histamine

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Structural formula
Structure of histamine
General
Surname histamine
other names

2- (1 H -imidazol-4-yl) -ethanamine ( IUPAC )

Molecular formula C 5 H 9 N 3
Brief description

white solid

External identifiers / databases
CAS number 51-45-6
EC number 200-100-6
ECHA InfoCard 100,000,092
PubChem 774
ChemSpider 753
DrugBank DB05381
Wikidata Q61233
Drug information
ATC code
properties
Molar mass 111.15 g mol −1
Physical state

firmly

Melting point

83-84 ° C

boiling point

167 ° C (1.1 h Pa )

solubility

Easily soluble in water and ethanol , insoluble in diethyl ether

safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS labeling of hazardous substances
06 - Toxic or very toxic 08 - Dangerous to health

danger

H and P phrases H: 301-315-317-319-334-335
P: 261-280-301 + 310-305 + 351 + 338-342 + 311
Toxicological data
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Histamine ( give a wiki. Ἱστός histos , tissue ') - in the nomenclature : 2- (4-imidazolyl) ethylamine - is a natural substance that in the human or animal organism as a tissue hormone and neurotransmitter acts and also in the plant kingdom and in bacteria is widespread . In humans and other mammals, histamine plays a central role in allergic reactions and is involved in the immune system , i. H. involved in the defense against foreign substances. It serves as one of the messenger substances in the inflammatory reaction to cause the tissue to swell. Histamine also acts as an important regulator in the gastrointestinal tract , in the regulation of gastric acid production and motility, as well as in the central nervous system in the control of the sleep-wake rhythm and appetite control . Biochemically , like tyramine , serotonin , dopamine , adrenaline , noradrenaline or octopamine , it is a biogenic amine . It is formed by splitting off carbon dioxide from the amino acid histidine and is stored in mast cells , basophilic granulocytes and nerve cells in particular .

history

The history of research into histamine began in 1907 with its synthesis as a chemical curiosity by the German chemists Adolf Windaus and W. Vogt. Just three years later, Henry H. Dale and George Barger succeeded in detecting histamine in ergot and thus discovering histamine as a natural substance. In the same year, Henry H. Dale and PP Laidlaw demonstrated that histamine was an endogenous substance. At the same time, Dale and Laidlaw clarified some of the basic functions of histamine. The biosynthesis of histamine from the amino acid histidine was also clarified by Dankwart Ackermann in 1910.

Daniel Bovet and Anne-Marie Staub discovered the first substances that inhibit the effects of histamine ( antihistamines ) in 1937 . Five years later, phenbenzamine and mepyramine were the first antihistamines to be used in therapy. In the early 1950s, the French pharmaceutical company Rhône-Poulenc developed the first neuroleptics as part of anti-histamine research. In 1972, James W. Black and co-workers succeeded in differentiating between H 1 and H 2 receptors. As further subtypes of the histamine receptor, the H 3 receptor was discovered in 1983 by Jean-Michel Arrang with the help of pharmacological methods and in 2000 the H 4 receptor by deciphering the human genome .

Chemical properties

Tautomers of histamine

Histamine forms colorless, hygroscopic crystals that melt at 84 ° C and that easily dissolve in water and ethanol, but not in diethyl ether . The compound is in an aqueous solution as a mixture of two tautomers , N π -H -histamine and N τ -H -histamine.

Histamine has two basic centers, i.e. H. two groups of atoms with nitrogen atoms to which protons can be attached. Under physiological conditions, the aliphatic N α - amino group with its pK a value of 9.4 is preferably protonated , while the imidazole ring (pK a  = 5.8) only takes up a proton in a more acidic environment.

biosynthesis

Biosynthesis of histamine from histidine

Histamine is synthesized in mast cells, cells of the epidermis and gastric mucosa and in nerve cells and stored in vesicles . In these cells, histamine is formed from the amino acid histidine by a pyridoxal phosphate- dependent decarboxylation using the enzyme histidine decarboxylase in a one-step reaction. The unspecific aromatic L-amino acid decarboxylase can also be involved in the biosynthesis of histamine to a lesser extent .

Dismantling

Degradation of histamine to N τ -methylimidazolylacetic acid and ribosylimidazolylacetic acid

Histamine is broken down in the body in two different ways. In particular in the central nervous system, the enzyme histamine- N -methyltransferase is inactivated to N τ -methylhistamine . N τ -methylhistamine is oxidatively below about monoamine oxidases , diamine oxidases and aldehyde oxidases for N τ degraded -Methylimidazolylessigsäure. In the periphery, however, histamine methylation plays a subordinate role. Here the degradation takes place mainly via diamine oxidases and aldehyde oxidases to form imidazolylacetic acid . This is excreted through the kidneys after ribosylation .

Storage and release

Cultivated mast cells in the light microscope ( toluidine blue )

Histamine occurs in increased concentrations in the mast cells , the basophilic granulocytes and in the histamine-storing cells of the mucous membranes , the bronchi and the gastrointestinal tract . In these cells, histamine is stored in vesicles bound to heparin . Histamine is released from these vesicles in IgE- mediated allergic reactions of the "immediate type" (Type I) or by complement factors (e.g. in the event of an endotoxin- induced shock ). In addition to tissue hormones , drugs such as opiates , muscle relaxants as well as plasma expanders and X-ray contrast media can also cause the release of histamine. Another important storage location for histamine are the ECL cells of the gastric mucosa, which make up histamine through hormones and tissue hormones, such as B. gastrin , acetylcholine and PACAP ( pituitary adenylate cyclase activating polypeptide ) can be released.

Elevated histamine concentrations can also be detected in parts of the central nervous system and the cerebrospinal fluid ( liquor cerebrospinalis ). The highest histamine concentration can be found in the hypothalamus . Within the central nervous system, histamine also functions as a neurotransmitter in histaminergic neurons . A release of histamine into the synaptic cleft is inhibited by acetylcholine, noradrenaline and histamine itself via presynaptic receptors .

function

In the human organism, histamine has a variety of functions, with particular emphasis on its involvement in defense reactions. At the molecular level, histamine mediates its functions by activating the histamine receptors H 1 , H 2 , H 3 and H 4 , which belong to the family of G-protein-coupled receptors .

Defense reactions

Important contributions of histamine are its function in the defense against exogenous substances and its pathological involvement in the symptoms of allergies and asthma . Histamine is also one of the mediator substances in inflammation and burns . Here, histamine leads to itching, pain and contraction of the smooth muscles (for example in the bronchi). It causes an increased permeability of the vessel walls of small blood vessels and thus leads to hives . A histamine-induced activation of the transcription factor NF-κB and an associated increased release of further inflammatory mediators are also involved in this process. Histamine also causes adrenaline to be released from the adrenal glands . These effects are mediated in particular by activating H 1 receptors.

Histamine has a chemotactic effect on various cells involved in the defense against foreign substances, for example eosinophilic granulocytes and T cells . Activation of H 4 receptors is primarily held responsible for these effects .

In contrast to humans, histamine plays only a minor role in the development of itching in dogs and cats.

Gastrointestinal tract

In the gastrointestinal tract, histamine is involved in the regulation of gastric acid production and (via its stimulating effect on the smooth muscles) of motility. The increase in gastric acid production mediated by histamine via activation of H 2 receptors can be interpreted as a component of a histamine-mediated defense reaction.

Cardiovascular system

The effect of histamine on the blood vessels can also be interpreted as part of a defense reaction. It contracts the H 1 -receptor-mediates the large blood vessels (diameter of more than 80 µm) and leads to an expansion of smaller blood vessels combined with reddening of the skin. In the heart , histamine has a positive inotropic effect (increasing the stroke force) and positive chronotropic effect (increasing the stroke frequency) by activating H 2 receptors.

Central nervous system

In the central nervous system , histamine is involved in triggering vomiting and regulating the sleep-wake cycle by activating H 1 receptors . Based on animal experiments, an antidepressant , anticonvulsant and appetite suppressant effect of histamine is discussed. It also seems to be involved in the regulation of body temperature, central control of blood pressure and pain perception. Via presynaptic receptors (especially H 3 receptors), histamine has a regulatory influence on noradrenergic , serotoninergic , cholinergic , dopaminergic and glutaminergic neurons by inhibiting neurotransmitter release in the central nervous system and in the peripheral nervous system . Histamine thus indirectly influences the effect of these neurotransmitters.

Studies are currently underway in Europe with histamine as a drug with a stimulating (vigilance-increasing) effect. The drug could be used in some time, for. B. come with pathological sleep-wake regulation disorders.

toxicology

The tolerance limit for histamine in adult primates is approximately 10 mg. Larger amounts of histamine lead to poisoning, which is characterized by acute symptoms such as shortness of breath, drop in blood pressure, reddening of the skin, hives, nausea, vomiting, headache and diarrhea; 100 mg of histamine already lead to significant symptoms of intoxication. The tolerance limit could be significantly reduced in patients with histamine intolerance . Consuming large amounts of foods containing histamine, e.g. B. in a certain form of fish poisoning can lead to symptoms of poisoning, as can the simultaneous intake of MAO inhibitors and tyramine - or histamine-containing foods such as fish, meat, cheese, vegetables and wine.

In animal experiments, histamine showed negative effects on the lungs and the entire respiratory system in various animal species (dog, mouse, guinea pig, rat, rabbit). In dogs, intravenous doses of 7 mg / kg led to cardiac dysfunction, subcutaneous doses of 28.5 mg / kg or more led to diarrhea and coma.

use

Histamine is used for medical diagnostics , v. a. of atopy and allergies , as well as in the inhalative provocation test and for positive control in the intracutaneous test . In addition, drugs that block the release of histamine from mast cells ( mast cell stabilizers ) or the effect of histamine on histamine receptors ( antihistamines ) are also used in therapy. Allergic symptoms are treated symptomatically with mast cell stabilizers ( e.g. cromoglicic acid (DNCG), nedocromil or lodoxamide ) and with H 1 antihistamines (e.g. diphenhydramine , loratadine or cetirizine ). In addition, sleep disorders , anxiety disorders , nausea and vomiting are treated with H 1 antihistamines. H 2 antihistamines (such as cimetidine , ranitidine or famotidine ) are important antacids as inhibitors of gastric acid production .

An analogue of histamine is the vasodilatory betahistine , which is used as an antiemetic and antivertiginous ( i.e. against dizziness) v. a. used for Menière's disease and hydrops cochleae .

Use as a medicine

Under the trade name Ceplene, histamine is used in cancer immunotherapy as an injection solution in combination with interleukin-2 as a drug for the treatment of acute myeloid leukemia (AML), a rare cancer that affects the white blood cells . Because few patients suffer from this form of cancer, was Ceplene than 2,005 orphan medicinal reported ( "orphan drug"). The drug approval followed in 2008.

Clinical information

Application areas (indications)

Histamine is approved for the treatment of acute myeloid leukemia in combination with interleukin-2 in cancer patients in first remission . Approval is limited to adult patients, although efficacy has not been fully demonstrated in patients over 60 years of age.

Contraindications (contraindications)

As an absolute contraindication for the use of histamine in cancer immunotherapy hypersensitivity reactions apply, moderate and severe congestive heart failure (NYHA III and IV) as well as the concurrent systemic administration of steroids, the antihypertensive drug clonidine or magensäuresekretionshemmender drugs from the group of H 2 antihistamines . Cancer immunotherapy with histamine and interleukin-2 is also contraindicated in patients with an allogeneic stem cell transplant . As indications of harmful effects on the offspring were found in preclinical studies on rodents after the use of histamine, its use in pregnant and breastfeeding women is contraindicated.

Histamine as a defense substance

The irritant of the nettle hairs of the nettle ( Urtica dioica L.) contains not only histamine but also acetylcholine .

Histamine is also produced and stored as a defense substance in some plants and animals. For example, the stinging nettle stores histamine in its stinging hair, along with other substances, which is released when touched. The grasshopper Poekilocerus bufonius ( Pyrgomorphidae ) releases a secretion that contains about 1% histamine in addition to cardenolides . Histamine is also contained in the skin gland secretion of the southern frogs . In addition, animal and plant defense substances, such as the mast cell degranulating peptide (MCD peptide) of bee venom , can release histamine from the mast cells of higher animals and thus trigger an inflammatory reaction.

literature

  • SJ Hill, CR Ganellin, H. Timmerman, JC Schwartz, NP Shankley, JM Young, W. Schunack, R. Levi, HL Haas: International Union of Pharmacology. XIII. Classification of histamine receptors. In: Pharmacol Rev . 49, 1997, pp. 253-278.
  • NJ Brown, LJ Roberts: Histamine, bradykinin, and their antagonists. In: JG Hardman, LE Limbird: Goodman & Gilman's - The pharmacological basis of therapeutics. McGraw-Hill, New York 2001, ISBN 0-07-135469-7 , pp. 645-667.
  • S1 guideline procedure for suspected intolerance to orally ingested histamine of the German Society for Allergology and Clinical Immunology e. V. (DGAKI). In: AWMF online (as of 2012)
  • Thilo Schleip: Histamine intolerance . Thrias Ehrenwirth, 2004, ISBN 3-8304-3204-6 .
  • Peter Dilg: Histamine. In: Werner E. Gerabek , Bernhard D. Haage, Gundolf Keil , Wolfgang Wegner (eds.): Enzyklopädie Medizingeschichte. De Gruyter, Berlin / New York 2005, ISBN 3-11-015714-4 , p. 604 f.

Web links

Wiktionary: Histamine  - explanations of meanings, word origins, synonyms, translations

Individual evidence

  1. ↑ a b Data sheet Histamine, Free Base (PDF) from Calbiochem, accessed on December 8, 2015.
  2. ↑ a b c Histamine data sheet from Sigma-Aldrich , accessed on April 4, 2011 ( PDF ).
  3. ↑ Entry on histamine. In: Römpp Online . Georg Thieme Verlag, accessed on June 12, 2014.
  4. ↑ a b c d D. Bovet, F. Bovet-Nitti: Structure et Activite Pharmacodyanmique des Medicaments du Systeme Nerveux Vegetatif. S. Karger, New York 1948, p. 718.
  5. ↑ a b Japanese Journal of Toxicology. Vol. 4, 1991, p. 105.
  6. ↑ A. Windaus, W. Vogt: Synthesis of Imidazoläthylamins. In: Chemical Reports. Volume 40, 1907, p. 3691.
  7. ^ G. Barger, HH Dale: Journal of the Chemical Society . Volume 97, pp. 466-473.
  8. ↑ HH Dale, PP Laidlaw: The physiological action of β-imidazolethylamine. In: The Journal of Physiology . Volume 41, 1910, pp. 318-344.
  9. ↑ D. Ackermann: Journal for Physiol. Chem. Vol. 60, 1910, pp. 482-501.
  10. ↑ D. Bovet, A. Staub: Action protectrice des éthers phenoliques au cours l'intoxication histaminique. In: Comptes Rendus des Séances et Mémoires de la Société de Biologie. Volume 124, 1937, pp. 547-549.
  11. ↑ Hans Bangen: History of the drug therapy of schizophrenia. Berlin 1992, ISBN 3-927408-82-4 , pp. 74-77.
  12. ↑ JW Black, WAM Duncan, CJ Durant, CR Ganellin, ME Parsons: Definition and antagonism of histamine H 2 receptors. In: Nature . Volume 236, 1972, pp. 385-390.
  13. ↑ JM Arrange, M. Garbarg, JC Schwartz: Auto-inhibition of brain histamine release mediated by a novel class (H 3 ) of histamine receptor. In: Nature. Volume 302, 1983, pp. 832-837.
  14. ↑ T. Nakamura, H. Itadani, Y. Hidaka, M. Ohta, K. Tanaka: Molecular cloning and characterization of a new human histamine receptor, HH4R. In: Biochem. Biophys. Res. Commun. Volume 279, 2000, pp. 615-620.
  15. ↑ TB Paiva, M. Tominaga, AC Paiva: Ionization of histamine, N-acetylhistamine, and their iodinated derivatives. In: Journal of medicinal chemistry. Volume 13, Number 4, July 1970, pp. 689-692. PMID 5452432 .
  16. ↑ J.-C. Schwartz, J.-M. Arrang, M. Garbarg, H. Pollard, M. Ruat: Histaminergic transmission in the mammalian brain. In: Physiol. Rev. 71, 1991, pp. 1-51. PMID 1846044 .
  17. ↑ JP Rihoux, L. Michel, R. Arnold, W. Konig: Hypothetical mechanisms of action of an H1 antihistamine in asthma. In: Int. Arch. Allergy Immunol. 118, 1999, pp. 380-383.
  18. ↑ M. Zhang, JD Venable, RL Thurmond: The histamine H4 receptor in autoimmune disease. In: Expert. Opin. Investig. Drugs. 15, 2006, pp. 1443-1452. PMID 17040202 .
  19. ^ I. Marshall: Characterization and distribution of histamine H1- and H2-receptors in precapillary vessels . In: J Cardiovasc Pharmacol . 6 Suppl 4, 1984, p. S587-S597 , PMID 6083401 .
  20. ↑ HH Pertz, S. Elz, W. Schunack: Structure-activity relationship of histamine H 1 -receptor agonists . In: Mini-Rev Med Chem . 4, 2004, pp. 935-940.
  21. ↑ P. Visciano, M. Schirone, R. Tofalo, G. Suzzi: Histamine poisoning and control measures in fish and fishery products. In: Frontiers in microbiology. Volume 5, 2014, p. 500, doi: 10.3389 / fmicb.2014.00500 . PMID 25295035 . PMC 4172148 (free full text).
  22. ^ A. Naila, S. Flint, G. Fletcher, P. Bremer, G. Meerdink: Control of biogenic amines in food - existing and emerging approaches. In: Journal of food science. Volume 75, number 7, September 2010, pp. R139-R150, doi: 10.1111 / j.1750-3841.2010.01774.x . PMID 21535566 . PMC 2995314 (free full text).
  23. ^ Indian Veterinary Journal. Vol. 57, 1980, p. 31.
  24. ↑ Ceplene: Summary of Product Characteristics . (PDF; 162 kB) on the website of the European Medicines Agency EMEA , as of October 7, 2008.
  25. ↑ a b Specialist information Ceplene. EpiCept GmbH. As of January 2011.
  26. ↑ Albert Gossauer: Structure and reactivity of biomolecules. Verlag Helvetica Chimica Acta, Zurich, 2006, ISBN 3-906390-29-2 , p. 247.
  27. ↑ F. Oliver, EU Amon, A. Breathnach, DM Francis, P. Sarathchandra, AK Black, MW Greaves: Contact urticaria due to the common stinging nettle (Urtica dioica) - histological, ultrastructural and pharmacological studies. In: Clinical and Experimental Dermatology . 16, 1991, pp. 1-7. PMID 2025924 .
  28. ^ Dieter Schlee: Ecological Biochemistry . Gustav Fischer, Jena 1992, ISBN 3-334-60393-8 , p. 404f.
  29. ^ Dieter Schlee: Ecological Biochemistry . Gustav Fischer, Jena 1992, ISBN 3-334-60393-8 , p. 421.
  30. ^ Dieter Schlee: Ecological Biochemistry . Gustav Fischer, Jena 1992, ISBN 3-334-60393-8 , p. 409.