Histamine is a naturally occurring chemical found in our cells that serves as a defender, safeguarding and supporting our immune system in fighting infections. However this protective role comes at a cost as histamine can cause various allergy symptoms, such as a runny nose and sneezing. It is also involved in a variety of allergies, such as hay fever, food allergies, and skin allergies. This remarkable molecule has unique characteristics that make it both a friend and a foe. In this article, we will delve deeper into the fascinating world of histamine and explore its intriguing dual nature.
A tiny but mighty molecule
Histamine is a compound that is widely distributed throughout the animal kingdom, in many plants, bacteria, and insect venoms. For example, stinging nettle plants produce histamine in hairlike structures on their leaves causing swelling and itching upon contact. Similarly, many species of wasps and bees contain histamine in their venom, which can cause allergic reactions ranging from mild to severe.
Histamine is a biologically active chemical classified as an amine. It is formed by the decarboxylation (removal of a carboxyl group) from the amino acid histidine, by the enzyme L-histidine decarboxylase, in a one-step reaction (Figure 1a). There are presently 4 human structures of histidine decarboxylase and 8 bacterial structures determined experimentally so far. PDB entry 7eiy contains histidine bound to the dimer of enzyme L-histidine decarboxylase in its active site, shown in Figure 1b.
Figure 1. Synthesis of Histamine. a) Histidine is converted to Histamine by the process of decarboxylation, using the enzyme L-histidine decarboxylase b) shown as a space fill model generated using Mol* (molstar.org). Histidine is seen in its binding pocket.
Histamine as a protector and signalling molecule
Histamine acts as a signalling molecule, playing a crucial role in transmitting messages between cells throughout the body. Despite its small size, histamine carries significant importance in various physiological processes. For instance it signals the stimulation of gastric acid secretion in the stomach and serves as a neurotransmitter, functioning as a chemical messenger between nerve cells. By influencing sleep-wake patterns, histamine contributes to maintaining our alertness and regulating our overall circadian rhythm.
Histamine also acts like a protector, assisting the body in removing allergens and foreign invaders. It works in conjunction with the immune system to accomplish this. When the immune system detects an invader, B-cells produce IgE antibodies that specifically bind to mast cells and basophils, types of white blood cells. This binding triggers the release of stored histamines into different parts of the body, including the skin, lungs, nose, mouth, gut, and blood. The release of histamines in these areas contributes to various immune responses and inflammatory processes, such as vasodilation, increased vascular permeability, bronchoconstriction, mucus production, and itching. This cascade of events highlights the role of histamine in the immune system's defence mechanism against potential threats.
Clearing histamine
Histamine undergoes either rapid inactivation or storage after its formation. The breakdown of histamine primarily occurs through the action of two key enzymes: diamine oxidase (DAO) and histamine-N-methyltransferase (HNMT).
Diamine oxidase (DAO) is the frontline enzyme responsible for metabolising histamine from ingested food or locally produced in the gut. It catalyses the oxidative deamination of histamine, breaking it down into imidazole acetaldehyde. This process helps regulate histamine levels in the gut, preventing excessive accumulation and potential adverse effects.
Impairment or deficiency of DAO activity can lead to elevated histamine levels in the gut, resulting in symptoms such as abdominal pain, bloating, diarrhoea, and other gastrointestinal disturbances. The presence of DAO in the digestive system underscores its role in maintaining histamine balance and ensuring proper gastrointestinal function.
In the central nervous system, HNMT plays a crucial role by breaking down histamine released into synapses. It transfers a methyl group from S-adenosyl-L-methionine to the nitrogen atom of the imidazole ring of histamine, inactivating it and forming N-methylhistamine. This reaction occurs only in the intracellular space of cells as HNMT is a cytosolic protein. Deficiency in this enzyme increases the risk of allergic reactions, as histamine accumulates in the synapses. Monoamine oxidase B (MAO-B) and aldehyde dehydrogenase 2 (ALDH2) are enzymes involved in further processing the immediate metabolites of histamine for excretion or recycling.
While MAO inhibitors are primarily prescribed for managing central nervous system-associated diseases such as depression, Alzheimer's, and Parkinson's, they also exhibit anti-inflammatory effects in the CNS and various non-CNS tissues.
Histamine Intolerance
Histamine intolerance occurs when histamine levels in the body are excessively high or are not properly broken down, resulting in symptoms similar to an allergic reaction. This can happen due to deficiencies in enzymes responsible for histamine breakdown, such as DAO or HNMT, or due to excessive intake of histamine-rich foods or drinks. Symptoms of histamine intolerance include headaches, flushing, hives, gastrointestinal issues, and respiratory problems. Treatment typically involves identifying and avoiding trigger foods and drinks, as well as supplementing with DAO and/or other supportive treatments.
Histamine Allergies and Poisoning: Our Foe
Histamine allergic symptoms vary depending on the severity and type of allergic reaction. Histamine works with nerve endings to produce itching. Common symptoms of a mild allergic reaction may include: sneezing, runny or stuffy nose, itchy or watery eyes, skin rash or hives, itchy or tingling sensation in the mouth or throat, mild abdominal discomfort or cramping.
Most worrisome is when histamine causes anaphylaxis, a severe and potentially fatal reaction. Anaphylaxis is particularly common in susceptible individuals following insect stings. It is a severe and potentially fatal allergic reaction caused by the release of histamine. Histamine triggers widespread effects, including vasodilation, increased vascular permeability, bronchoconstriction, gastrointestinal symptoms, and systemic manifestations. Prompt medical attention, including the administration of epinephrine, is necessary to treat anaphylaxis and counteract the effects of histamine.
In addition to animals, histamine can also be produced by bacteria by using histidine decarboxylase enzymes. When food, especially fish, is spoiled, bacteria can produce histamine, leading to a non-infectious foodborne illness known as scombroid poisoning or histamine fish poisoning. Fermented foods and beverages also contain small amounts of histamine due to conversion by fermenting bacteria or yeasts. For instance, sake contains histamine in the range of 20-40 mg/L, while wine contains approximately 2-10 mg/L of histamine. In food allergies it can cause vomiting and diarrhoea. It is important to be aware of histamine levels in various foods and beverages to prevent adverse reactions and ensure food safety. Proper handling, storage, and preparation of histamine-rich foods can help mitigate the risk of histamine poisoning and related illnesses.
Antihistamines
Histamine exerts its effect through the action on G-protein coupled receptors, H1, H2, H3, and H4, play a vital role in modulating allergic and inflammatory responses, making them crucial drug targets. Antihistamines control allergies and histamine-induced reactions, by blocking the effects of histamine in the body. Antihistamines come in various forms of tablets, capsules, liquids, nasal sprays, and eye drops. Blocking H1 receptors throughout the body relieves symptoms like itching, redness, swelling, and muscle contraction.
First-generation antihistamines (e.g., Benadryl) alleviate allergies but may cause drowsiness and have shorter duration. Second-generation antihistamines (e.g Zyrtec, Claritin) are less sedating, provide longer relief, and are preferred for daytime use. Antihistamines like Dramamine and Bonine treat motion sickness by blocking H1 receptors in the brain, with sedative properties for calming effects. H2 receptors in the stomach stimulate acid secretion, therefore H2 antagonists (e.g., Tagamet, Zantac) reduce acid production and treat conditions like GERD and ulcers. H3 receptors in the central nervous system are potential targets for cognitive disorders and addictions, while H4 receptors modulate immune responses and have potential in asthma and allergies treatment.
While antihistamines are generally safe when used correctly, they can cause side effects such as dry mouth, drowsiness, blurred vision, and constipation. It is important to follow the recommended dosage and consult healthcare professionals. Maintaining proper control of histamine is essential, as it is a stimulating and excitatory chemical that should work in our favour rather than against us.
Deepti Gupta
About the artwork
Ella Buchanan and Scarlett Tran (Year 7) from the Viewbank College (Melbourne, Australia) worked collaboratively, pairing up to create their artwork on histamine. During the process, they found it captivating to delve into the structure and properties of histamine, despite not having allergies themselves. This exploration significantly enhanced their comprehension of proteins and their crucial role in supporting life. Overall, both developed a deeper understanding of proteins, including small molecules like histamine, and their functions within the body. To bring their artistic vision to life, they chose gouache as the medium for their final artwork.
View the artwork in the .
Structures mentioned in this article
Histamine-N-methyltransferase (HNMT)
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