histamine

ヒスタミン

　 　

WordNet

1. amine formed from histidine that stimulates gastric secretions and dilates blood vessels; released by the human immune system during allergic reactions
2. a medicine used to treat the gastric effects of histamine in cases of peptic ulcers and gastritis and gastroesophageal reflux; works by blocking the effects of histamine on the receptor site known as H2

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1. ヒスタミン(子宮収縮・血圧降下の薬)

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2013/05/02 08:09:35」(JST)

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For the use as an immunostimulant drug, see Histamine dihydrochloride.

Histamine
IUPAC name 2-(1H-imidazol-4-yl)ethanamine
Identifiers
CAS number	51-45-6 Y
PubChem	774
ChemSpider	753 Y
UNII	820484N8I3 Y
KEGG	D08040 Y
MeSH	Histamine
ChEBI	CHEBI:18295 Y
ChEMBL	CHEMBL90 Y
IUPHAR ligand	1204
ATC code	L03AX14,(2HCl) V04CG03 (phosphate)
Jmol-3D images	Image 1
SMILES n1cc(nc1)CCN
InChI InChI=1S/C5H9N3/c6-2-1-5-3-7-4-8-5/h3-4H,1-2,6H2,(H,7,8) Y Key: NTYJJOPFIAHURM-UHFFFAOYSA-N Y InChI=1/C5H9N3/c6-2-1-5-3-7-4-8-5/h3-4H,1-2,6H2,(H,7,8) Key: NTYJJOPFIAHURM-UHFFFAOYAP
Properties
Molecular formula	C5H9N3
Molar mass	111.15 g mol−1
Melting point	83.5 °C (182.3 °F)
Boiling point	209.5 °C (409.1 °F)
Solubility in water	Easily soluble in cold water, hot water
Solubility	Easily soluble in methanol. Very slightly soluble in diethyl ether. Easily soluble in ethanol.
Y (verify) (what is: Y/N?) Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)
Infobox references

Histamine is an organic nitrogen compound involved in local immune responses as well as regulating physiological function in the gut and acting as a neurotransmitter. Histamine triggers the inflammatory response. 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.

Properties

Histamine forms color hygroscopic crystals that melt at 84°C, and are easily dissolved in water or ethanol, but not in ether. In aqueous solution histamine exists in two tautomeric forms, N^π-H-histamine and N^τ-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 pK_a around 9.4) will be protonated, whereas the second nitrogen of the imidazole ring (pK_a ≈ 5.8) will not be protonated. 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.

Storage and release

Mast cells.

Most histamine in the body is generated in granules in mast cells or 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 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

Histamine exerts its actions by combining with specific cellular histamine receptors. The four histamine receptors that have been discovered in humans and animals are designated H1 through H4, and are all G protein-coupled receptors (GPCR).

Histamine biology is a series of weak interactions. In all of the known physiological reactions, the histamine backbone is unchanged.

In the H2 receptor mechanism, histamine is protonated at the end-chain amine group. This amine group interacts with aspartic acid in the transmembrane domains of cells. The other nitrogens in the molecule interact with threonine and aspartic acid in different transmembrane domains. This is a three-pronged interaction. It brings the transmembrane domains close to each other, causing a signal transduction cascade.

Histamine receptors in insects, like Drosophila melanogaster, are histamine-gated chloride channels that function in inhibition of neurons. Histamine-gated chloride channels are implicated in neurotransmission of peripheral sensory information in insects, especially in photoreception/vision. Two receptor subtypes have been identified in Drosophila: HClA and HClB. There are no known GPCRs for histamine in insects.

Type	Location	Function
H1 histamine receptor	Found on smooth muscle, endothelium, and central nervous system tissue	Causes bronchoconstriction, bronchial smooth muscle contraction, vasodilation, separation of endothelial cells (responsible for hives), and pain and itching due to insect stings; the primary receptors involved in allergic rhinitis symptoms and motion sickness; sleep and appetite suppression.
H2 histamine receptor	Located on parietal cells and vascular smooth muscle cells	Primarily involved in vasodilation. Also stimulate gastric acid secretion
H3 histamine receptor	Found on central nervous system and to a lesser extent peripheral nervous system tissue	Decreased neurotransmitter release: histamine, acetylcholine, norepinephrine, serotonin
H4 histamine 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 chemotaxis.

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:

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

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 so many physiological functions because of its chemical properties that allow it to be so versatile in binding. It is Coulombic (able to carry a charge), conformational, and flexible. This allows it to interact and bind more easily.

Sleep regulation

Histamine is released as a neurotransmitter. The cell bodies of histaminergics, the neurons which release histamine, are found in the posterior hypothalamus, in various tuberomammillary nuclei. From here, these neurons project throughout the brain, to the cortex through the medial forebrain bundle. Histaminergic action is known to modulate sleep. Classically, antihistamines (H1 histamine receptor antagonists) produce sleep. Likewise, destruction of histamine releasing neurons, or inhibition of histamine synthesis leads to an inability to maintain vigilance. Finally, H3 receptor antagonists increase wakefulness.

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 REM and NREM (non-REM) sleep. Histaminergic cells can be recorded firing just before an animal shows signs of waking.

Suppressive effects

While histamine has stimulatory effects upon neurons, it also has suppressive ones that protect against the susceptibility to convulsion, drug sensitization, denervation supersensitivity, ischemic lesions and stress. It has also been suggested that histamine controls the mechanisms by which memories and learning are forgotten.

Erection and sexual function

Libido loss and erectile failure can occur following histamine (H2) antagonists such as cimetidine and ranitidine. The injection of histamine into the corpus cavernosum in men with psychogenic impotence produces full or partial erections in 74% of them. It has been suggested that H2 antagonists may cause sexual difficulties by reducing the uptake of testosterone.

Schizophrenia

Metabolites of histamine are increased in the cerebrospinal fluid of people with schizophrenia, while the efficiency of H(1) receptor binding sites is decreased. Many atypical antipsychotic medications have the effect of increasing histamine turnover.

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 decrease 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 immune system attacks its own myelin sheaths on nerve cells (which causes loss of signaling function and eventual nerve degeneration). By helping T cells to differentiate, the T cells will be less likely to attack the body's own cells, and instead attack invaders.

Disorders

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

History

The properties of histamine, then called β-iminazolylethylamine, were first described in 1910 by the British scientists Henry H. Dale and P.P. Laidlaw.

"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

• Scombroid food poisoning
• Histamine antagonist
• Hay fever (allergic rhinitis)

References

External links

• DrugBank EXPT01785
• Histamine bound to proteins in the PDB

UpToDate Contents

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• 1. アナフィラキシーの臨床診断を裏付ける臨床検査 laboratory tests to support the clinical diagnosis of anaphylaxis
• 2. Mastocytosis (cutaneous and systemic): Evaluation and diagnosis in adults
• 3. スコンブロイド（ヒスタミン）中毒 scombroid histamine poisoning
• 4. アレルギーのin vitro検査の概要 overview of in vitro allergy tests
• 5. 肥満細胞活性化障害 mast cell activation disorders

English Journal

• Bioactive amines in Mozzarella cheese from milk with varying somatic cell counts.

• Ubaldo JC1, Carvalho AF2, Fonseca LM3, Glória MB4.
• Food chemistry.Food Chem.2015 Jul 1;178:229-35. doi: 10.1016/j.foodchem.2015.01.084. Epub 2015 Jan 24.
• The influence of somatic cells counts (SCC) in milk on bioactive amines in Mozzarella cheese was investigated. High SCC milk had lower lactose and higher pH compared to low and medium SCC. Low spermine levels were found in milk irrespective of SCC. The cheeses had similar characteristics, but the ex
• PMID 25704706

• Reduction of biogenic amines production by eliminating the PEP4 gene in Saccharomyces cerevisiae during fermentation of Chinese rice wine.

• Guo X1, Guan X1, Wang Y1, Li L1, Wu D1, Chen Y1, Pei H1, Xiao D2.
• Food chemistry.Food Chem.2015 Jul 1;178:208-11. doi: 10.1016/j.foodchem.2015.01.089. Epub 2015 Jan 24.
• Biogenic amines in Chinese rice wine have a potential threat of toxicity to human health. In this study, PEP4 gene in Saccharomyces cerevisiae was knocked out in order to evaluate its effect on biogenic amines production; the enzyme encodes proteinase A (PrA), an enzyme that is responsible for the p
• PMID 25704703

• Optimization of Maillard reaction with ribose for enhancing anti-allergy effect of fish protein hydrolysates using response surface methodology.

• Yang SY1, Kim SW1, Kim Y2, Lee SH3, Jeon H2, Lee KW4.
• Food chemistry.Food Chem.2015 Jun 1;176:420-5. doi: 10.1016/j.foodchem.2014.12.090. Epub 2014 Dec 30.
• Halibut is served on sushi and as sliced raw fish fillets. We investigated the optimal conditions of the Maillard reaction (MR) with ribose using response surface methodology to reduce the allergenicity of its protein. A 3-factored and 5-leveled central composite design was used, where the independe
• PMID 25624251

• Brewing effect on levels of biogenic amines in different coffee samples as determined by LC-UV.

• Restuccia D1, Spizzirri UG2, Parisi OI2, Cirillo G2, Picci N2.
• Food chemistry.Food Chem.2015 May 15;175:143-50. doi: 10.1016/j.foodchem.2014.11.134. Epub 2014 Nov 29.
• Eight biogenic amines (spermine, spermidine, putrescine, histamine, tyramine, phenylethylamine, cadaverine and serotonin) were determined by LC-UV after derivatization with dansyl-chloride in both ground coffee and coffee beverages obtained by different methods. In ground coffee, the most relevant a
• PMID 25577063

Japanese Journal

• 創薬ターゲット膜蛋白質の立体構造解析 : アデノシンA2a受容体とヒスタミンH1受容体

• 島村 達郎,小笠原 諭,岩田 想
• 内分泌・糖尿病・代謝内科 35(6), 557-564, 2012-12
• NAID 40019554347

• 花粉性結膜炎の診断と治療 (特集 花粉症治療のupdate)

• 海老原 伸行
• 臨床免疫・アレルギー科 58(6), 697-701, 2012-12
• NAID 40019542127

• コリン性蕁麻疹 (特集 特異なアレルギーの発症機序 : 最近の知見)

• 松井 佐起,室田 浩之,片山 一朗
• 臨床免疫・アレルギー科 58(6), 671-675, 2012-12
• NAID 40019542066

• 魚醤油のヒスタミン蓄積機構と除去法について

• 里見 正隆
• 日本醸造協会誌 107(11), 842-852, 2012-11
• NAID 40019490974

Related Links

• Histamine - Wikipedia, the free encyclopedia

Histamine is an organic nitrogen compound involved in local immune responses as well as regulating physiological function in the gut and acting as a neurotransmitter. Histamine triggers the inflammatory response. As part of an immune ...

• ヒスタミン - Wikipedia

ヒスタミンを産生する菌は、ヒスチジン脱炭酸酵素を有するもので、Morganella morganii（モルガン菌）、Klebsiella oxytoca及び好塩性菌のPhotobacterium phosphoreum、Photobacterium damsela等が知られている。なお、Photobacterium 属菌の中に ...

Related Pictures

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★リンクテーブル★

リンク元	「ヒスタミン」
拡張検索	「histamine N-methyltransferase」「histamine H1 receptor antagonist」「histamine receptor」「antihistamine poisoning」

「ヒスタミン」

　　[★]

英

histamine

関

抗ヒスタミン薬、H2受容体拮抗薬

概念

• ヒスチジンから生合成される。
• ヒスチジンを脱炭酸する酵素は、ヒスチジンデカルボキシラーゼ(補酵素はピリドキサル5'-リン酸(PLP))
• この反応は肥満細胞で起こる。

作用、受容体

一般的作動薬	受容体	G protein subunit	作用
ヒスタミン	H1	Gq	鼻、器官粘膜分泌、細気管支収縮、かゆみ、痛み
	H2	Gs	胃酸分泌

ヒスタミンの主要な生理的効果

PPC.770

組織	効果	臨床効果	サブタイプ
肺	気管支収縮	喘息様症状	H1
血管平滑筋	後毛細血管細静脈の拡張	紅斑	H1
	終末細動脈の拡張
	静脈収縮
血管内皮	内皮細胞の収縮と分離	浮腫、蕁麻疹反応	H1
末梢神経	求心性神経終末の感作	掻痒、疼痛	H1
心臓	心拍数と心収縮力のわずかな増加	小さい	H2
胃	胃酸分泌増加	消化性潰瘍、胸焼け	H2
中枢神経	神経伝達	概日時計、覚醒	H3

構造式

 　N－C                            N－C
　||　　＼                            ||　　＼
　||      C-CH2-CH(NH3+)-COO-　→ ||      C-CH2-CH-NH3+
　||    ／                           ||    ／
   C－N　　                         　 C－N
     H                              H

「histamine N-methyltransferase」

　　[★]

ヒスタミン-N-メチル基転移酵素、ヒスタミン-N-メチルトランスフェラーゼ、ヒスタミンN-メチルトランスフェラーゼ

同

HNMT

「histamine H1 receptor antagonist」

　　[★]

• ヒスタミンH1受容体遮断薬、ヒスタミンH1受容体拮抗薬

関

antihistamine、H1 blocker、histamine H1 antagonist

「histamine receptor」

　　[★]

• ヒスタミン受容体、ヒスタミンレセプター

「antihistamine poisoning」

　　[★] 抗ヒスタミン薬中毒