histamine n methyltransferase


Summary: An enzyme that catalyzes the transfer of a methyl group from S-adenosylmethionine to histamine, forming N-methylhistamine, the major metabolite of histamine in man. EC

Top Publications

  1. Horton J, Sawada K, Nishibori M, Cheng X. Structural basis for inhibition of histamine N-methyltransferase by diverse drugs. J Mol Biol. 2005;353:334-344 pubmed publisher
    ..The maximized shape complementarity between the protein aromatic side-chains and aromatic ring(s) of the inhibitors are responsible for the tight binding of these varied inhibitors. ..
  2. Taraschenko O, Barnes W, Herrick Davis K, Yokoyama Y, Boyd D, Hough L. Actions of tacrine and galanthamine on histamine-N-methyltransferase. Methods Find Exp Clin Pharmacol. 2005;27:161-5 pubmed
    ..Galanthamine (up to 10 microM) did not influence the activity of rat kidney or human HNMT. Tacrine, but not galanthamine, may achieve brain levels sufficient to influence histamine metabolism in some patients treated for AD. ..
  3. Horton J, Sawada K, Nishibori M, Zhang X, Cheng X. Two polymorphic forms of human histamine methyltransferase: structural, thermal, and kinetic comparisons. Structure. 2001;9:837-49 pubmed
    ..The interactions between HNMT and quinacrine provide the first structural insights into a large group of pharmacologic HNMT inhibitors and their mechanisms of inhibition. ..
  4. Nishibori M, Tahara A, Sawada K, Sakiyama J, Nakaya N, Saeki K. Neuronal and vascular localization of histamine N-methyltransferase in the bovine central nervous system. Eur J Neurosci. 2000;12:415-24 pubmed
    ..The localization of HMT in the blood vessel wall may mean that blood-borne histamine and histamine released from mast cells associated with the blood vessels are catabolized in this structure. ..
  5. Hon Y, Jusko W, Spratlin V, Jann M. Altered methylprednisolone pharmacodynamics in healthy subjects with histamine N-methyltransferase C314T genetic polymorphism. J Clin Pharmacol. 2006;46:408-17 pubmed
    ..031 and .033, respectively, Wilcoxon rank sum test). Subjects who are heterozygous for the T314 variant allele thus appeared less sensitive to the suppressive effects of methylprednisolone on cortisol secretion. ..
  6. Garcia Martin E, Mendoza J, Martinez C, Taxonera C, Urcelay E, Ladero J, et al. Severity of ulcerative colitis is associated with a polymorphism at diamine oxidase gene but not at histamine N-methyltransferase gene. World J Gastroenterol. 2006;12:615-20 pubmed
    ..The His645Asp polymorphism of the histamine metabolising enzyme ABP1 is related to severity of ulcerative colitis. ..
  7. Takemura M, Tanaka T, Taguchi Y, Imamura I, Mizuguchi H, Kuroda M, et al. Histamine N-methyltransferase from rat kidney. Cloning, nucleotide sequence, and expression in Escherichia coli cells. J Biol Chem. 1992;267:15687-91 pubmed
    ..All of the inhibitors of the natural enzyme tested showed similar Ki values on both recombinant and natural enzyme. ..
  8. Yan L, Galinsky R, Bernstein J, Liggett S, Weinshilboum R. Histamine N-methyltransferase pharmacogenetics: association of a common functional polymorphism with asthma. Pharmacogenetics. 2000;10:261-6 pubmed
  9. Chen G, Wang W, Xu Z, Zhu B, Wang L, Zhou G, et al. Genotype-phenotype correlation for histamine N-methyltransferase in a Chinese Han population. Clin Chim Acta. 2003;334:179-83 pubmed
    ..Additional unknown genetic or epigenetic factors should also play important roles in the regulation of HNMT activity. ..

More Information


  1. Chen G, Xu Z, Wang W, Wang G, Zhou G, Wang D, et al. Analysis of the C314T and A595G mutations in histamine N-methyltransferase gene in a Chinese population. Clin Chim Acta. 2002;326:163-7 pubmed
  2. Aschenbach J, Ahrens F, Garz B, Gäbel G. Paracellular tightness and catabolism restrict histamine permeation in the proximal colon of pigs. Pflugers Arch. 2002;445:115-22 pubmed
    ..It is concluded that histamine permeation across the porcine proximal colon is restricted by low permeability and sequential catabolism by histamine N-methyltransferase and diamine oxidase. ..
  3. Garcia Martin E, García Menaya J, Sanchez B, Martinez C, Rosendo R, Agúndez J. Polymorphisms of histamine-metabolizing enzymes and clinical manifestations of asthma and allergic rhinitis. Clin Exp Allergy. 2007;37:1175-82 pubmed
    ..However, patients carrying the His645Asp polymorphism of ABP1 are more prone to developing symptoms with lower IgE levels. ..
  4. Ogasawara M, Yamauchi K, Satoh Y, Yamaji R, Inui K, Jonker J, et al. Recent advances in molecular pharmacology of the histamine systems: organic cation transporters as a histamine transporter and histamine metabolism. J Pharmacol Sci. 2006;101:24-30 pubmed
  5. Aschenbach J, Schwelberger H, Ahrens F, Fürll B, Gäbel G. Histamine inactivation in the colon of pigs in relationship to abundance of catabolic enzymes. Scand J Gastroenterol. 2006;41:712-9 pubmed
    ..While previous studies have shown that colonic HMT essentially catabolizes the bulk of histamine during permeation, DAO activity seems to be more variable and limiting for the overall efficiency of the catabolic process. ..
  6. Chen G, Wang H, Wang W, Xu Z, Zhou G, He F, et al. Histamine N-methyltransferase gene polymorphisms in Chinese and their relationship with enzyme activity in erythrocytes. Pharmacogenetics. 2003;13:389-97 pubmed
  7. Kim S, Krapfenbauer K, Cheon M, Fountoulakis M, Cairns N, Lubec G. Human brain cytosolic histamine-N-methyltransferase is decreased in Down syndrome and increased in Pick's disease. Neurosci Lett. 2002;321:169-72 pubmed
    ..Decreased HMT in DS would be compatible with findings of decreased histamine synthesis, thus reflecting a compensation mechanism to antagonize reduced synthesis by decreased degradation. ..
  8. Kitanaka J, Kitanaka N, Tsujimura T, Terada N, Takemura M. Histamine N-methyltransferase regulates histamine-induced phosphoinositide hydrolysis in guinea pig cerebellum. Neurosci Lett. 2001;308:5-8 pubmed
    ..These observations suggest that HMT regulates histaminergic neurotransmission in guinea pig cerebellum more predominantly than diamine oxidase in histamine degradation. ..
  9. Garcia Martin E, Ayuso P, Martinez C, Blanca M, Agundez J. Histamine pharmacogenomics. Pharmacogenomics. 2009;10:867-83 pubmed publisher
    ..This review summarizes relevant polymorphisms, discusses controversial findings on association of histamine-related polymorphisms and allergies and other diseases, and identifies topics requiring further investigation. ..
  10. Imajo N, Matsui S, Yasui Y, Matsui N, Fukuishi N, Akagi M. The protective effect of H2-receptor activation against the duration of myocardial hypoxia/reoxygenation-induced ventricular fibrillation in sensitized guinea-pig hearts. J Pharmacol Sci. 2005;99:400-7 pubmed
  11. Yamauchi K, Sekizawa K, Suzuki H, Nakazawa H, Ohkawara Y, Katayose D, et al. Structure and function of human histamine N-methyltransferase: critical enzyme in histamine metabolism in airway. Am J Physiol. 1994;267:L342-9 pubmed
    ..In situ chromosomal hybridization demonstrated that human HMT gene was localized in chromosome 1 p32...
  12. Kang Y, Kim S, Cho B, Ye Y, Hur G, Park H. Histamine N-methyltransferase 939A>G polymorphism affects mRNA stability in patients with acetylsalicylic acid-intolerant chronic urticaria. Allergy. 2009;64:213-21 pubmed publisher
    ..The HNMT 939A>G polymorphism lowers HNMT enzymatic activity by decreasing HNMT mRNA stability, which leads to an increase in the histamine level and contributes to the development of AICU. ..
  13. Vinogradova L, Shatskova A, Tuomisto L. Histaminergic modulation of acoustically induced running behavior in rats. Brain Res. 2007;1148:198-204 pubmed
    ..Possible roles of histaminergic mechanisms in seizure, motor and aversive aspects of sound-induced running are discussed. ..
  14. Petroianu G, Arafat K, Sasse B, Stark H. Multiple enzyme inhibitions by histamine H3 receptor antagonists as potential procognitive agents. Pharmazie. 2006;61:179-82 pubmed
    ..The compounds acting as hybrid drugs simultaneously on four different targets to enhance cognitive functions via different pathways are promising lead structures for a new approach in the treatment of Alzheimer's disease. ..
  15. Abe Y, Ogino S, Irifune M, Imamura I, Liu Y, Fukui H, et al. Histamine content, synthesis and degradation in nasal mucosa and lung of guinea-pigs treated with toluene diisocyanate (TDI). Clin Exp Allergy. 1993;23:512-7 pubmed
    ..These data suggest that the turnover rate of histamine is increased in the nasal mucosa and the lung of guinea pigs with respiratory hypersensitivity. ..
  16. Stevenson J, Sonuga Barke E, McCann D, Grimshaw K, Parker K, Rose Zerilli M, et al. The role of histamine degradation gene polymorphisms in moderating the effects of food additives on children's ADHD symptoms. Am J Psychiatry. 2010;167:1108-15 pubmed publisher
    ..Genes influencing a range of neurotransmitter systems and their interplay with environmental factors, such as diet, need to be examined to understand genetic influences on ADHD symptoms. ..
  17. Rajtar S, Irman Florjanc T. Amitriptyline affects histamine-N-methyltransferase and diamine oxidase activity in rats and guinea pigs. Eur J Pharmacol. 2007;574:201-8 pubmed
    ..Our study proved that amitriptyline enhances the histamine degrading processes in guinea pig, what might importantly contribute to lower histamine levels. ..
  18. Harle D, Baldo B. Structural features of potent inhibitors of rat kidney histamine N-methyltransferase. Biochem Pharmacol. 1988;37:385-8 pubmed
    ..Investigation of the structure-activity relationships by examining space-filling models revealed marked similarities in the conformations of the arrangement of three N atoms in histamine and in each of the compounds tested. ..
  19. Jochem J, Zwirska Korczala K, Rybus Kalinowska B, Jagodzinska J, Korzonek Szlacheta I. Influence of SKF 91488, histamine N-methyltransferase inhibitor, on the central cardiovascular regulation during controlled, stepwise hemorrhagic hypotension in rats. Pol J Pharmacol. 2002;54:237-44 pubmed
    ..In conclusion, the study demonstrates that the histaminergic system influences the central cardiovascular regulation during pronounced hemorrhagic hypotension, probably as a result of the activation of compensatory mechanisms. ..
  20. Vinod P, Konkimalla B, Chandra N. In-silico pharmacodynamics: correlation of adverse effects of H2-antihistamines with histamine N-methyl transferase binding potential. Appl Bioinformatics. 2006;5:141-50 pubmed
    ..Implications for design of safer H(2)-antihistamines are discussed. The method reported here has the potential for application as a general strategy in understanding drug effects. ..
  21. Cleary J, Schwartz M, Rogers P, de Mestral J, Chapman S. Effects of amphotericin B and caspofungin on histamine expression. Pharmacotherapy. 2003;23:966-73 pubmed
    ..These data suggest that infusion-related reactions associated with caspofungin may be mediated by histamine release secondary to caspofungin. ..
  22. Garcia Martin E, Martinez C, Benito Leon J, Calleja P, Diaz Sanchez M, Pisa D, et al. Histamine-N-methyl transferase polymorphism and risk for multiple sclerosis. Eur J Neurol. 2010;17:335-8 pubmed publisher
    ..The HNMT polymorphism is not related with the risk for MS. ..
  23. Oroszi G, ENOCH M, Chun J, Virkkunen M, Goldman D. Thr105Ile, a functional polymorphism of histamine N-methyltransferase, is associated with alcoholism in two independent populations. Alcohol Clin Exp Res. 2005;29:303-9 pubmed
    ..070) after correcting for alcoholism diagnosis. Decreased levels of brain histamine consequent to the Thr105 allele may result in higher levels of anxiety and, as a consequence, vulnerability to alcoholism. ..
  24. Feurle J, Rajtar S, Irman Florjanc T, Schwelberger H. Molecular cloning of guinea-pig diamine oxidase and histamine N-methyltransferase. Inflamm Res. 2006;55 Suppl 1:S59-60 pubmed
  25. Jochem J. Involvement of the sympathetic nervous system in the reversal of critical haemorrhagic hypotension by endogenous central histamine in rats. Naunyn Schmiedebergs Arch Pharmacol. 2004;369:418-27 pubmed
    ..In conclusion, the study demonstrates the activation of the sympathetic nervous system elicited by endogenous central histamine in haemorrhage-shocked rats and confirms its involvement in histamine-induced resuscitation. ..
  26. Osredkar D, Burnik Papler T, Pecavar B, Kralj Iglic V, Krzan M. Kinetic and pharmacological properties of [(3)H]-histamine transport into cultured type 1 astrocytes from neonatal rats. Inflamm Res. 2009;58:94-102 pubmed publisher
    ..Taken up histamine can be converted to tele-methylhistamine within astrocytes thus indicating the involvement of astrocytes not only in clearance but also in the inactivation of histamine. ..
  27. Agundez J, Luengo A, Herraez O, Martinez C, Alonso Navarro H, Jimenez Jimenez F, et al. Nonsynonymous polymorphisms of histamine-metabolising enzymes in patients with Parkinson's disease. Neuromolecular Med. 2008;10:10-6 pubmed
    ..0001). These results, combined with previous findings indicating alterations in histamine levels in patients with PD, suggest that alterations of histamine homeostasis in the SNC are associated with the risk for PD. ..
  28. Wang L, Thomae B, Eckloff B, Wieben E, Weinshilboum R. Human histamine N-methyltransferase pharmacogenetics: gene resequencing, promoter characterization, and functional studies of a common 5'-flanking region single nucleotide polymorphism (SNP). Biochem Pharmacol. 2002;64:699-710 pubmed
    ..These results represent an additional step in the definition of molecular genetic mechanisms involved in the regulation of this important autacoid-metabolizing enzyme in humans. ..
  29. Kitanaka N, Kitanaka J, Oue T, Tada Y, Tanaka T, Takemura M. Genomic structure of the rat and mouse histamine N-methyltransferase gene. Jpn J Pharmacol. 2002;88:85-92 pubmed
    ..This observation may explain the species difference of the tissue expression pattern of HMT mRNA. ..
  30. Aschenbach J, Honscha K, von Vietinghoff V, Gabel G. Bioelimination of histamine in epithelia of the porcine proximal colon of pigs. Inflamm Res. 2009;58:269-76 pubmed publisher
    ..Histamine is partially released back into the blood after initial biotransformation to 1-MH. ..
  31. Ledesma M, Garcia Martin E, Alonso Navarro H, Martinez C, Jimenez Jimenez F, Benito Leon J, et al. The nonsynonymous Thr105Ile polymorphism of the histamine N-methyltransferase is associated to the risk of developing essential tremor. Neuromolecular Med. 2008;10:356-61 pubmed publisher
  32. Kuefner M, Schwelberger H, Weidenhiller M, Hahn E, Raithel M. Both catabolic pathways of histamine via histamine-N-methyltransferase and diamine oxidase are diminished in the colonic mucosa of patients with food allergy. Inflamm Res. 2004;53 Suppl 1:S31-2 pubmed
  33. Barnes W, Grinde E, Crawford D, Herrick Davis K, Hough L. Characterization of a new mRNA species from the human histamine N-methyltransferase gene. Genomics. 2004;83:168-71 pubmed
    ..These studies show that HNMT-S is a new mRNA species and putative protein product from HNMT. The physiological role of HNMT-S remains to be investigated. ..
  34. Apelt J, Ligneau X, Pertz H, Arrang J, Ganellin C, Schwartz J, et al. Development of a new class of nonimidazole histamine H(3) receptor ligands with combined inhibitory histamine N-methyltransferase activity. J Med Chem. 2002;45:1128-41 pubmed
  35. Wang L, Yan L, McGuire C, Kozak C, Wang M, Kim U, et al. Mouse histamine N-methyltransferase: cDNA cloning, expression, gene cloning and chromosomal localization. Inflamm Res. 2001;50:300-8 pubmed
    ..Cloning and functional characterization of the mouse HNMT cDNA and gene will now make it possible to study in the mouse molecular genetic mechanisms involved the regulation of this important histamine-metabolizing enzyme. ..
  36. Saito S, Iida A, Sekine A, Miura Y, Sakamoto T, Ogawa C, et al. Identification of 197 genetic variations in six human methyltranferase genes in the Japanese population. J Hum Genet. 2001;46:529-37 pubmed
    ..These variants may contribute to a more precise understanding of possible correlations between genotypes and disease-susceptibility phenotypes or risk for side effects from drugs. ..
  37. Yawata I, Tanaka K, Nakagawa Y, Watanabe Y, Murashima Y, Nakano K. Role of histaminergic neurons in development of epileptic seizures in EL mice. Brain Res Mol Brain Res. 2004;132:13-7 pubmed
    ..They inhibit convulsion in a H1-dependent fashion, while the neurons enhance it in a H3-receptor-mediated way. ..
  38. Klaus A, Weiss H, Nguyen J, Margreiter R, Obrist P, Schwelberger H. Histamine-degrading enzymes as cellular markers of acute small bowel allograft rejection. Transpl Int. 2003;16:474-9 pubmed
    ..01). We can conclude that DAO and HNMT activities in gut mucosa are reliable quantitative markers of acute intestinal allograft rejection in the rat that support histopathological analysis. ..
  39. Grassmann S, Apelt J, Sippl W, Ligneau X, Pertz H, Zhao Y, et al. Imidazole derivatives as a novel class of hybrid compounds with inhibitory histamine N-methyltransferase potencies and histamine hH3 receptor affinities. Bioorg Med Chem. 2003;11:2163-74 pubmed
    ..The most interesting compound (14) is simultaneously a highly potent H(3) receptor ligand (K(i)=4.1nM) and a highly potent HMT inhibitor (IC(50)=24nM), which makes this derivative a valuable pharmacological tool for further development. ..
  40. Torres M, Ace C, Okulicz W. Assessment and application of laser microdissection for analysis of gene expression in the rhesus monkey endometrium. Biol Reprod. 2002;67:1067-72 pubmed
  41. Farag N, Mohamed S, Soliman G. Design, synthesis, and docking studies of novel benzopyrone derivatives as H(1)-antihistaminic agents. Bioorg Med Chem. 2008;16:9009-17 pubmed publisher
    ..Also, it was concluded that in order for the compounds to be active, they must bind with both active sites of HNMT enzyme (two pockets) to inhibit it. Compounds 8c, 8i, 11g, 11i, and 11k; observe the maximum activities. ..
  42. Kennedy M, Loehle J, Griffin A, Doll M, Kearns G, Sullivan J, et al. Association of the histamine N-methyltransferase C314T (Thr105Ile) polymorphism with atopic dermatitis in Caucasian children. Pharmacotherapy. 2008;28:1495-501 pubmed publisher
    ..Additional longitudinal studies will be required to assess the relationship between genotype, disease severity, and antihistamine response. ..
  43. Aksoy S, Raftogianis R, Weinshilboum R. Human histamine N-methyltransferase gene: structural characterization and chromosomal location. Biochem Biophys Res Commun. 1996;219:548-54 pubmed
    ..HNMT mapped to human chromosome 2. Structural characterization of the gene for HNMT will make it possible to study molecular genetic mechanisms involved in the regulation of this important enzyme in humans. ..
  44. Reuter M, Jeste N, Klein T, Hennig J, Goldman D, ENOCH M, et al. Association of THR105Ile, a functional polymorphism of histamine N-methyltransferase (HNMT), with alcoholism in German Caucasians. Drug Alcohol Depend. 2007;87:69-75 pubmed
  45. Preuss C, Wood T, Szumlanski C, Raftogianis R, Otterness D, Girard B, et al. Human histamine N-methyltransferase pharmacogenetics: common genetic polymorphisms that alter activity. Mol Pharmacol. 1998;53:708-17 pubmed
    ..These observations will make it possible to test the hypothesis that genetic polymorphisms for HNMT may play a role in the pathophysiology of human disease. ..
  46. Schwelberger H, Drasche A. Structure and expression of porcine histamine N-methyltransferase. Inflamm Res. 2002;51 Suppl 1:S85-6 pubmed
  47. Jochem J. Cardiac and regional haemodynamic effects of histamine N-methyltransferase inhibitor metoprine in haemorrhage-shocked rats. Inflamm Res. 2004;53:316-23 pubmed
    ..05 vs. the saline-pre-treated group). The results support the hypothesis that histaminergic system activation leads to mobilisation of compensatory mechanisms in haemorrhagic hypotension. ..
  48. Girard B, Otterness D, Wood T, Honchel R, Wieben E, Weinshilboum R. Human histamine N-methyltransferase pharmacogenetics: cloning and expression of kidney cDNA. Mol Pharmacol. 1994;45:461-8 pubmed
    ..3, 3.8, and 4.0 kilobases in length. Cloning of a cDNA for HNMT may now make it possible to determine the molecular basis for the HNMT genetic polymorphism in humans. ..
  49. Inoue H, Hisamatsu K, Yamauchi M, Kumagai N. Rapid and simple determination of histamine-N-methyl transferase activity by high-performance liquid chromatography with UV detection. Mediators Inflamm. 2001;10:273-7 pubmed
    ..Therefore, the present method could be applicable for the enzymatic investigation of histamine metabolism in central nervous system or inflammatory reactions. ..
  50. Kuefner M, Schwelberger H, Hahn E, Raithel M. Decreased histamine catabolism in the colonic mucosa of patients with colonic adenoma. Dig Dis Sci. 2008;53:436-42 pubmed
    ..A significant correlation was found between HNMT and DAO in all investigated samples. Histamine concentrations were elevated in adenoma patients. Histamine catabolism is decreased in the colonic mucosa of patients with colonic adenoma. ..
  51. Jochem J. Involvement of the renin-angiotensin system in endogenous central histamine-induced reversal of critical haemorrhagic hypotension in rats. J Physiol Pharmacol. 2004;55:39-55 pubmed
    ..Neither capropril, nor angiotensin receptor antagonists influence the survival at 2 h after treatment. In conclusion, the renin-angiotensin system is involved in central histamine-induced resuscitating action in rats. ..
  52. Hon Y, Jusko W, Zhou H, Chen G, Guo D, Zhou G, et al. Endogenous histamine and cortisol levels in subjects with different histamine N-methyltransferase C314T genotypes : a pilot study. Mol Diagn Ther. 2006;10:109-14 pubmed
    ..Wide variability of plasma and whole-blood histamine levels was observed in subjects with different HNMT C314T genotypes. Endogenous levels of histamine are likely to be affected by various genes and polymorphisms. ..
  53. Futo J, Kupferberg J, Moss J. Inhibition of histamine N-methyltransferase (HNMT) in vitro by neuromuscular relaxants. Biochem Pharmacol. 1990;39:415-20 pubmed
    ..2 to 44.8 microM. Our data suggest that HNMT-based radioenzymatic assays for histamine should be susceptible to inhibition by concurrent use of NMRs, particularly vecuronium. ..