Histamine N-methyltransferase
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.
In mammals, HNMT operates alongside diamine oxidase (DAO) as the only two enzymes responsible for histamine metabolism; however, what sets HNMT apart is its unique presence within the central nervous system (CNS), where it governs histaminergic neurotransmission, that is a process where histamine acts as a messenger molecule between the neurons—nerve cells—in the brain.
Research on knockout mice—that are genetically modified mice lacking the Hnmt gene—has revealed that the absence of this enzyme leads to increased brain histamine concentrations and behavioral changes such as heightened aggression and disrupted sleep patterns.
These findings highlight the critical role played by HNMT in maintaining normal brain function through precise regulation of neuronal signaling involving histamine.
[6] In the human genome, six exons from the 50-kb HNMT contribute to forming a unique mRNA species, approximately 1.6 kb in size.
[10][19] This specific protein, histamine N-methyltransferase, is found in vertebrates, including mammals, birds, reptiles, amphibians, and fishes, but not in invertebrates and plants.
[16] To understand the role of histamine N-methyltransferase in brain function, researchers have studied Hnmt-deficient (knockout) mice, that were genetically modified to have the Hnmt gene "knocked out", i.e., deactivated.
[25] In humans, the protein is present in many tissues and is most abundantly expressed in the brain, thyroid gland, bronchus, duodenum, liver, gallbladder, kidney, and skin.
[39] Such histamine can be exogenous (from food or intestinal flora) or endogenous (released from granules of mast cells and basophils, such as during allergic reactions).
[36][40] In contrast, HNMT is expressed in CNS and involved in the metabolism of intracellular (inside cells) histamine, which is primarily endogenous and persistently present.
HNMT enzyme is found in cells of diverse tissues: neurons and glia, brain, kidneys, liver, bronchi, large intestine, ovary, prostate, spinal cord, spleen, and trachea, etc.
While HNMT has a strong preference for histamine, DAO can metabolize other biogenic amines—substances, produced by a life form (like a bacteria or an animal) that has an amine functional group (−NH2).
[50][51][47] It also affects vasodilation, fluid production in tissues like the nose and eyes, gastric acid secretion, sexual function, and immune responses.
[48][49] HNMT is the only enzyme in the human body responsible for metabolizing histamine within the CNS, playing a role in brain function.
This enzymatic activity ensures that histamine remains at appropriate levels to carry out its physiological functions without causing unwanted effects or triggering allergic reactions.
[48][49] HNMT also plays a role in the airway response to harmful particles,[53] which is the body's physiological reaction to immune allergens, bacteria, or viruses in the respiratory system.
When exposed to immune allergens or harmful particles, histamine is released from these storage granules and quickly diffuses into the surrounding tissues.
[56][41] However, this link between DAO and HNMT enzymes and adverse reactions to ingested histamine in food is not shared by mainstream science due to insufficient evidence.
[56] The exact underlying mechanisms by which deficiency in these enzymes can cause these adverse reactions are not fully understood but are hypothesized to involve genetic factors.
[56] Despite extensive research, there are no definitive, objective measures or indicators that could unambiguously define histamine intolerance as a distinct medical condition.
Additionally, reduced histamine levels in cerebrospinal fluid have been consistently reported in patients with narcolepsy and other conditions characterized by excessive daytime sleepiness.
Despite these findings, the role of HNMT in human health is not fully understood and continues to be an active area of research.
[28] The following substances are known to be HNMT inhibitors: amodiaquine, chloroquine, dimaprit, etoprine, metoprine, quinacrine, SKF-91488, tacrine, and diphenhydramine.
[64] It is a central nervous system stimulant, which can be abused up to the lethal consequences: numerous deaths related to methamphetamine overdoses have been reported.
Therefore, by targeting HNMT, it might be possible to increase the levels of histamine in the brain, which could, in turn, help to mitigate the effects of a methamphetamine overdose.
