View source for Histamine

{{Refimprove|date=January 2008}}

{{chembox
| verifiedrevid = 309419866
|ImageFile=Histamin - Histamine.svg
|ImageSize=
|ImageFile2=Histamine3d.png
|ImageSize2=200px
|IUPACName=2-(1''H''-imidazol-4-yl)ethanamine
|OtherNames=
|Section1= {{Chembox Identifiers
|  CASNo_Ref = {{cascite}}
| CASNo=51-45-6
|  PubChem=774
| IUPHAR_ligand = 1204
|   ChemSpiderID = 753
|  SMILES=C1=C(NC=N1)CCN
|  MeSHName=Histamine
  }}
|Section2= {{Chembox Properties
| C=5|H=9|N=3
|  MolarMass=111.145
|  Appearance=
|  Density=
|  MeltingPt= 83.5 °C (182.3 °F)
|  BoilingPt= 209.5 °C (409.1 °F)
|  pK<sub>imidazole</sub> 6.04
|  pK<sub>NH2</sub> 9.75
|  Solubility=
  }}
|Section3= {{Chembox Hazards
|  MainHazards=
|  FlashPt=
|  Autoignition=
  }}
}}
'''Histamine''' is an organic nitrogen compound involved in local [[immune system|immune responses]] as well as regulating physiological function in the gut and acting as a [[neurotransmitter]].<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 [[inflammatory response]].  As part of an immune response to foreign [[pathogens]], histamine is produced by [[basophil]]s and by [[mast cell]]s found in nearby connective tissues.  Histamine increases the permeability of the capillaries to white blood cells and other proteins, in order to allow them to engage foreign invaders 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> It is found in virtually all animal body cells.{{Fact|date=November 2007}}

==Properties==

Histamine forms colorless [[hygroscopic]] [[crystal]]s that melt at 84°C, and are easily dissolved in [[water]] or [[ethanol]], but not in [[diethyl ether|ether]]. In [[aqueous solution]] histamine exists in two [[tautomer]]ic forms, ''N<sup>π</sup>-H''-histamine and ''N<sup>τ</sup>-H''-histamine.

{|align="left"
[[Image:Histamine tautomers.svg|thumb|350px|Tautomers of histamine]]
|}
Histamine has two [[base (chemistry)|basic]] centres, namely the [[aliphatic]] [[amino group]] and whichever [[nitrogen]] atom of the [[imidazole]] ring does not already have a [[hydrogen|proton]]. Under physiological conditions, the aliphatic amino group (having a [[dissociation constant|pK]]<sub>a</sub> around 9.4) will be [[protonated]], whereas the second nitrogen of the imidazole ring (pK<sub>a</sub> ≈ 5.8) will not be protonated.<ref name="Paiva 1970">Paiva, T. B., Tominaga, M., & Paiva, A. C. M. (1970). Ionization of histamine, N-acetylhistamine, and their iodinated derivatives. ''Journal of Medicinal Chemistry'', '''13''', 689–692.</ref>
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 [[catalyst|catalyzed]] by the [[enzyme]] [[L-histidine decarboxylase]]. It is a [[hydrophilic]] [[vasoactive]] [[amine]].

[[Image:Histidine decarboxylase.svg|thumb|center|433px|Conversion of [[histidine]] to [[histamine]] by [[histidine decarboxylase]]]]

Once formed, histamine is either stored or rapidly inactivated. Histamine released into the [[synapse]]s is broken down by [[acetaldehyde dehydrogenase]]. <!-- Sentence makes no sense:  the same enzyme used in the processing of alcohol and acetaldehyde gas produced during combustion. --> It is the deficiency of this [[enzyme]] that triggers an allergic reaction as histamines pool in the synapses.  Histamine is broken down by [[histamine-N-methyltransferase]] and [[diamine oxidase]]. Some forms of foodborne disease, so-called "[[food poisoning]]s," are due to conversion of histidine into histamine in spoiled food, such as fish.  Fermented foods and beverages naturally contain histamine due to this same conversion.  Sake contains histamine in the 20-40 mg/L range; wines contain it in the 2-10 mg/L range.  <ref>http://astrobiology.berkeley.edu/PDFs_articles/WineAnalysisAnalChem.pdf</ref>

==Storage and release==
[[Image:SMCpolyhydroxysmall.jpg|thumb|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 cell|enterochromaffin-like (ECL) cell]] of the [[stomach]].

The most important pathophysiologic mechanism of mast cell and basophil histamine release is [[immune system|immunologic]].  These cells, if sensitized by [[IgE]] [[antibody|antibodies]] attached to their [[cell membrane|membranes]], [[degranulation|degranulate]] when exposed to the appropriate [[antigen]].  Certain [[amine]]s and [[alkaloid]]s, including such drugs as [[morphine]], and [[curare alkaloid]]s, can displace histamine in granules and cause its release. [[Antibiotic]]s like [[polymyxin]] are also found to stimulate histamine release.

==Mechanism of action==
Histamine exerts its actions by combining with specific cellular [[histamine receptors]]. The four histamine receptors that have been discovered are designated H1 through H4, and are all [[G protein-coupled receptor]]s.

{| class="wikitable"
| '''Type''' || '''Location''' || '''Function''' 
 |- 
 | [[Histamine H1 receptor|H<sub>1</sub> histamine receptor]]  || Found on [[smooth muscle]], [[endothelium]], and [[central nervous system]] tissue || Causes [[vasodilation]], [[bronchoconstriction]], bronchial [[smooth muscle]] contraction, separation of [[endothelial cells]] (responsible for [[hives]]), and [[pain]] and [[itching]] due to insect stings; the primary receptors involved in [[hay fever|allergic rhinitis]] symptoms and [[motion sickness]]; sleep regulation. 
 |- 
 | [[Histamine H2 receptor|H<sub>2</sub> histamine receptor]]  || Located on [[parietal cells]] || Primarily stimulate [[gastric acid]] secretion
 |- 
 | [[Histamine H3 receptor|H<sub>3</sub> histamine receptor]]  || Found on [[central nervous system]] and to a lesser extent [[peripheral nervous system]] tissue  || Decreased [[neurotransmitter]] release: histamine, [[acetylcholine]], [[norepinephrine]], [[serotonin]]
 |- 
 | [[Histamine H4 receptor|H<sub>4</sub> histamine receptor]]  || Found primarily in the  [[basophil]]s and in the [[bone marrow]]. It is also found on [[thymus]], [[small intestine]], [[spleen]], and [[colon (anatomy)|colon]].  || Plays a role in [[chemotaxis]].
|}

=== Effects on Nasal Mucosa ===

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 mucosa, which leads to three clinical responses: sneezing results from histamine-associated sensory neural stimulation; hypersecretion from glandular tissue occurs; nasal mucosal congestion results due to vascular engorgement associated with vasodilation and increased capillary permeability. <ref> Monroe, E., MD, Daly, A., and Shalhoub, R., MD. 1997. Appraisal of the validity of histmine-induced wheal and flare to predict the clinical efficacy of antihistamines. The Journal of Allergy and Clinical Immunology 99(2): S789-806. </ref>

== Roles in the body ==
=== Sleep regulation ===
Histamine is released as a neurotransmitter. The cell bodies of neurons which release histamine are found in the posterior [[hypothalamus]], in various [[tuberomammillary nucleus|tuberomammillary nuclei]]. From here, these histaminergic neurons project throughout the brain, to the [[brain|cortex]] through the [[medial forebrain bundle]]. Histaminergic action is known to modulate [[sleep]]. Classically, [[Histamine antagonist|antihistamines]] (H1 histamine receptor antagonists) produce sleep. Likewise, destruction of histamine releasing neurons, or inhibition of histamine synthesis leads to an inability to maintain [[Alertness|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 [[Rapid eye movement sleep|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.<ref>Yanai, K., & Tashiro, M. (2007). The physiological and pathophysiological roles of neuronal histamine: an insight from human positron emission tomography studies. ''Pharmacology and Therapeutics'', '''113(1)''':1-15. PMID 16890992 </ref> It has also been suggested that histamine controls the mechanisms by which memories and learning are forgotten.<ref>Alvarez, E. O. (2009). The role of histamine on cognition. ''Behavioral Brain Research'', '''199(2)''':183-9. PMID 19126417</ref>

===Erection and sexual function===

Libido loss and erectile failure can occur following histamine (H2) antagonists such as [[cimetidine]] and [[ranitidine]].<ref name="White">White, J. M., & Rumbold, G. R. (1988). Behavioural effects of histamine and its antagonists: a review. ''Psychopharmacology,'' '''95(1)''':1-14. PMID 3133686</ref> The injection of histamine into the [[corpus cavernosum penis|corpus cavernosum]] in men with psychogenic impotence  produces full or partial erections in 74% of them.<ref>Cará, A. M., Lopes-Martins, R. A., Antunes, E., Nahoum, C. R., & De Nucci, G. (1995). The role of histamine in human penile erection. ''British Journal of Urology'', '''75(2)''':220-4. PMID 7850330 </ref> It has been suggested that H2 antagonists may cause sexual difficulties by reducing the uptake of testosterone.<ref name="White"/>

=== 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.<ref>Ito, C. (2004). The role of the central histaminergic system on schizophrenia. ''Drug News Perspect'', '''17(6)''':383-7. PMID 15334189</ref>

== Disorders ==
As an integral part of the immune system, histamine may be involved in [[immune system disorder]]s and [[allergies]].

==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.

== See also ==
* [[Scombroid food poisoning]]
* [[Histamine antagonist]]

== References ==
<references/>

==External links==
*{{DrugBank|EXPT01785}}
*[http://www.ajcn.org/cgi/content/full/85/5/1185 Histamine and Histamine intolerance]

{{Histaminergics}}
{{Neurotransmitters}}

[[Category:Biogenic amines]]
[[Category:Ethylamines]]
[[Category:Imidazoles]]
[[Category:Immune system]]
[[Category:Vasodilators]]
[[Category:Immunostimulants]]
[[Category:Neurotransmitters]]

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