = Maintz L, Yu CF, Rodríguez E, Baurecht H, Bieber T, Illig T, Weidinger S, Novak N | display-authors = 6 | title = Association of single nucleotide polymorphisms in the diamine oxidase gene with diamine oxidase serum activities | journal = Allergy | volume = 66 | issue = 7 | pages = 893–902 | date = July 2011 | pmid = 21488903 | doi = 10.1111/j.1398-9995.2011.02548.x | s2cid = 205405463 | url = http://mediatum.ub.tum.de/doc/1099433/document.pdf }}{{Dead link|date=March 2024 |bot=InternetArchiveBot |fix-attempted=yes }}</ref> 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 ]s they are taking contain any histamine-producing strains and consult with their doctor to receive proper support {{Citation needed|date=September 2023|reason=This implicitly assumes that digested histamine can enter the bloodstream, which hasn't been established in this section.}}.
			HNMT is expressed in the ], where deficiencies have been shown to lead to aggressive behavior and abnormal sleep-wake cycles in mice.<ref>{{cite journal | vauthors = Branco AC, Yoshikawa FS, Pietrobon AJ, Sato MN | title = Role of Histamine in Modulating the Immune Response and Inflammation | journal = Mediators of Inflammation | volume = 2018 | pages = 9524075 | date = 2018-08-27 | pmid = 30224900 | pmc = 6129797 | doi = 10.1155/2018/9524075 | doi-access = free }}</ref> 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.<ref name="Histamine N-Methyltransferase i"/> These mutations can have either a positive or negative impact. Some patients with ] have been shown to exhibit exacerbated symptoms in response to food additives and preservatives, due in part to histamine release. In a ] 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.<ref>{{cite journal | vauthors = Stevenson J, Sonuga-Barke E, McCann D, Grimshaw K, Parker KM, Rose-Zerilli MJ, Holloway JW, Warner JO | display-authors = 6 | title = The role of histamine degradation gene polymorphisms in moderating the effects of food additives on children's ADHD symptoms | journal = The American Journal of Psychiatry | volume = 167 | issue = 9 | pages = 1108–15 | date = September 2010 | pmid = 20551163 | doi = 10.1176/appi.ajp.2010.09101529 }}</ref> 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.<ref name="Altered expression of histamine sig"/>
			Mast cells serve an important immunological role by defending the body from ]s and maintaining ] in the ]. 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 ]s entering the body. People who suffer from widespread sensitivities and allergic reactions may have ] (MCAS), in which excessive amounts of histamine are released from ]s, 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 ] ].<ref name=":0">{{cite journal | vauthors = Haenisch B, Nöthen MM, Molderings GJ | title = Systemic mast cell activation disease: the role of molecular genetic alterations in pathogenesis, heritability and diagnostics | journal = Immunology | volume = 137 | issue = 3 | pages = 197–205 | date = November 2012 | pmid = 22957768 | pmc = 3482677 | doi = 10.1111/j.1365-2567.2012.03627.x }}</ref> 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 ] and ].<ref name=":0" />
			Histamine is often explored as a potential cause for diseases related to hyper-responsiveness of the immune system. In patients with ], abnormal histamine receptor activation in the lungs is associated with ], 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 ] are significantly more common among children with allergic asthma, the latter of which is overrepresented in African-American children.<ref>{{cite journal | vauthors = Anvari S, Vyhlidal CA, Dai H, Jones BL | title = Genetic Variation along the Histamine Pathway in Children with Allergic versus Nonallergic Asthma | journal = American Journal of Respiratory Cell and Molecular Biology | volume = 53 | issue = 6 | pages = 802–9 | date = December 2015 | pmid = 25909280 | pmc = 4742940 | doi = 10.1165/rcmb.2014-0493OC }}</ref>
			== Mechanism of action ==
			In humans, histamine exerts its effects primarily by binding to ] ], designated H<sub>1</sub> through H<sub>4</sub>.<ref name="Histamine receptors" /> {{As of|2015}}, histamine is believed to activate ligand-gated chloride channels in the brain and intestinal epithelium.<ref name="Histamine receptors" /><ref name="FGID mast cell" />
	{| class="wikitable"		{| class="wikitable"
			|+ Biological targets of histamine in the human body
	| '''Type''' || '''Location''' || '''Function'''
	|-		|-
			! {{nowrap|]}} !! Location !! Function !! <small>Sources</small>
	| ] || Found on ], ], and ] tissue || Causes, ], bronchial ] contraction, separation of ] (responsible for ]), and ] and ] due to insect stings; the primary receptors involved in ] symptoms and ]; sleep regulation.
	|-
	| ] || Located on ] and ] || Primarily involved in vasodilation. Also stimulate ] secretion
	|-
	| ] || Found on ] and to a lesser extent ] tissue || Decreased ] release: histamine, ], ], ]
	|-
	| ] || Found primarily in the ]s and in the ]. It is also found on ], ], ], and ]. || Plays a role in ].
	|}
			|- <!-- HRH1 -->
	=== Effects on nasal mucous membrane {{Anchor|Effects on Nasal Mucosa}}===
			| style="text-align:center" | ]
	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 ]-loaded ]s in the ]'s ]s. This can lead to three clinical responses:<ref>Monroe, E., Daly, A., and Shalhoub, R. 1997. "Appraisal of the validity of histamine-induced wheal and flare to predict the clinical efficacy of antihistamines". ''Journal of Allergy and Clinical Immunology'' 99(2): S789-806.</ref>
			| style="vertical-align:top"|
			{{bull}}'''CNS''': Expressed on the ]s of the output neurons of the histaminergic ], which projects to the ], ], and additional structures.<br />
			{{bull}}'''Periphery''': ], ], ], sensory nerves
			| style="vertical-align:top"|
			{{bull}} '''CNS''': ] (promotes wakefulness), ], ], ], regulates ], involved in cognition<br />
			{{bull}}'''Periphery''': Causes ], bronchial ] contraction, urinary bladder contractions, ], promotes hypernociception (]), involved in ] and ].
			| <ref name="Histamine receptors" /><ref name="FGID mast cell">{{cite journal | vauthors = Wouters MM, Vicario M, Santos J | title = The role of mast cells in functional GI disorders | journal = Gut | volume = 65 | issue = 1 | pages = 155–68 | date = January 2016 | pmid = 26194403 | doi = 10.1136/gutjnl-2015-309151 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Blandina P, Munari L, Provensi G, Passani MB | title = Histamine neurons in the tuberomamillary nucleus: a whole center or distinct subpopulations? | journal = Frontiers in Systems Neuroscience | volume = 6 | pages = 33 | year = 2012 | pmid = 22586376 | pmc = 3343474 | doi = 10.3389/fnsys.2012.00033 | doi-access = free }}</ref><ref name="Urinary Bladder">{{cite journal | vauthors = Stromberga Z, Chess-Williams R, Moro C | title = Histamine modulation of urinary bladder urothelium, lamina propria and detrusor contractile activity via H1 and H2 receptors | journal = Scientific Reports | volume = 9 | issue = 1 | pages = 3899 | date = March 2019 | pmid = 30846750 | pmc = 6405771 | doi = 10.1038/s41598-019-40384-1 | bibcode = 2019NatSR...9.3899S }}</ref><ref name="Histamine mediated autocrine signal">{{cite journal | vauthors = Pal S, Gasheva OY, Zawieja DC, Meininger CM, Gashev AA J | title = Histamine mediated autocrine signalling in mesenteric perilymphatic mast cells | journal = Am J Physiol Regul Integr Comp Physiol | volume = 318 | issue = 3 | pages = 590–604 | date = January 2020 | pmid = 31913658 | doi = 10.1152/ajpregu.00255.2019 | pmc = 7099465 | s2cid = 210119438 }}</ref>
			|- <!-- HRH2 -->
	*sneezing due to histamine-associated sensory neural stimulation;
			| style="text-align:center" | ]
	*hyper-] from glandular tissue; and
			| style="vertical-align:top"|
			{{bull}}'''CNS''': ] (] and ]), ] (external layers), ], ] of the ]<br />
			{{bull}}'''Periphery''': Located on ], ], ], ], as well as on cells in the ] and ]
			| style="vertical-align:top"|
			{{bull}}'''CNS''': Not established (note: most known H<sub>2</sub> receptor ligands are unable to cross the ] in sufficient concentrations to allow for neuropsychological and behavioral testing)<br />
			{{bull}}'''Periphery''': Primarily involved in vasodilation and stimulation of ] secretion. Urinary bladder relaxation. Modulates gastrointestinal function.
			| <ref name="Histamine receptors" /><ref name="FGID mast cell" /><ref name="IUPHAR HRH2">{{cite web |title=H<sub>2</sub> receptor |url=http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=263 |work=IUPHAR/BPS Guide to Pharmacology |publisher=International Union of Basic and Clinical Pharmacology |access-date=20 March 2017 |vauthors=Maguire JJ, Davenport AP |date=29 November 2016 |url-status=dead |archive-url=https://web.archive.org/web/20170321084255/http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=263 |archive-date=21 March 2017 }}</ref><ref name="Histamine mediated autocrine signal"/>
			|- <!-- HRH3 -->
	*nasal congestion due to vascular engorgement associated with ] and increased ] ].
			| style="text-align:center" | ]
			| Located in the ] and to a lesser extent ] tissue
			| ] and ] functions: decreased ] release of histamine, ], ], ]. Modulates nociception, gastric acid secretion, and food intake.
			| <ref name="Histamine receptors" />
			|- <!-- HRH4 -->
			| style="text-align:center" | ]
			| Located primarily on ]s and in the ]. It is also expressed in the ], ], ], and ].
			| Plays a role in mast cell ], itch perception, cytokine production and secretion, and visceral hypersensitivity. Other putative functions (e.g., inflammation, allergy, cognition, etc.) have not been fully characterized. || <ref name="Histamine receptors">{{cite journal | vauthors = Panula P, Chazot PL, Cowart M, Gutzmer R, Leurs R, Liu WL, Stark H, Thurmond RL, Haas HL | display-authors = 6 | title = International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors | journal = Pharmacological Reviews | volume = 67 | issue = 3 | pages = 601–55 | date = July 2015 | pmid = 26084539 | pmc = 4485016 | doi = 10.1124/pr.114.010249 }}</ref>
			|-
			! scope="col" | ] !! Location !! Function !! <small>Sources</small>
			|-
			| style="text-align:center" | {{nowrap|Histamine-gated}} {{nowrap|]}}
			| Putatively: CNS (hypothalamus, thalamus) and intestinal epithelium
			| Brain: Produces fast ]s<br /> Intestinal epithelium: chloride secretion (associated with ])
			| <ref name="Histamine receptors" /><ref name="FGID mast cell" />
			|}
	== Roles in the body ==		== 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.<ref name="Noszal, B. pp 15-28">{{cite book | vauthors = Noszal B, Kraszni M, Racz A |chapter=Histamine: fundamentals of biological chemistry | veditors = Falus A, Grosman N, Darvas Z |title=Histamine: Biology and Medical Aspects |publisher=SpringMed |location=Budapest |year=2004 |isbn=380557715X |pages=15–28 }}</ref>
	=== Sleep regulation ===
	Histamine is released as a neurotransmitter. The cell bodies of ''histaminergics'', the neurons which release histamine, are found in the posterior ], in various ]. From here, these neurons project throughout the brain, to the ] through the ]. Histaminergic action is known to modulate ]. Classically, ] (H1 histamine receptor antagonists) produce sleep. Likewise, destruction of histamine releasing neurons, or inhibition of histamine synthesis leads to an inability to maintain ]. Finally, H3 receptor antagonists increase wakefulness.
			=== Vasodilation and fall in blood pressure ===
	It has been shown that histaminergic cells have the most wakefulness-related firing pattern of any neuronal type thus far recorded. They fire rapidly during waking, fire more slowly during periods of relaxation/tiredness and completely stop firing during ] and ] (non-REM) sleep. Histaminergic cells can be recorded firing just before an animal shows signs of waking.
			It has been known for more than one hundred years that an intravenous injection of histamine causes a fall in the blood pressure.<ref>{{cite journal | vauthors = Dale HH, Laidlaw PP | title = The physiological action of beta-iminazolylethylamine | journal = The Journal of Physiology | volume = 41 | issue = 5 | pages = 318–44 | date = December 1910 | pmid = 16993030 | pmc = 1512903 | doi = 10.1113/jphysiol.1910.sp001406 }}</ref> 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 ], ]s and other compounds, resulting in blood vessel dilation.<ref name="Abbas et al (2018). Cellular and molecular immunology p.447">{{Cite book |title= Cellular and molecular immunology | vauthors = Abbas A |publisher=Elsevier |year=2018 |isbn=978-0-323-47978-3 |pages=447}}</ref> These two mechanisms play a key role in the pathophysiology of ].
			=== Effects on nasal mucous membrane {{Anchor|Effects on Nasal Mucosa}} ===
	===Suppressive effects ===
			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 ]-loaded ]s in the ]'s ]s. This can lead to three clinical responses:<ref>
			{{cite journal | vauthors = Monroe EW, Daly AF, Shalhoub RF | title = Appraisal of the validity of histamine-induced wheal and flare to predict the clinical efficacy of antihistamines | journal = The Journal of Allergy and Clinical Immunology | volume = 99 | issue = 2 | pages = S798-806 | date = February 1997 | pmid = 9042073 | doi = 10.1016/s0091-6749(97)70128-3 | doi-access = free }}</ref>
			# sneezing due to histamine-associated sensory neural stimulation
	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.<ref>{{cite journal | last1 = Yanai | first1 = K | last2 = Tashiro | first2 = M | title = The physiological and pathophysiological roles of neuronal histamine: an insight from human positron emission tomography studies. | journal = Pharmacology & therapeutics | volume = 113 | issue = 1 | pages = 1–15 | year = 2007 | pmid = 16890992 | doi = 10.1016/j.pharmthera.2006.06.008 }}</ref> It has also been suggested that histamine controls the mechanisms by which memories and learning are forgotten.<ref>{{cite journal | last1 = Alvarez | first1 = EO | title = The role of histamine on cognition. | journal = Behavioural brain research | volume = 199 | issue = 2 | pages = 183–9 | year = 2009 | pmid = 19126417 | doi = 10.1016/j.bbr.2008.12.010 }}</ref>
			# hyper-] from glandular tissue
			# nasal congestion due to vascular engorgement associated with ] and increased ] ]
			=== Sleep-wake regulation ===
	===Erection and sexual function===
			{{Further|Ascending reticular activating system}}
			Histamine is a ] that is released from histaminergic ]s which project out of the ]ian ]. The cell bodies of these neurons are located in a portion of the posterior ] known as the ] (TMN). The histamine neurons in this region comprise the ], which projects widely throughout the brain and includes ]s to the ], ], other hypothalamic nuclei, medial septum, the nucleus of the diagonal band, ventral tegmental area, amygdala, striatum, substantia nigra, hippocampus, thalamus and elsewhere.<ref>{{Cite book| vauthors = Brady S |title= Basic Neurochemistry - Principles of Molecular, Cellular and Medical Neurobiology|publisher=Elsevier|year=2012|isbn=978-0-12-374947-5|location=Waltham, USA|pages=337}}</ref> The histamine neurons in the TMN are involved in regulating the ] and promote arousal when activated.<ref>{{cite journal | vauthors = Brown RE, Stevens DR, Haas HL | title = The physiology of brain histamine | journal = Progress in Neurobiology | volume = 63 | issue = 6 | pages = 637–72 | date = April 2001 | pmid = 11164999 | doi = 10.1016/s0301-0082(00)00039-3 | s2cid = 10170830 }}</ref> The ] of histamine neurons in the TMN is strongly ] 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 ] and ] (non-REM) sleep.<ref>{{cite journal | vauthors = Takahashi K, Lin JS, Sakai K | title = Neuronal activity of histaminergic tuberomammillary neurons during wake-sleep states in the mouse | journal = The Journal of Neuroscience | volume = 26 | issue = 40 | pages = 10292–10298 | date = October 2006 | pmid = 17021184 | pmc = 6674640 | doi = 10.1523/JNEUROSCI.2341-06.2006 }}</ref>
			First-generation ] (i.e., ] of ]) are capable of crossing the ] and produce ] by antagonizing histamine H<sub>1</sub> receptors in the tuberomammillary nucleus. The newer class of ] 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, ]s increase wakefulness. Similar to the sedative effect of first-generation H<sub>1</sub> antihistamines, an inability to maintain ] can occur from the inhibition of histamine biosynthesis or the loss (i.e., degeneration or destruction) of histamine-releasing neurons in the TMN.
	Libido loss and erectile failure can occur following histamine (H2) antagonists such as ] and ].<ref name="White">{{cite journal | last1 = White | first1 = JM | last2 = Rumbold | first2 = GR | title = Behavioural effects of histamine and its antagonists: a review. | journal = Psychopharmacology | volume = 95 | issue = 1 | pages = 1–14 | year = 1988 | pmid = 3133686 }}</ref> The injection of histamine into the ] in men with psychogenic impotence produces full or partial erections in 74% of them.<ref>{{cite journal | last1 = Cará | first1 = AM | last2 = Lopes-Martins | first2 = RA | last3 = Antunes | first3 = E | last4 = Nahoum | first4 = CR | last5 = De Nucci | first5 = G | title = The role of histamine in human penile erection. | journal = British journal of urology | volume = 75 | issue = 2 | pages = 220–4 | year = 1995 | pmid = 7850330 }}</ref> It has been suggested that H2 antagonists may cause sexual difficulties by reducing the uptake{{clarify|date=November 2010}} of testosterone.<ref name="White"/>
			=== Gastric acid release ===
			]s in the stomach release histamine, stimulating parietal cells via H<sub>2</sub> receptors. This triggers carbon dioxide and water uptake from the blood, converted to carbonic acid by carbonic anhydrase. The acid dissociates into hydrogen and bicarbonate ions within the parietal cell. Bicarbonate returns to the bloodstream, while hydrogen is pumped into the stomach lumen. Histamine release ceases as stomach pH decreases.{{medical citation needed|date=March 2024}} ] molecules, such as ] or ], block the H<sub>2</sub> receptor and prevent histamine from binding, causing decreased hydrogen ion secretion.{{medical citation needed|date=March 2024}}
			=== Protective effects ===
			While histamine has stimulatory effects upon neurons, it also has suppressive ones that protect against the susceptibility to ], drug sensitization, ], ischemic lesions and stress.<ref>{{cite journal | vauthors = Yanai K, Tashiro M | title = The physiological and pathophysiological roles of neuronal histamine: an insight from human positron emission tomography studies | journal = Pharmacology & Therapeutics | volume = 113 | issue = 1 | pages = 1–15 | date = January 2007 | pmid = 16890992 | doi = 10.1016/j.pharmthera.2006.06.008 }}</ref> It has also been suggested that histamine controls the mechanisms by which memories and learning are forgotten.<ref>{{cite journal | vauthors = Alvarez EO | title = The role of histamine on cognition | journal = Behavioural Brain Research | volume = 199 | issue = 2 | pages = 183–9 | date = May 2009 | pmid = 19126417 | doi = 10.1016/j.bbr.2008.12.010 | s2cid = 205879131 | hdl = 11336/80375 | hdl-access = free }}</ref>
			=== Erection and sexual function ===
			{{missing information|section|]|date=October 2023}}
			] and ] can occur during treatment with histamine H<sub>2</sub> receptor antagonists such as ], ], and ].<ref name="White">{{cite journal | vauthors = White JM, Rumbold GR | title = Behavioural effects of histamine and its antagonists: a review | journal = Psychopharmacology | volume = 95 | issue = 1 | pages = 1–14 | year = 1988 | pmid = 3133686 | doi = 10.1007/bf00212757 | s2cid = 23148946 }}</ref> The injection of histamine into the ] in males with psychogenic impotence produces full or partial erections in 74% of them.<ref>{{cite journal | vauthors = Cará AM, Lopes-Martins RA, Antunes E, Nahoum CR, De Nucci G | title = The role of histamine in human penile erection | journal = British Journal of Urology | volume = 75 | issue = 2 | pages = 220–4 | date = February 1995 | pmid = 7850330 | doi = 10.1111/j.1464-410X.1995.tb07315.x }}</ref> It has been suggested that H<sub>2</sub> antagonists may cause sexual dysfunction by reducing the functional binding of testosterone to its androgen receptors.<ref name="White"/>
	=== Schizophrenia ===		=== Schizophrenia ===
			Metabolites of histamine are increased in the cerebrospinal fluid of people with ], while the efficiency of H<sub>1</sub> receptor binding sites is decreased. Many atypical ] medications have the effect of increasing histamine production, because histamine levels seem to be imbalanced in people with that disorder.<ref>{{cite journal | vauthors = Ito C | title = The role of the central histaminergic system on schizophrenia | journal = Drug News & Perspectives | volume = 17 | issue = 6 | pages = 383–7 | year = 2004 | pmid = 15334189 | doi = 10.1358/dnp.2004.17.6.829029 | quote = Many atypical antipsychotics also increased histamine turnovers. }}</ref>
			=== Multiple sclerosis ===
	Metabolites of histamine are increased in the cerebrospinal fluid of people with ], while the efficiency of H(1) receptor binding sites is decreased. Many atypical ] medications have the effect of increasing histamine turnover{{clarify|date=November 2010}}.<ref>{{cite journal | last1 = Ito | first1 = C | title = The role of the central histaminergic system on schizophrenia. | journal = Drug news & perspectives | volume = 17 | issue = 6 | pages = 383–7 | year = 2004 | pmid = 15334189 }}</ref>
			Histamine therapy for treatment of ] is currently being studied. The different H receptors have been known to have different effects on the treatment of this disease. The H<sub>1</sub> and H<sub>4</sub> receptors, in one study, have been shown to be counterproductive in the treatment of MS. The H<sub>1</sub> and H<sub>4</sub> 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 H<sub>2</sub> and H<sub>3</sub> 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.<ref>{{cite journal | vauthors = Jadidi-Niaragh F, Mirshafiey A | title = Histamine and histamine receptors in pathogenesis and treatment of multiple sclerosis | journal = Neuropharmacology | volume = 59 | issue = 3 | pages = 180–9 | date = September 2010 | pmid = 20493888 | doi = 10.1016/j.neuropharm.2010.05.005 | s2cid = 7852375 }}</ref>
	== Disorders ==		== Disorders ==
			As an integral part of the immune system, histamine may be involved in ]s<ref>{{cite journal | vauthors = Zampeli E, Tiligada E | title = The role of histamine H4 receptor in immune and inflammatory disorders | journal = British Journal of Pharmacology | volume = 157 | issue = 1 | pages = 24–33 | date = May 2009 | pmid = 19309354 | pmc = 2697784 | doi = 10.1111/j.1476-5381.2009.00151.x }}</ref> and ]. '']'' is a rare disease in which there is a proliferation of mast cells that produce excess histamine.<ref>{{cite journal | vauthors = Valent P, Horny HP, Escribano L, Longley BJ, Li CY, Schwartz LB, Marone G, Nuñez R, Akin C, Sotlar K, Sperr WR, Wolff K, Brunning RD, Parwaresch RM, Austen KF, Lennert K, Metcalfe DD, Vardiman JW, Bennett JM | display-authors = 6 | title = Diagnostic criteria and classification of mastocytosis: a consensus proposal | journal = Leukemia Research | volume = 25 | issue = 7 | pages = 603–25 | date = July 2001 | pmid = 11377686 | doi = 10.1016/S0145-2126(01)00038-8 }}</ref>
	As an integral part of the immune system, histamine may be involved in ]s and ].
			] 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.<ref name="pmid34651098">{{cite journal |vauthors=Reese I, Ballmer-Weber B, Beyer K, Dölle-Bierke S, Kleine-Tebbe J, Klimek L, Lämmel S, Lepp U, Saloga J, Schäfer C, Szepfalusi Z, Treudler R, Werfel T, Zuberbier T, Worm M |title=Guideline on management of suspected adverse reactions to ingested histamine: Guideline of the German Society for Allergology and Clinical Immunology (DGAKI), the Society for Pediatric Allergology and Environmental Medicine (GPA), the Medical Association of German Allergologists (AeDA) as well as the Swiss Society for Allergology and Immunology (SGAI) and the Austrian Society for Allergology and Immunology (ÖGAI) |journal=Allergol Select |volume=5 |issue= |pages=305–314 |date=2021 |pmid=34651098 |pmc=8511827 |doi=10.5414/ALX02269E}}{{Creative Commons text attribution notice|cc=by4|from this source=yes}}</ref>
			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 ] 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.<ref name="pmid38447930">{{cite journal|pmid=38447930 |date=2024 |title=Is calcitonin gene-related peptide (CGRP) the missing link in food histamine-induced migraine? A review of functional gut-to-trigeminovascular system connections |journal=Drug Discovery Today |volume=29 |issue=4 |doi=10.1016/j.drudis.2024.103941 | vauthors = De Mora F, Messlinger K |doi-access=free }}</ref>
			== Measurement ==
			Histamine, a biogenic amine, involves many physiological functions, including the immune response, gastric acid secretion, and ]. However, its rapid metabolism makes it challenging to measure histamine levels directly in plasma.<ref>{{cite journal | url=https://doi.org/10.1016/j.jpba.2017.06.029 | doi=10.1016/j.jpba.2017.06.029 | title=New approach for the diagnosis of histamine intolerance based on the determination of histamine and methylhistamine in urine | date=2017 | journal=Journal of Pharmaceutical and Biomedical Analysis | volume=145 | pages=379–385 | pmid=28715791 | vauthors=Comas-Basté O, Latorre-Moratalla M, Bernacchia R, Veciana-Nogués M, Vidal-Carou M | access-date=18 August 2024 | archive-date=18 August 2024 | archive-url=https://web.archive.org/web/20240818203311/https://www.sciencedirect.com/unsupported_browser | url-status=live }}</ref>
			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.<ref>{{cite journal | url=https://doi.org/10.1016/S0021-9673(01)98675-3 | doi=10.1016/S0021-9673(01)98675-3 | title=Gas chromatographic analysis of histamine metabolites in urine | date=1966 | journal=Journal of Chromatography A | volume=23 | issue=2 | pages=207–216 | pmid=4165374 | vauthors=Tham R | access-date=18 August 2024 | archive-date=18 August 2024 | archive-url=https://web.archive.org/web/20240818203222/https://www.sciencedirect.com/unsupported_browser | url-status=live }}</ref>
			Commercial laboratories provide a ] 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.<ref>{{cite journal | url=https://doi.org/10.1016/j.talanta.2020.121328 | doi=10.1016/j.talanta.2020.121328 | title=Development of a HILIC-MS/MS method for the quantification of histamine and its main metabolites in human urine samples | date=2020 | journal=Talanta | volume=220 | pmid=32928382 | vauthors = Nelis M, Decraecker L, Boeckxstaens G, Augustijns P, Cabooter D }}</ref><ref>{{Cite web |work = PubChem |title=2-(1-methyl-1H-imidazol-4-yl)acetic acid |url=https://pubchem.ncbi.nlm.nih.gov/compound/2-_1-methyl-1H-imidazol-4-yl_acetic-acid#section=Synonyms |access-date=2024-08-18 |publisher = U.S. National Library of Medicine |language=en |archive-date=18 August 2024 |archive-url=https://web.archive.org/web/20240818204421/https://pubchem.ncbi.nlm.nih.gov/compound/2-_1-methyl-1H-imidazol-4-yl_acetic-acid#section=Synonyms |url-status=live }}</ref><ref name="pmid28321587">{{cite journal|pmid=28321587 |date=2017 |title=Analytical Methods for the Quantification of Histamine and Histamine Metabolites |journal=Handbook of Experimental Pharmacology |volume=241 |pages=3–19 |doi=10.1007/164_2017_22 |isbn=978-3-319-58192-7 | vauthors = Bähre H, Kaever V }}</ref>
			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,<ref>{{cite journal | url=https://doi.org/10.1016/j.jpba.2017.06.029 | doi=10.1016/j.jpba.2017.06.029 | title=New approach for the diagnosis of histamine intolerance based on the determination of histamine and methylhistamine in urine | date=2017 | journal=Journal of Pharmaceutical and Biomedical Analysis | volume=145 | pages=379–385 | pmid=28715791 | vauthors=Comas-Basté O, Latorre-Moratalla M, Bernacchia R, Veciana-Nogués M, Vidal-Carou M | access-date=18 August 2024 | archive-date=18 August 2024 | archive-url=https://web.archive.org/web/20240818203311/https://www.sciencedirect.com/unsupported_browser | url-status=live }}</ref><ref>{{cite journal | url=https://doi.org/10.1016/S0022-5347(17)36844-1 | doi=10.1016/S0022-5347(17)36844-1 | title=Stimulated Release of Urine Histamine in Interstitial Cystitis | date=1992 | journal=Journal of Urology | volume=148 | issue=4 | pages=1145–1148 | pmid=1404625 | vauthors=Yun SK, Laub DJ, Weese DL, Lad PM, Leach GE, Zimmern PE | access-date=18 August 2024 | archive-date=18 August 2024 | archive-url=https://web.archive.org/web/20240818203231/https://www.auajournals.org/doi/10.1016/S0022-5347%2817%2936844-1 | url-status=live }}</ref> such as to diagnose ].<ref>{{cite journal | url=https://doi.org/10.1016/S0022-5347(17)32737-4 | doi=10.1016/S0022-5347(17)32737-4 | title=Increased Urine Histamine and Methylhistamine in Interstitial Cystitis | date=1994 | journal=Journal of Urology | volume=152 | issue=2 Part 1 | pages=350–353 | pmid=8015069 | vauthors = El-Mansoury M, Boucher W, Sant G, Theoharides T | url-access=subscription }}</ref>
			== History ==
			The properties of histamine, then called β-imidazolylethylamine, were first described in 1910 by the British scientists ] and ].<ref>{{cite journal | vauthors = Dale HH, Laidlaw PP | title = The physiological action of beta-iminazolylethylamine | journal = The Journal of Physiology | volume = 41 | issue = 5 | pages = 318–44 | date = December 1910 | pmid = 16993030 | pmc = 1512903 | doi = 10.1113/jphysiol.1910.sp001406 }}{{Dead link|date=January 2020 |bot=InternetArchiveBot |fix-attempted=yes }}</ref> By 1913 the name ''histamine'' was in use, using ] of '']'' + '']'', yielding "tissue amine".
	==Nomenclature==
	"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.		"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.
	== See also ==		== See also ==
			* ]
			* ]
			* ]
			* ]
			* ]
			* ]
	* ]		* ]
	* ]		* ]
	== References ==		== References ==
			{{Reflist|2}}
	<references/>
			== External links ==
			*
			* in the ]
	==External links==
	*{{DrugBank|EXPT01785}}
	*
	{{-}}
	{{Histaminergics}}		{{Histaminergics}}
	{{Neurotransmitters}}		{{Neurotransmitters}}
			{{TAAR ligands}}
			{{Authority control}}
			]
	]		]
	]		]
	]		]
	]		]
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	]		]
	]		]
			]
			]
	]
	]
	]
	]
	]
	]
	]
	]
	]
	]
	]
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	]
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	]
	]
	]
	]
	]
	]
	]