Histamine liberators

Last updated September 17, 2024

Histamine is an organic compound that primarily functions in service of the human body's immune responses as well as for the regulation of many physiological functions.^[1] Since their discovery in 1910,^[2] histamines have been known to trigger inflammatory responses such as itching as part of an immune response to foreign pathogens; for example, mosquito bites or allergens. It is released in granular form by mast cells, a type of white blood cell in connective tissues close to the site of interaction.^[3] Upon releasing, it increases the permeability of the blood capillaries for white blood cells and other proteins to enter in order to eliminate the foreign pathogens. The highest concentrations in mammalian tissue occur in the skin, intestines and lungs,^[4] sites where most symptoms of allergic responses are felt.

Histamine liberators are substances that contain low amounts of histamine themselves but are capable of releasing histamine from the mast cells.^[5] The existence of these liberators were introduced by theories propounded during the 1950s-1970's after the use of certain anaesthetics were shown to cause flushing and discoloration of the upper limbs of rodents in vitro (within cells and tissues extracted from a living organism). This immune response was accompanied by an increase in plasma histamine levels, thus, specific compounds in different anaesthetics were extracted and identified as ‘histamine liberators’ after experimental study.^[5]

However, the validity in their mechanism of even being able to degranulate the histamine from the mast cells for its release have been questioned in recent research. Nonetheless, the suggestion of its existence is still important as those with histamine intolerance are highly sensitive to its release due to inadequate breakdown, resulting in excess accumulation. Its profusion increases the risk for bronchiole constriction of the lungs or the hepatic veins, leading to anaphylactic shock and death if left untreated.^[6]

Furthermore, such postulations has instigated research into foods that could potentially be histamine liberators, such as egg whites, peanuts, and shellfish; allergic reactions upon the consumption of said foods are ubiquitous and widespread.

Proposed mechanisms of histamine liberators

MRGPRX2 receptor activation

Binding to the Mas-related G protein–coupled receptor-X2 (MRGPRX2) in cutaneous mast cell is the only proven mechanism of direct mast cell degranulation that corresponds to proposed histamine liberators action. So far, few substances, such as drugs dextromethorphan, morphine, and related opioid ligands have been shown to serve as ligands for the MRGPRX2.^[7]

The protease theory

When research on histamine liberators peaked during the 1950s, the ‘Protease theory’, proposed during 1962 by Börje Uvnäs,^[8] was one of the most prominent explanations attempting to explain the mechanisms of histamine liberators. Experimental studies were conducted to elucidate the mechanism of histamine liberators found in anaesthetics; for instance, one particular experiment demonstrated that proteolytic enzymes (a type of enzyme that digests proteins such as pepsin and trypsin) were able to split histamine compounds from the polypeptides (proteins within the mast cell) to which they were bound to.^[8] The activity of these proteolytic enzymes were also seen to increase in the presence of compound 48/80^[8] (along with other histamine liberator compounds). Thus, it was hypothesized that when these enzymes were activated, they liberated and freed histamine molecules by degrading the mast cell, triggering a response in the surrounding tissue.

However, the exact, precise mechanism as to how the proteolytic enzymes split the polypeptides remains convoluted. Despite this, the main argument compounding this theory is the activity of another set of enzymes (known as kinases) splits groups of pro-activators to yield activators. This engenders a downstream effect: activators activate proteolytic enzymes, causing an attack on the attachment between histamine molecules and mast cell polypeptides is triggered. The ultimate effect is that histamine is released.^[8]

Nonetheless, the protease theory did contain flaws undermining its validity. Firstly, biochemical literature^[8] has shown that trypsin has a weak ability to liberate histamine, being only effective when present at high concentrations. Fibrolysin is simply unable to release histamine at all per se.^[8] Moreover, a quantitative relationship between protease concentration and the amount of histamine released has not been found. A lack of even a meagre, weak positive correlation means that this theory cannot stand to point to histamine liberators as the causation of histamine release, or in fact, the mere existence of histamine liberators at all. Furthermore, despite there being evidence suggesting that histamine is bonded to polypeptides (most likely through covalent bonding), concrete evidence directly proving this fact has not been found yet.^[8]

The displacement theory

A second theory put forward was the ‘displacement theory’,^[8] that suggested histamine's chemical makeup to be the basis of its own liberation. Histamine is a weak base (a compound able to react with a hydrogen ion to form an acid) that can link with acid groups within the granules of the mast cells.^[8]

The crux of this theory lies in the assumption that histamine liberators release histamine by displacing it from cells. The mechanism hypothesised by which histamine is displaced occurs in two steps: firstly, the liberator penetrate the membranes of mast cells, compromising the integrity of its membrane. Secondly, now that the cell membrane is pierced, the liberator enters the cell.^[8] Since there is no air or free space, this forces the histamine already existing in the mast cell to be displaced outside the cell, thereby releasing and “liberating” it. Some histamine liberators were thought to be organic bases as they are synonymous with histamine since it is a base as well, thus facilitating its displacement.^[8]

Experimental evidence supporting this theory has shown that organic bases and compound 48/80, when administered in tandem, triggered a release of histamine in guinea pigs. Such results were replicable both in vivo (within an entire living organism) and in vitro. Nevertheless, experiments actually showed a smaller amount of compound 48/80 could “displace” a much larger amount of histamine. For instance, an experiment performed on a cat paw demonstrated that 10 micrograms of 48/80 released 7 times more, 75 micrograms to be exact, of histamine. This seems to undermine the validity of the theory as it does not make logical sense for a small amount of compound to displace a much a larger amount of histamine. Additionally, the degree of mast cell membrane permeability was also fragmentary and its disruption may not even be sufficient to cause the intracellular histamine to be released.^[8]

The enzymatic theory

It has also been postulated that enzymatic theories underpin the mechanism of histamine liberators. In an experiment conducted in the early 1950s, a team of scientists procured active histamine-liberating chemicals from jellyfish and swine. They attempted to acquire experimental evidence supporting the hypothesis that compound 48/80 ruptures mast cells, thereby acting as histamine liberator through an enzymatic mechanism.

It was also found that specific ions such as Zn²⁺, as well as enzyme inhibitors such as phenylhydrazine, were effective at substantially reducing or completely stopping the action of histamine liberators – most notably the aforementioned compound 48/80.^[8] This constituted as evidence suggesting that such compounds acted like competitive inhibitors, a mechanism that inhibits the activity of enzymes needed for histamine release. Moreover, the action and potency of compound 48/80 was found to be temperature dependent: it only functioned effectively as a histamine liberator at optimal temperatures and was rendered ineffective at extreme temperatures.^[8] These specificities provided more evidence supporting the claim that histamine liberators (such as compound 48/80) acted through enzymatic mechanisms as these characteristics are synonymous with existing enzymes.

The action of compound 48/80 varies with pH – another distinctive characteristic that enzymes also exhibit. Experimental data revealed that at a pH of 7.8, the amount of histamine released peaks. pH values deviating above or below 7.8 show less histamine being released; yet, at a pH higher than 9.2,^[9] the amount of histamine released again increases.^[9] This was hypothesised to be caused by changes in acidity of the internal environment of the mast cells. However, other histamine-liberating substances, such as decylamine, manifested a steady increase in histamine activity with rising pH.

During the 1960s, this enzymatic theory was deemed to the most plausible mechanism and garnered the most support and approval from scientists; however, there were still some uncertainties associated with it. Just because histamine liberators share common characteristics with enzymes does not necessarily prove that they act as enzymes. However, during the 1960s to the 1970s, much of the different disciplines of biochemistry was still at its infancy. Modern analytical techniques involving nuclear magnetic resonance (NMR) or X-ray crystallography, which is needed to determine the 3-dimensional structures of proteins and enzymes, had not been discovered yet during that time. It is now known that such technology is crucial for determining the exact mechanism of enzymes.^[10]

Significance

When the theory of histamine liberators was at the forefront of medical research back in the 1950s, the findings of such research was of particular relevance for individuals prone to food allergies.^[11] During that time, many dietitians advised that a diet devoid of histamine-liberating foods was the ideal strategy to prevent symptoms of histamine intolerance from manifesting. Lists of foods deemed to be histamine-liberating were published in various scientific articles, which included fermented sausages, cured cheese, wine and beer.^[11]

On a molecular level, there were scientists who sought to find more precise lists of chemicals which could have histamine-liberating potencies. For instance, in a scientific journal, MacIntosh and Paton publicized a list of various compounds thought to be histamine liberators, such as organic bases, amines and guanidines.^[8] Many of such occurred naturally in organisms such as sea anemones, jellyfish and caterpillars. This proved to be of great use to dietitians; they could confirm whether a certain food was histamine-liberating or not through checking if its chemical constituents were included in the aforementioned list of chemicals.

Recent research and studies

Notwithstanding the fact that the theory of histamine liberators dates back to the 1950s, there have been contemporary attempts to re-evaluate the validity and significance of the histamine liberator theory.

Scientists attempted to elucidate the theory of Histamine Liberators back in the 1950s to the early 1970s. However, despite many years of research, it was held that there was insufficient evidence conclusively supporting the theory and mechanism of histamine liberators. Thus, further scientific research on this topic ceased towards the end of the 1970s. Nonetheless, in 2005, a group of scientists in the Netherlands sought to peruse over and re-evaluate the dated scientific literature on histamine liberators.^[12] Many of such scientific articles recurrently purported that histamine-releasing foods exacerbated symptoms of mastocytosis (a build-up of mast cells in specific bodily areas) There was a belief that histamine-releasing foods could induce allergy-like symptoms. However, upon carefully considering the validity of the scientific methods, it was held that the validity of the original mechanism is somewhat questionable and perhaps needs more evidence to support it. Notwithstanding, the scientists noted that this is a very interesting area with lots of potential, due to its important implications for anaesthesia usage and those with food allergies.^[12]

Related Research Articles

<span class="mw-page-title-main">Allergy</span> Immune system response to a substance that most people tolerate well

Allergies, also known as allergic diseases, are various conditions caused by hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include hay fever, food allergies, atopic dermatitis, allergic asthma, and anaphylaxis. Symptoms may include red eyes, an itchy rash, sneezing, coughing, a runny nose, shortness of breath, or swelling. Note that food intolerances and food poisoning are separate conditions.

A mast cell is a resident cell of connective tissue that contains many granules rich in histamine and heparin. Specifically, it is a type of granulocyte derived from the myeloid stem cell that is a part of the immune and neuroimmune systems. Mast cells were discovered by Paul Ehrlich in 1877. Although best known for their role in allergy and anaphylaxis, mast cells play an important protective role as well, being intimately involved in wound healing, angiogenesis, immune tolerance, defense against pathogens, and vascular permeability in brain tumors.

Basophils are a type of white blood cell. Basophils are the least common type of granulocyte, representing about 0.5% to 1% of circulating white blood cells. They are the largest type of granulocyte. They are responsible for inflammatory reactions during immune response, as well as in the formation of acute and chronic allergic diseases, including anaphylaxis, asthma, atopic dermatitis and hay fever. They also produce compounds that coordinate immune responses, including histamine and serotonin that induce inflammation, and heparin that prevents blood clotting, although there are less than that found in mast cell granules. Mast cells were once thought to be basophils that migrated from the blood into their resident tissues, but they are now known to be different types of cells.

<span class="mw-page-title-main">Histamine</span> Organic compound involved in immune responses

Histamine is an organic nitrogenous compound involved in local immune responses communication, as well as regulating physiological functions in the gut and acting as a neurotransmitter for the brain, spinal cord, and uterus. Discovered in 1910, histamine has been considered a local hormone (autocoid) because it's produced without involvement of the classic endocrine glands; however, in recent years, histamine has been recognized as a central neurotransmitter. Histamine is involved in the inflammatory response and has a central role as a mediator of itching. 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. It consists of an imidazole ring attached to an ethylamine chain; under physiological conditions, the amino group of the side-chain is protonated.

Granulocytes are cells in the innate immune system characterized by the presence of specific granules in their cytoplasm. Such granules distinguish them from the various agranulocytes. All myeloblastic granulocytes are polymorphonuclear, that is, they have varying shapes (morphology) of the nucleus ; and are referred to as polymorphonuclear leukocytes. In common terms, polymorphonuclear granulocyte refers specifically to "neutrophil granulocytes", the most abundant of the granulocytes; the other types have varying morphology. Granulocytes are produced via granulopoiesis in the bone marrow.

Digestive enzymes take part in the chemical process of digestion, which follows the mechanical process of digestion. Food consists of macromolecules of proteins, carbohydrates, and fats that need to be broken down chemically by digestive enzymes in the mouth, stomach, pancreas, and duodenum, before being able to be absorbed into the bloodstream. Initial breakdown is achieved by chewing (mastication) and the use of digestive enzymes of saliva. Once in the stomach further mechanical churning takes place mixing the food with secreted gastric acid. Digestive gastric enzymes take part in some of the chemical process needed for absorption. Most of the enzymatic activity, and hence absorption takes place in the duodenum.

Cromoglicic acid (INN)—also referred to as cromolyn (USAN), cromoglycate, or cromoglicate—is traditionally described as a mast cell stabilizer, and is commonly marketed as the sodium salt sodium cromoglicate or cromolyn sodium. This drug prevents the release of inflammatory chemicals such as histamine from mast cells.

Allergic conjunctivitis (AC) is inflammation of the conjunctiva due to allergy. Although allergens differ among patients, the most common cause is hay fever. Symptoms consist of redness, edema (swelling) of the conjunctiva, itching, and increased lacrimation. If this is combined with rhinitis, the condition is termed allergic rhinoconjunctivitis (ARC).

Phospholipase A<sub>2</sub> Peripheral membrane protein

The enzyme phospholipase A₂ (EC 3.1.1.4, PLA2, systematic name phosphatidylcholine 2-acylhydrolase) catalyses the cleavage of fatty acids in position 2 of phospholipids, hydrolyzing the bond between the second fatty acid “tail” and the glycerol molecule:

<span class="mw-page-title-main">Ketotifen</span> Antihistamine medication

Ketotifen is an antihistamine medication and a mast cell stabilizer used to treat allergic conditions such as conjunctivitis, asthma, and urticaria (hives). Ketotifen is available in ophthalmic and oral forms: the ophthalmic form relieves eye itchiness and irritation associated with seasonal allergies, while the oral form helps prevent systemic conditions such as asthma attacks and allergic reactions. In addition to treating allergies, ketotifen has shown efficacy in managing systemic mast cell diseases such as mastocytosis and mast cell activation syndrome (MCAS), which involve abnormal accumulation or activation of mast cells throughout the body. Ketotifen is also used for other allergic-type conditions like atopic dermatitis (eczema) and food allergies.

The enzyme histidine decarboxylase is transcribed on chromosome 15, region q21.1-21.2, and catalyzes the decarboxylation of histidine to form histamine. In mammals, histamine is an important biogenic amine with regulatory roles in neurotransmission, gastric acid secretion and immune response. Histidine decarboxylase is the sole member of the histamine synthesis pathway, producing histamine in a one-step reaction. Histamine cannot be generated by any other known enzyme. HDC is therefore the primary source of histamine in most mammals and eukaryotes. The enzyme employs a pyridoxal 5'-phosphate (PLP) cofactor, in similarity to many amino acid decarboxylases. Eukaryotes, as well as gram-negative bacteria share a common HDC, while gram-positive bacteria employ an evolutionarily unrelated pyruvoyl-dependent HDC. In humans, histidine decarboxylase is encoded by the HDC gene.

Catechol oxidase is a copper oxidase that contains a type 3 di-copper cofactor and catalyzes the oxidation of ortho-diphenols into ortho-quinones coupled with the reduction of molecular oxygen to water. It is present in a variety of species of plants and fungi including Ipomoea batatas and Camellia sinensis. Metalloenzymes with type 3 copper centers are characterized by their ability to reversibly bind dioxygen at ambient conditions. In plants, catechol oxidase plays a key role in enzymatic browning by catalyzing the oxidation of catechol to o-quinone in the presence of oxygen, which can rapidly polymerize to form the melanin that grants damaged fruits their dark brown coloration.

Degranulation is a cellular process that releases antimicrobial, cytotoxic, or other molecules from secretory vesicles called granules found inside some cells. It is used by several different cells involved in the immune system, including granulocytes. It is also used by certain lymphocytes such as natural killer (NK) cells and cytotoxic T cells, whose main purpose is to destroy invading microorganisms.

Histamine <i>N</i>-methyltransferase Mammalian enzyme involved in the metabolism of histamine

Histamine N-methyltransferase (HNMT) is a protein encoded by the HNMT gene in humans. It belongs to the methyltransferases superfamily of enzymes and plays a role in the inactivation of histamine, a biomolecule that is involved in various physiological processes. Methyltransferases are present in every life form including archaeans, with 230 families of methyltransferases found across species.

<span class="mw-page-title-main">Antihistamine</span> Drug that blocks histamine or histamine agonists

Antihistamines are drugs which treat allergic rhinitis, common cold, influenza, and other allergies. Typically, people take antihistamines as an inexpensive, generic drug that can be bought without a prescription and provides relief from nasal congestion, sneezing, or hives caused by pollen, dust mites, or animal allergy with few side effects. Antihistamines are usually for short-term treatment. Chronic allergies increase the risk of health problems which antihistamines might not treat, including asthma, sinusitis, and lower respiratory tract infection. Consultation of a medical professional is recommended for those who intend to take antihistamines for longer-term use.

One of the most prevalent forms of adverse drug reactions is cutaneous reactions, with drug-induced urticaria ranking as the second most common type, preceded by drug-induced exanthems. Urticaria, commonly known as hives, manifests as weals, itching, burning, redness, swelling, and angioedema—a rapid swelling of lower skin layers, often more painful than pruritic. These symptoms may occur concurrently, successively, or independently. Typically, when a drug triggers urticaria, symptoms manifest within 24 hours of ingestion, aiding in the identification of the causative agent. Urticaria symptoms usually subside within 1–24 hours, while angioedema may take up to 72 hours to resolve completely.

Compound 48/80 is a polymer produced by the condensation of N-methyl-p-methoxyphenethylamine with formaldehyde. It promotes histamine release, and in biochemical research, compound 48/80 is used to promote mast cell degranulation.

Pseudoallergy, sometimes known as nonallergic hypersensitivity, is a type of hypersensitivity reaction mostly described in the context of drug allergy. The mechanism is somewhat similar to the type 1 hypersensitivity in the Gell and Coombs classification in that the effector cell is also mast cell. In pseudoallergic reaction, the mast cell is directly activated, rather than through the mediation of Immunoglobulin E (IgE). Therefore, it is also known as direct mast cell activation.

Histamine intolerance is a presumed set of adverse reactions 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. There is a common suspicion that ingested histamine in persons with deficiencies in the enzymes that metabolize histamine may be responsible for various non-specific health complaints, which some individuals categorize as histamine intolerance, still, histamine intolerance is not recognized as an explicit medical condition with that name in the International Classification of Diseases (ICD) Edition 11, or any previous edition. The scientific proof that supports the idea that eating food containing histamine can cause health problems is currently limited and not consistent.

Exercise-induced anaphylaxis is a rare condition in which anaphylaxis, a serious or life-threatening allergic response, is brought on by physical activity. Approximately 5–15% of all reported cases of anaphylaxis are thought to be exercise-induced.

References

↑ Fowler P (2020). "What Are Histamines?". WebMD.
↑ "A timeline of histamine and its receptors". Nature Medicine. 16 (10): 1064. October 2010. doi: 10.1038/nm1010-1064 . PMID 20930738. S2CID 20918501.
↑ Borriello F, Iannone R, Marone G (2017). "Histamine Release from Mast Cells and Basophils". Handbook of Experimental Pharmacology. Handbook of Experimental Pharmacology. Vol. 241. pp. 121–139. doi:10.1007/164_2017_18. ISBN 978-3-319-58192-7. PMID 28332048.
↑ Thangam EB, Jemima EA, Singh H, Baig MS, Khan M, Mathias CB, et al. (2018-08-13). "The Role of Histamine and Histamine Receptors in Mast Cell-Mediated Allergy and Inflammation: The Hunt for New Therapeutic Targets". Frontiers in Immunology. 9: 1873. doi: 10.3389/fimmu.2018.01873 . PMC 6099187 . PMID 30150993.
1 2 Alm PE (1984). "Histamine liberators and the mechanisms of mediator release". Acta Oto-Laryngologica. Supplementum. 414: 102–107. doi:10.3109/00016488409122889. PMID 6085445.
↑ Maintz L, Novak N (May 2007). "Histamine and histamine intolerance". The American Journal of Clinical Nutrition. 85 (5): 1185–1196. doi: 10.1093/ajcn/85.5.1185 . PMID 17490952.
↑ Roy S, Chompunud Na Ayudhya C, Thapaliya M, Deepak V, Ali H (August 2021). "Multifaceted MRGPRX2: New insight into the role of mast cells in health and disease". The Journal of Allergy and Clinical Immunology. 148 (2): 293–308. doi:10.1016/j.jaci.2021.03.049. PMC 8355064 . PMID 33957166.
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Uvnas B (January 1958). "The mechanism of histamine liberation". The Journal of Pharmacy and Pharmacology. 10 (1): 1–13. doi:10.1111/j.2042-7158.1958.tb10267.x. PMID 13492191. S2CID 85159941.
1 2 Rothschild AM (January 1970). "Mechanisms of histamine release by compound 48-80". British Journal of Pharmacology. 38 (1): 253–262. doi:10.1111/j.1476-5381.1970.tb10354.x. PMC 1702640 . PMID 4189829.
↑ Lai J, Niks D, Wang Y, Domratcheva T, Barends TR, Schwarz F, et al. (January 2011). "X-ray and NMR crystallography in an enzyme active site: the indoline quinonoid intermediate in tryptophan synthase". Journal of the American Chemical Society. 133 (1): 4–7. doi:10.1021/ja106555c. PMID 21142052.
1 2 Sánchez-Pérez S, Comas-Basté O, Veciana-Nogués MT, Latorre-Moratalla ML, Vidal-Carou MC (April 2021). "Low-Histamine Diets: Is the Exclusion of Foods Justified by Their Histamine Content?". Nutrients. 13 (5): 1395. doi: 10.3390/nu13051395 . PMC 8143338 . PMID 33919293.
1 2 Vlieg-Boerstra BJ, van der Heide S, Oude Elberink JN, Kluin-Nelemans JC, Dubois AE (2005). "Mastocytosis and adverse reactions to biogenic amines and histamine-releasing foods: what is the evidence?". The Netherlands Journal of Medicine. 63 (7): 244–249. PMID 16093574.

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[1] Fowler P (2020). "What Are Histamines?". WebMD.

[2] "A timeline of histamine and its receptors". Nature Medicine. 16 (10): 1064. October 2010. doi: 10.1038/nm1010-1064 . PMID 20930738. S2CID 20918501.

[3] Borriello F, Iannone R, Marone G (2017). "Histamine Release from Mast Cells and Basophils". Handbook of Experimental Pharmacology. Handbook of Experimental Pharmacology. Vol. 241. pp. 121–139. doi:10.1007/164_2017_18. ISBN 978-3-319-58192-7. PMID 28332048.

[4] Thangam EB, Jemima EA, Singh H, Baig MS, Khan M, Mathias CB, et al. (2018-08-13). "The Role of Histamine and Histamine Receptors in Mast Cell-Mediated Allergy and Inflammation: The Hunt for New Therapeutic Targets". Frontiers in Immunology. 9: 1873. doi: 10.3389/fimmu.2018.01873 . PMC 6099187 . PMID 30150993.

[Alm_1984-5] 1 2 Alm PE (1984). "Histamine liberators and the mechanisms of mediator release". Acta Oto-Laryngologica. Supplementum. 414: 102–107. doi:10.3109/00016488409122889. PMID 6085445.

[pmid17490952-6] Maintz L, Novak N (May 2007). "Histamine and histamine intolerance". The American Journal of Clinical Nutrition. 85 (5): 1185–1196. doi: 10.1093/ajcn/85.5.1185 . PMID 17490952.

[7] Roy S, Chompunud Na Ayudhya C, Thapaliya M, Deepak V, Ali H (August 2021). "Multifaceted MRGPRX2: New insight into the role of mast cells in health and disease". The Journal of Allergy and Clinical Immunology. 148 (2): 293–308. doi:10.1016/j.jaci.2021.03.049. PMC 8355064 . PMID 33957166.

[Uvnas_1958-8] 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Uvnas B (January 1958). "The mechanism of histamine liberation". The Journal of Pharmacy and Pharmacology. 10 (1): 1–13. doi:10.1111/j.2042-7158.1958.tb10267.x. PMID 13492191. S2CID 85159941.

[Rothschild_1970-9] 1 2 Rothschild AM (January 1970). "Mechanisms of histamine release by compound 48-80". British Journal of Pharmacology. 38 (1): 253–262. doi:10.1111/j.1476-5381.1970.tb10354.x. PMC 1702640 . PMID 4189829.

[pmid21142052-10] Lai J, Niks D, Wang Y, Domratcheva T, Barends TR, Schwarz F, et al. (January 2011). "X-ray and NMR crystallography in an enzyme active site: the indoline quinonoid intermediate in tryptophan synthase". Journal of the American Chemical Society. 133 (1): 4–7. doi:10.1021/ja106555c. PMID 21142052.

[Sánchez-Pérez_2021-11] 1 2 Sánchez-Pérez S, Comas-Basté O, Veciana-Nogués MT, Latorre-Moratalla ML, Vidal-Carou MC (April 2021). "Low-Histamine Diets: Is the Exclusion of Foods Justified by Their Histamine Content?". Nutrients. 13 (5): 1395. doi: 10.3390/nu13051395 . PMC 8143338 . PMID 33919293.

[pmid16093574-12] 1 2 Vlieg-Boerstra BJ, van der Heide S, Oude Elberink JN, Kluin-Nelemans JC, Dubois AE (2005). "Mastocytosis and adverse reactions to biogenic amines and histamine-releasing foods: what is the evidence?". The Netherlands Journal of Medicine. 63 (7): 244–249. PMID 16093574.

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