Histamine N MethyltransferaseEdit

Histamine N-methyltransferase (HNMT) is a cytosolic enzyme that inactivates histamine by transferring a methyl group from S-adenosyl-L-methionine (SAM) to the primary amine of histamine, producing N-methylhistamine. This reaction constitutes the first major step in one intracellular pathway for histamine catabolism in humans, complementing the extracellular oxidation pathway driven largely by diamine oxidase (DAO). The balance between these routes helps regulate histamine signaling in different tissues and contexts.

HNMT is widely expressed across tissues, with notable activity in the liver, kidney, and brain. The enzyme operates inside cells (cytosol) rather than being secreted, and it is encoded by the HNMT gene. In humans, a principal isoform appears to be produced, with expression levels influenced by tissue type, developmental stage, and possibly genetic variation. The histamine produced in local cells or entering cells can be inactivated through the HNMT pathway, while extracellular histamine tends to be metabolized by DAO in many peripheral compartments.

In the broader biology of histamine signaling, HNMT sits alongside other histamine catabolic routes. Histamine governs diverse physiological processes through its receptors Histamine receptors, influencing allergy and inflammation, gastric acid secretion, and neurotransmission. In the brain, HNMT contributes to the inactivation of neuronal histamine and thereby can affect processes such as wakefulness, cognition, and nociception. By contrast, peripheral histamine from dietary or inflammatory sources is often subject to DAO-mediated degradation prior to cellular uptake, highlighting a tissue-specific division of labor in histamine metabolism.

Genetics and variation in HNMT have drawn considerable scientific attention. A well-studied polymorphism is the Thr105Ile (rs1137071) variant, which in vitro tends to reduce catalytic activity. Population studies have yielded mixed results about associations with allergic diseases, migraine, and certain psychiatric or neurological conditions. Effect sizes in these studies are typically small, and replication across cohorts is inconsistent, reflecting the complex, multifactorial nature of these traits and potential gene-environment interactions. The relative contribution of HNMT activity to overall histamine balance can differ by tissue and context, so single polymorphisms rarely determine clinical outcomes on their own.

Pharmacology and clinical relevance of HNMT are mainly exploratory at this stage. Because HNMT modulates intracellular histamine levels, it has attracted interest as a potential modifier of histamine signaling in the central nervous system and in tissues involved in inflammation. Researchers have identified various small-molecule inhibitors of HNMT in laboratory studies, but there are no clinically approved drugs that target HNMT at present. In practice, antihistamines (agents that block histamine receptors) remain the standard clinical tool for managing many histamine-mediated conditions, and their effectiveness is not contingent on modulating HNMT activity. Nonetheless, understanding HNMT function can inform pharmacogenomic considerations and the interpretation of individual variations in histamine metabolism, particularly in the brain where histaminergic signaling plays a distinct role from peripheral histamine pathways.

Controversies and debates in the field center on the relative importance of HNMT versus DAO in different tissues, the strength and generalizability of associations between HNMT polymorphisms and disease phenotypes, and the translational potential of HNMT as a therapeutic target. Some researchers emphasize the brain-specific role of HNMT in shaping histamine tone and its possible influence on neurological phenotypes, while others stress that DAO-driven peripheral metabolism dominates histamine clearance in many contexts. Additionally, the clinical significance of modest genetic associations remains unsettled, as study design, sample size, population stratification, and environmental factors all shape outcome interpretation.

See also - Histamine - Histamine receptors - N-methylhistamine - Diamine oxidase - Monoamine oxidase - HNMT