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. Since their discovery in 1910, 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. 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, 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. The existence of these liberators were introduced by theories propounded during the 1950s-1970s 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. 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. 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.
The protease theory
When research on histamine liberators peaked during the 1950s, the ‘Protease theory’, proposed during 1962 by Börje Uvnäs, 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. The activity of these proteolytic enzymes were also seen to increase in the presence of compound 48/80 (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. Nonetheless, the protease theory did contain flaws undermining its validity. Firstly, biochemical literature 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. 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.
The displacement theory A second theory put forward was the ‘displacement theory’, 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.
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