Histamine is a bioactive amine that is synthesized by decarboxylation of its precursor amino acid, histidine, in an enzymatic reaction first described by Windaus and Vogt in 1907.

The name histamine comes from the Greek histos meaning tissue, because it is present in many body tissues. The physiological and pathophysiological effects of histamine in the body were first described in 1910 by Dale and Laidlaw, two pioneering researchers who studied its functions at the Wellcome Physiological Research Laboratories (Dale HH, Laidlaw PP. 1910). Histamine is found throughout our body, although in higher concentrations in the lungs, skin and the gastrointestinal tract. It is synthesized and stored mainly in basophils and mast cells, and also in gastric enterochromaffin cells, lymph nodes and thymus (Panula P, et al. 2015). It is involved in various immunological and physiological mechanisms: stimulating the secretion of gastric acid, in the process of inflammation, the contraction of smooth muscle cells, vasodilation and the production of cytokines, among others. (Maintz. L. 2007; Vlieg-Boerstra BJ. Et al. 2005).

Histamine is a mediator of the neuro-immuno-endocrine system

In addition, it also functions as a neurotransmitter, being synthesized by neurons located in the posterior region of the hypothalamus whose axons extend throughout the brain. (Worm J, et al. 2019).

The variability of its physiological effects is produced by the interaction with four different receptors: H1, H2, H3 and H4, which activate signal transduction pathways when perceiving histamine. (Panula P, et al. 2015). Two main metabolic pathways of histamine are known that involve two enzymes:

• Diamine oxidase (DAO)
• Histamine-N-Methyltransferase (HNMT)

And when did your research with pathologies or diseases begin?

Well, over a hundred years ago. The first antihistamines to be put into clinical use were about 70 years ago. In 1926, Harmer and Harris were the first scientists to describe the relationship between headache and histamine after providing an infusion of histamine in the study (Harmer IM, 1926). In 1927 it was purified for the first time from human tissues. In 1930, the scientist Pickering carried out a series of experimental studies. Although none of them were placebo controlled, histamine was further investigated for its ability to induce vascular headache. Histamine was shown to induce headache in a dose- and susceptibility-dependent manner, but there was great variability between them. Researcher Pickering proposed that the origin of histamine-related headache of vascular origin was due to vasodilation of the intracranial arteries and that the headache could arise through the trigeminal nerve (Pickering GW, 1033).  

The study of the relationship between histamine and migraine has been investigated for many years and other scientists have analyzed how histamine could induce headaches. Later, Northfield injected histamine into the external and internal carotid arteries and concluded that the headache could originate from the internal carotid artery (Northfield’s DWC, 1938). Von Storch studied what could be the minimum doses of histamine to induce a headache in a person, however, he observed that they depended on the context, since those people who suffered from migraine and were selected in the study were much more susceptible to suffering headache induced by histamine delivery than subjects without migraines. (Arch Neurol Psychiatr. 1940; 44:316–322) Therefore, the oldest scientific literature demonstrates the relationship between histamines and headaches. To this day, researchers continue to investigate endogenous mediators, including histamine, for their ability to generate migraine pain and other pathologies and diseases. (De Logu F, et al. 2019). In addition, science advances and more and more studies are emerging where histamine is related as a mediator in different pathologies and diseases. Another important piece of information observed in recent studies is that, depending on its location, the histamine present in the body is deaminated or methylated by the action of the enzymes DAO and/or HNMT (histamine-N-methyltransferase), respectively. (Maintz, L. 2015) It should be noted that the enzyme DAO is responsible for the degradation of extracellular histamine. This enzyme is mainly expressed in the small intestine, ascending colon, placenta, and kidneys. In the intestine, DAO activity increases progressively from the duodenum to the ileum and is located mainly in the intestinal villi. (Eisenhans, B. 1999) DAO can also metabolize other biogenic amines such as putrescine and cadaverine. (Elmore Bo, et al. 2002). The HNMT enzyme is expressed in various tissues and organs of our body, especially in the kidneys and liver, also in the spleen, colon, prostate, ovaries, spinal cord cells, trachea and respiratory tract . (Maintz, L. 2007).

The main route of entry into the body for histamine from food is the intestinal epithelium.

Therefore, although HNMT is also present in the gastrointestinal tract, it is the enzyme DAO that plays a major role in protecting the body against exogenous histamine, the one that comes from food. (Bohem T. et al. 2019; Maršavelski A, et al 2018).