Histamine is a biogenic amine that stimulates multiple histamine receptor types. In mammals, histamine is found within granules of basophils and mast cells (>90% of body stores) and within tuberomammillary neurons of the CNS. When released, histamine induces complex physiological and pathological effects, including allergic reactions, gastric acid secretion, multiple CNS-regulated effects, smooth muscle contraction and profound vasodilation that can lead to cardiovascular collapse.

In mammals, physiological levels of L-histidine are converted to histamine by specific L-histidine decarboxylase (HD), which differs from the nonspecific DOPA decarboxylase. α-Fluoromethylhistidine (α-FMH) has been shown to be an irreversible, highly selective "suicide" inhibitor of HD, although this mode of inhibition often has little or no immediate effect on histamine stores or transmission. Once released, histamine is metabolized almost exclusively by methylation or oxidation, the propensity of which varies between species and between tissues and organs within species. For example, in brain relatively small amounts of histamine are oxidized with most being methylated. As a survival mechanism, only traces of histamine escape metabolism, particularly following systemic injection or release, with inhibition of one metabolic route resulting in histamine being shunted to another.

Histamine is methylated at the imidazole nitrogen furthest from the ethylamine side chain (termed tele-N or Nt) by the enzyme histamine-N-methyltransferase (HMT) through a ping-pong mechanism using S-adenosyl-L-methionine as cofactor. The tele-methylhistamine (t-MH) produced is a substrate for monoamine oxidase-B (MAO-B) and semicarbazide-sensitive amine oxidases (SSAOs), such as diamine oxidase (DAO) and benzylamine oxidase (Bz.SSAO). The aldehyde intermediate is further oxidized by aldehyde dehydrogenase (ALD-DH) to tele-methylimidazoleacetic acid (t-MIAA). In rats, histamine possesses a Km value of ~10 mM for HMT yet shows substrate inhibition at 30-60 mM. Several substances inhibit HMT, of which tacrine (Ki <50 nM) and metoprine are among the most potent. t-MH also induces product inhibition.

In the oxidative pathway, histamine is oxidized by the SSAOs, particularly DAO and Bz.SSAO, but is a poor substrate for the MAOs. The resultant imidazolacetaldehyde is rapidly converted by ALD-DH to imidazole-4-acetic acid (IAA). IAA induces numerous effects in the CNS where it has been shown to act as both a GABAA receptor agonist and a GABAC receptor partial agonist. IAA is conjugated with phosphoribosyl-pyrophosphate by the action of imidazoleacetic acid 5´-phosphoribosyl transferase (IPRT) to produce imidazoleacetic acid-ribotide (IAA-RP), a compound that has been shown to behave as a potent ligand at multiple imidazoline binding sites (EC50~50 nM), in addition to displacing clonidine from its non α-adrenoceptor binding sites. Immunohistochemical studies have shown that IAA-RP is present in neurons throughout the brain. Both phosphatases and 5´-ecto-nucleotidases can convert IAA-RP to IAA-riboside (IAA-R); preliminary findings suggest a rank order of in vitro enzyme activities of alkaline-phosphatase> acid-phosphatase> 5´-ecto-nucleotidase.

Histamine' s oxidative products can also be derived from pathways independent of histamine. Thus, L-histidine-pyruvate aminotransferase (HPAT), recently termed kyneuramine aminotransferase (KAT) and glutamine transaminase-K (GTK), also leads to IAA production and appears to generate most of the IAA found in brain. In contrast, t-MH and t-MIAA are unique products of histamine metabolism. For example, in plasma and urine of patients with mastocytosis, a state of constant excessive systemic histamine release, levels of histamine may increase only slightly, while levels of t-MH and t-MIAA may increase by as much as 20-fold. Furthermore, because HMT is distal to sites of histamine release, levels of t-MH and t-MIAA together have been used as indices of general histaminergic activity.

The Table below contains accepted modulators and additional information. For a list of additional products, see the "Similar Products" section below.


a) The propensity for histamine to be methylated (by HMT) or oxidized directly (by DAO or other SSAOs) in mammals varies between species and varies between tissues and organs within species. However, in brains of all mammals, under physiological conditions, histamine is mainly methylated.


B24: 3,5-Diethoxy-4-aminomethylpyridine
Ro 16-6491: N-(2-Aminoethyl-4-chlorobenzamide
Ro 19-6327: Lazabemide
SKF 91488: 4-(N,N-Dimethylamino)butylisothiourea

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Battelle B, Hart MK. 2002. Histamine metabolism in the visual system of the horseshoe crab Limulus polyphemus. Comparative Biochemistry and Physiology Part A: Molecular & Integrative Physiology. 133(1):135-142. http://dx.doi.org/10.1016/s1095-6433(02)00133-2
Brown RE, Stevens DR, Haas HL. 2001. The physiology of brain histamine. Progress in Neurobiology. 63(6):637-672. http://dx.doi.org/10.1016/s0301-0082(00)00039-3
Furukawa F, Yoshimasu T, Yamamoto Y, Kanazawa N, Tachibana T. 2009. Mast cells and histamine metabolism in skin lesions from MRL/MP-lpr/lpr mice. Autoimmunity Reviews. 8(6):495-499. http://dx.doi.org/10.1016/j.autrev.2008.12.016
Hough L, G.J. Siegel B, Agranoff R, Albers S, Fisher M, Uhler. 1999. âHistamine.â in: Basic Neurochemistry. 293-313. Lippincott Raven, Philadelphia, PA:
Kinemuchi H. 2004. Selective Inhibitors of Membrane-Bound Semicarbazide-Sensitive Amine Oxidase (SSAO) Activity in Mammalian Tissues. NeuroToxicology. 25(1-2):325-335. http://dx.doi.org/10.1016/s0161-813x(03)00118-9
O'Sullivan J. 2004. Semicarbazide-Sensitive Amine Oxidases: Enzymes with Quite a Lot to Do. NeuroToxicology. 25(1-2):303-315. http://dx.doi.org/10.1016/s0161-813x(03)00117-7
Ogasawara M, Yamauchi K, Satoh Y, Yamaji R, Inui K, Jonker JW, Schinkel AH, Maeyama K. 2006. Recent Advances in Molecular Pharmacology of the Histamine Systems: Organic Cation Transporters as a Histamine Transporter and Histamine Metabolism. J Pharmacol Sci. 101(1):24-30. http://dx.doi.org/10.1254/jphs.fmj06001x6
Ohtsu H, Watanabe T. 2003. New functions of histamine found in histidine decarboxylase gene knockout mice. Biochemical and Biophysical Research Communications. 305(3):443-447. http://dx.doi.org/10.1016/s0006-291x(03)00696-x
Ohtsu H. 2010. Histamine Synthesis and Lessons Learned from Histidine Decarboxylase Deficient Mice.21-31. http://dx.doi.org/10.1007/978-1-4419-8056-4_3
Prell GD, Martinelli GP, Holstein GR, Matulic-Adamic J, Watanabe KA, Chan SLF, Morgan NG, Haxhiu MA, Ernsberger P. 2004. Imidazoleacetic acid-ribotide: An endogenous ligand that stimulates imidazol(in)e receptors. Proceedings of the National Academy of Sciences. 101(37):13677-13682. http://dx.doi.org/10.1073/pnas.0404846101
Prell GD, Morrishow AM, Duoyon E, Lee WS. Inhibitors of Histamine Methylation in Brain Promote Formation of Imidazoleacetic Acid, Which Interacts with GABA Receptors. Journal of Neurochemistry. 68(1):142-151. http://dx.doi.org/10.1046/j.1471-4159.1997.68010142.x
Smits RA, Leurs R, de Esch IJ. 2009. Major advances in the development of histamine H4 receptor ligands. Drug Discovery Today. 14(15-16):745-753. http://dx.doi.org/10.1016/j.drudis.2009.05.007
Thomas B, Prell GD. Imidazoleacetic Acid, a ?-Aminobutyric Acid Receptor Agonist, Can Be Formed in Rat Brain by Oxidation of Histamine. Journal of Neurochemistry. 65(2):818-826. http://dx.doi.org/10.1046/j.1471-4159.1995.65020818.x
Tunnicliff G. 1998. Pharmacology and Function of Imidazole 4-Acetic Acid in Brain. General Pharmacology: The Vascular System. 31(4):503-509. http://dx.doi.org/10.1016/s0306-3623(98)00079-2
Weinshilboum RM, Otterness DM, Szumlanski CL. 1999. METHYLATION PHARMACOGENETICS: Catechol O-Methyltransferase, Thiopurine Methyltransferase, and Histamine N-Methyltransferase. Annu. Rev. Pharmacol. Toxicol.. 39(1):19-52. http://dx.doi.org/10.1146/annurev.pharmtox.39.1.19
Yamaguchi K. 2000. Induction of histidine decarboxylase, the histamine-forming enzyme, in mice by interleukin-12. 156(1):57-65. http://dx.doi.org/10.1016/s0300-483x(00)00324-3

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