ヒスタミン

外観

白色～黄褐色, 結晶～粉末又は塊又は顆粒

性質

ヒスタミンの融点は83〜84°C、沸点は380.29°Cです。ヒスタミンの塩酸塩やリン酸塩は吸湿性の白色結晶です。水やエタノールには容易に溶けますが、エーテルには溶解しません。

イミダゾール環の窒素原子のpK_aは6.04、脂肪族アミノ基のpK_aは9.75です。生理学的条件下で、脂肪族アミノ基はプロトン化されますが、イミダゾール環の窒素原子はプロトン化されません。したがって、通常ヒスタミンは、一価の陽イオンになります。

ヒトの血液のpHは7.35〜7.45で、わずかに塩基性であり、ヒトの血液中に存在するヒスタミンは主に脂肪族窒素だけプロトン化しています。

溶解性

水、エタノール及びアセトンに溶ける。

解説

ヒスタミン，針状結晶．融点83～84 ℃，沸点209～210 ℃．水，エタノールに可溶，エーテルに難溶．中枢神経にも局在し，神経伝達に関与している．毛細血管を拡張する．組織内で多量に生成するとアレルギーやアナフィラキシー症状を起こす．胃液分泌促進剤．

森北出版「化学辞典（第2版）

用途

血圧降下、血管透過性亢進、平滑筋収縮、血管拡張、腺分泌促進などの薬理作用があり、アレルギー反応や炎症の発現に介在物質として働く。ヒスタミンが過剰に分泌されると、ヒスタミン1型受容体(H1受容体)というタンパク質と結合して、アレルギー疾患の原因となる。
神経組織では神経伝達物質として働き、音や光などの外部刺激および情動、空腹、体温上昇といった内部刺激などによっても放出が促進され、オキシトシン分泌や覚醒状態の維持、食行動の抑制、記憶学習能の修飾などの生理機能を促進することで知られている。

構造

図1. ヒスタミンの構造

水溶液中でヒスタミンのイミダゾール環は、2種類の互変異性型として存在しています。窒素原子のいずれかがプロトン化されています。側鎖から遠い窒素原子はτ、側鎖に近い窒素原子はπと表され、N^π-H-ヒスタミンよりもN^τ-H-ヒスタミンの方が溶液中で安定です。

ヒスタミンはβ‐イミダゾールエチルアミンとも呼ばれ、モノアミン神経伝達物質 (英: monoamine neurotransmitter) です。モノアミン神経伝達物質とは、アミノ基を1つ有する神経伝達物質や神経修飾物質の総称で、アドレナリン、ノルアドレナリン、ドーパミン、ヒスタミン、セロトニンなども含まれます。

合成

図2. ヒスタミンの合成

チオシアン化カリウムを用いて、1,4-ジアミノ-2-ブタノンを環化させ、塩化鉄 (III) で処理すると、ヒスタミンを生成可能です。体内では、食品中に含まれるアミノ酸の1種であるヒスチジンに、ヒスタミン産生菌の酵素が作用して、ヒスタミンは合成されます。

ヒスタミンは主に肥満細胞に貯蔵され、刺激に応じて放出されてアレルギー反応を生じます。中枢では視床下部乳頭体にヒスタミンニューロンが集まっていて、脳内各部位に神経伝達物質として作用可能です。睡眠、覚醒、摂食調節などに関与しています。

毒性

ヒスタミンが細菌によって合成された食品が原因で、食中毒が起きます。血小板輸血後には、敗血性ショック症状も知られています。熟成チーズ、シイタケ、発酵食品、魚醤、ワイン、魚などの食品中に蓄積され、赤身魚や青身魚などはとくに食中毒の原因になりやすいです。

高濃度のヒスタミンを含む食品を食べた場合には、アレルギー様症状を呈すこともあり、口のまわりや耳たぶの紅潮のほか、頭痛やじんましんなどの症状が出ます。ただし通常、症状は1日以内に回復します。

ヒスタミンは調理による加熱では分解しません。蓄積によって味や臭いが変わらないため、汚染の有無の判断は困難です。予防策として、保存時に温度の管理や鮮度の確認などが重要です。

製法

ヒスタミン，肉などの腐敗に際し，ヒスチジンの脱炭酸によって生成するが，種々の動物，植物組織に広く分布している．1,4-ジアミノ-2-ブタノンをチオシアン化カリウムで環化したのち，塩化鉄(Ⅲ)で処理して合成する．

効能

診断薬 (胃機能)

化学的特性

White to slightly yellow powder

来歴

Histamine is an important protein involved in many allergic reactions. Allergies are caused by an immune response to a normally innocuous substance (i.e. pollen, dust) that comes in contact with lymphocytes specific for that substance, or antigen. The history of histamine and the development of antihistamines have been reviewed in [Drugs of Today (1986) and the Journal of Allergy & Clinical Immunology]. Histamine was the first to be characterized of a series of biogenic amines that are released in the inflammatory process. As early as 1910, it was shown that histamine caused constriction of isolated guinea pig ileum and, subsequently, it was found that histamine induced a shock-like syndrome. In 1927 the presence of histamine in normal tissues was demonstrated. Attempts to reduce histamine manifestations led to the report, in 1933, that certain phenolic ethers inhibited histamine action. Toxicity precluded clinical use. In 1942 phenbenzamine (Antergan), C17H22N2, was the first antihistamine to be successfully used in humans.
In 1966, the name H1 was proposed for receptors blocked by the at that time known antihistamines. It was also speculated that the other actions of histamine were likely to be mediated by other histamine receptors. The existence of the H2 receptor was accepted in 1972 and the H3 receptor was recognized in rat brain in 1983. H3 receptors in the brain appear to be involved in the feedback control of both histamine synthesis and release, whereas release of various other neurotransmitters, eg, serotinin (5-HT), dopamine, noradrenaline, and acetylcholine, is also modulated. H3 receptor effects have also been demonstrated in various peripheral tissues and H3 agonists and antagonists are undergoing intensive study for therapeutic applications.

使用

Histamine inhibits the synthesis of IL-2 and γ-IFN in peripheral blood mononuclear cells and lipopolysaccharide-induced synthesis of TNF-α in monocytes via H2?receptor activation. It is a powerful stimulant of gastric secretion, a constrictor of bronchial smooth muscle, a vasodilator, and also a centrally acting neurotransmitter.

適応症

Sinus problems, hay fever, bronchial asthma, hives, eczema, contact dermatitis, food allergies, and reactions to drugs are all allergic reactions associated with the release of histamine and other autocoids, such as serotonin, leukotrienes, and prostaglandins. Histamine release is frequently associated with various inflammatory states and may be increased in urticarial reactions, mastocytosis, and basophilia. Histamine also acts as a neurotransmitter in the central nervous system (CNS). Upon release from its storage sites, histamine exerts effects ranging from mild irritation and itching to anaphylactic shock and eventual death.

定義

ChEBI: A member of the class of imidazoles that is 1H-imidazole substituted at position C-4 by a 2-aminoethyl group.

生合成

Virtually all of the histamine found in individual organs and tissues is synthesized locally and stored in subcellular secretory granules. Within the tissues, the mast cells are the principal sites of storage; in the blood, the basophils serve this function. Histamine is also present in neurons of the CNS, where it acts as a neurotransmitter.
Histamine is synthesized from the amino acid histidine by an action of the enzyme histidine decarboxylase. Following synthesis, histamine is either rapidly inactivated or stored in the secretory granules of mast cells and basophils as an inactive complex with proteases and heparin sulfate or chondroitin sulfate.

生物学の機能

Histamine occurs in the brain, particularly in certain hypothalamic neurons, and evidence is strong that histamine is a neurotransmitter. Distribution of histamine, its synthetic enzyme (histidine decarboxylase), and methyl histamine (the major brain metabolite) is not uniform. Possible roles for histamine in the regulation of food and water intake, thermoregulation, hormone release, and sleep have been suggested.

一般的な説明

Histamine is a neurotransmitter produced by neurons of the posterior hypothalamus. In the brain, histamine is predominantly present in the gray matter.

使用用途

ヒスタミンは、胃液分泌機能の検査やクロム親和細胞腫の検査に利用可能です。ただし、薬理作用としてヒスタミンは、平滑筋の収縮、細動脈の拡張による急激な血圧降下、炎症時の発赤、毛細血管透過性亢進による浮腫の発生、分泌腺の機能亢進などを生じる場合があります。

作用機序

Non–Antigen-Mediated Release of Histamine Histamine may be released from mast cells by mechanisms that do not require prior sensitization of the immune system. Drugs, high-molecular-weight proteins, venoms, and other substances that damage or disrupt cell membranes can induce the release of histamine. Any thermal or mechanical stress of sufficient intensity also will result in histamine release. Cytotoxic compounds, may release histamine as the result of disruption of cell membranes.

薬理学

Histamine is found in animal tissues and venoms and in many bacteria and plants.Within the human body, the largest histamine concentrations are in the skin, lungs, and gastrointestinal mucosa, while concentrations are smaller in almost all other organs and tissues.Histamine is present in human plasma at relatively low concentrations (usually less than 0.5 ng/mL); in contrast, wholeblood levels can be as high as 30-fold greater. Substantial quantities of histamine are present in urine, with excretion rates varying from 10 to 40μg per 24 hours.

臨床応用

Histamine has only minor uses in clinical medicine. In the past it was used to diagnose pernicious anemia, in which histamine fails to evoke the usual secretion of gastric acid. Histamine has been used to assess bronchial hyperreactivity, although this test may be quite hazardous for asthmatics. Today the main clinical use of histamine is as a positive control injection for allergy skin testing.

副作用

Sedation is the most frequent adverse reaction to the first-generation antihistamines. An additive effect on alertness and motor skills will result if alcohol or another depressant is taken with these drugs. Antimuscarinic effects caused by these drugs include dry mouth and respiratory passages, urinary retention, and dysuria. Nausea, vomiting, constipation or diarrhea, dizziness, insomnia, nervousness, and fatigue also have been reported. Drug allergy, especially after topical application, is fairly common.Tolerance to certain antihistamines may develop after prolonged administration. Teratogenic effects of the piperazine antihistamines have been shown in animal studies. Epidemiological studies have not shown such an association in humans. The effects of toxic doses of first-generation antihistamines, similar to those seen following atropine administration, include excitement, hallucinations, dry mouth, dilated pupils, flushing, convulsions, urinary retention, sinus tachycardia, coma, and death.
The second-generation H1-antagonists are often referred to as nonsedating antihistamines; however, doses above the usual therapeutic level can cause sleepiness in certain individuals.A more serious adverse effect of some earlier second-generation antihistamines is cardiotoxicity.

純化方法

It crystallises from *benzene or chloroform. [Beilstein 25 I 628, 25 II 302, 25 III/IV 2049.]