Diamine oxidase explained

Diamine oxidase
Ec Number:1.4.3.22
Go Code:0052600

Diamine oxidase (DAO), also known "amine oxidase, copper-containing, 1" (AOC1), formerly called histaminase,[1] is an enzyme involved in the metabolism, oxidation, and inactivation of histamine and other polyamines such as putrescine or spermidine. The enzyme belongs to the amine oxidase (copper-containing) (AOC) family of amine oxidase enzymes.

The enzyme is expressed in bilateria, a biological group of animals. The enzyme is encoded by the AOC1 gene. This gene is highly conserved across the bilateria group which includes mammals, birds, reptiles, fish and insects, to name a few.

Chemical activity

Histamine metabolites

Histamine, a biogenic amine, undergoes metabolism through three distinct enzymatic pathways:[2]

  1. The first pathway (see the reaction illustrated below) involves the deamination of histamine by the enzyme diamine oxidase to form imidazoleacetic acid.[2]
  2. In the second pathway, histamine is metabolized into Nτ-methylhistamine (also known as 1-Methylhistamine), which also has some biological activity, albeit much weaker than that of histamine.[3] Still, NMT, being a product in a reaction catalyzed by HNMT, may inhibit expression of HNMT in a negative feedback loop.[4] This reaction is Nτ-methylation of histamine by the histamine N-methyltransferase (HNMT) enzyme. The Nτ-methylhistamine, unless excreted by the kindney, is subsequently oxidized into Nτ-methylimidazoleacetic acid (NτMIAA) by the enzyme monoamine oxidase (MAO). This two-step process effectively reduces the activity of histamine in the body and is particularly important for quick deactivation of histamine in the brain.[2]
  3. The third pathway involves the acetylation of histamine by an acetylase to form 4-(-acetylaminoethyl)imidazole. However, it’s important to note that this pathway is found exclusively in enterobacteria and has not been identified in mammals. This suggests a unique metabolic pathway for histamine in these bacteria.[2]

These pathways highlight the complex and varied mechanisms through which histamine is metabolized in different organisms. Understanding these pathways is crucial for biomedical professionals as it can provide insights into the regulation of histamine levels and its role in various physiological and pathological processes.[2] DAO catalyzes the oxidative deamination of polyamines, such as histamine and putrescine, to produce aminoaldehydes,[2] hydrogen peroxide,[2] and ammonia.[2]

Reaction catalyzed by DAO

DAO metabolizes histamine into imidazole-4-acetaldehyde:

Imidazole-4-acetaldehyde is then further oxidized by a NAD-dependent aldehyde dehydrogenase, leading to imidazole-4-acetic acid,[5] which is also called 1,4–metil-imidazolacetic acid.[6]

Commercial laboratories provide a 24-hour urine sample test for 1,4–metil-imidazolacetic acid, the metabolite of histamine. This test is a valuable tool in assessing the metabolism of histamine in the body.[7] [8]

Histamine, a biogenic amine, involves many physiological functions, including the immune response, gastric acid secretion, and neuromodulation. However, its rapid metabolism makes it challenging to measure histamine levels directly in plasma.[9]

As a solution for the rapid metabolism of histamine, the measurement of histamine and its metabolites, particularly the 1,4–metal-imidazole acetic acid in a 24-hour urine sample, provides an efficient alternative to histamine measurement because the values of these metabolites remain elevated for a much longer period than the histamine itself.[10]

The urine test involves collecting all urine produced in a 24-hour period, which is then analyzed for the presence of 1,4–metil-imidazolacetic acid. This comprehensive approach ensures a more accurate reflection of histamine metabolism over an extended period; as such, the 1,4–metil-imidazolacetic acid urine test offered by commercial labs is currently the most reliable method to determine the rate of histamine metabolism, which may be helpful for the health care practitioners to assess individual’s health status,[11] [12] such as to diagnose interstitial cystitis.[13]

Biological role

DAO is involved in the physiology of digestion and other physiological processes, such as inflammation, immune response, and wound healing. Dysfunction of DAO has been associated with various diseases, including allergies, autoimmune disorders, and cancer. DAO also plays a role in healthy pregnancy in placental mammals.

In case of a shortage or low enzymatic activity of diamine oxidase in the human body, it may appear as an allergy or histamine intolerance.[14] [15] [16]

Expression

In placental mammals, including humans, the highest levels of DAO expression are observed in the digestive tract (intestinal mucosa) and the placenta. DAO expression is also observed in kidney of various species.

DAO is also expressed in eosinophils.[17] [18]

The role in human pregnancy

In humans, a certain subtype of cells of the placenta, namely the extravillous trophoblasts, express the enzyme and secrete it into the blood stream of a pregnant woman.[19]

During pregnancy, DAO plays a crucial role in maintaining fetal growth and development by regulating histamine levels.[19] DAO levels in the blood circulation increases vastly in pregnant women suggesting a protective mechanism against adverse histamine. Histamine is a potent vasodilator and can cause uterine contractions, which can lead to premature labor. DAO in the placenta breaks down histamine to prevent its accumulation and maintain a healthy pregnancy. Low levels of DAO in the placenta may contribute to preeclampsia, a pregnancy-related disorder characterized by mother's high blood pressure and damage to mother's organs such as the liver and kidneys; the baby may also be affected if the condition is severe or left untreated, but it is not the primary target of the disorder.

Lowered diamine oxidase values in maternal blood in early pregnancy might be an indication for trophoblast-related pregnancy disorders like early-onset preeclampsia.[20]

Supplementation

Exogenous DAO (supplements) are being studied as complementary treatment[21] for the relief of symptoms associated with histamine intolerance, and for the relief of other conditions, such as migraine[22] or fibromyalgia.[23] However, the results are inconclusive because studies to date have involved small study populations and short intervention periods.[24] [25] [26]

In the United States, DAO supplements are available over the counter but are not FDA-approved.[27]

In Europe, two investigations, financially backed by the manufacturer of the oral DAO supplementation, have posited that DAO supplementation could alleviate patient symptoms. The first study sought to "objectify and quantify histamine-associated symptoms and to analyze whether oral administration of the histamine-degrading enzyme DAO caused a reduction of symptoms". In this study, neither major nor minor symptoms could be replicated in 39 patients who initially responded to an open challenge with 75 mg histamine in peppermint tea, using a double-blind, placebo-controlled challenge. Consequently, the primary endpoint of the study was not achieved, and the basis for the authors' conclusion that DAO supplementation intake resulted in a "statistically significant reduction in symptoms" remains unclear. The second study was purely observational, lacking a control group: it compared symptomatology with and without DAO use in 28 patients. The chosen design was not suitable to demonstrate causal effects and carried a high risk of attributing placebo effects. The effectiveness of DAO supplementation has not been scientifically validated and is not recommended by the medical associations in Germany, Austria and Switzerland.[28]

Research directions

DAO is related on possible links to migraine conditions. During migraine episodes, there is a noted elevation in the plasma concentrations of both calcitonin gene-related peptide (CGRP) and histamine. These substances are known for their potent vasodilatory effects and have been observed to mutually stimulate each other's release within the trigeminovascular system, potentially contributing to the onset of migraines, so that individuals with genetic variants in the DAO gene often experience migraines when consuming a diet high in histamine. As such, exploring the functional interplay between exogenous histamine and CGRP could provide valuable insights into the mechanisms underlying diet-induced migraines. This area of research continues to be actively investigated.[29]

Notes and References

  1. Wolvekamp MC, de Bruin RW . Diamine oxidase: an overview of historical, biochemical and functional aspects . Digestive Diseases . 12 . 1 . 2–14 . 1994 . 8200121 . 10.1159/000171432 .
  2. Determination of Nτ-methylimidazoleacetic acid (A histamine metabolite) in urine by gas chromatography using nitrogen-phosphorus detection . 10.1016/0009-8981(82)90247-9 . 1982 . Clinica Chimica Acta . 121 . 3 . 379–387 . 6955073 . Keyzer J, Wolthers B, Breukelman H, Kauffman H, De Monchy J .
  3. Book: 10.1007/978-90-481-9349-3_4. Biological and Pharmacological Aspects of Histamine Receptors and Their Ligands . Biomedical Aspects of Histamine . 2010 . Mohammed T. 61–100 . Springer . 978-90-481-9348-6 .
  4. 25164630 . 2009 . Histamine: Metabolism, physiology, and pathophysiology with applications in veterinary medicine . Journal of Veterinary Emergency and Critical Care (San Antonio, Tex. : 2001) . 19 . 4 . 311–328 . 10.1111/j.1476-4431.2009.00434.x . Peters LJ, Kovacic JP .
  5. 28321587 . 2017 . Analytical Methods for the Quantification of Histamine and Histamine Metabolites . Handbook of Experimental Pharmacology . 241 . 3–19 . 10.1007/164_2017_22 . 978-3-319-58192-7 . Bähre H, Kaever V .
  6. Web site: PubChem . 2-(1-methyl-1H-imidazol-4-yl)acetic acid . 2024-08-18 . pubchem.ncbi.nlm.nih.gov . en . 18 August 2024 . https://web.archive.org/web/20240818204421/https://pubchem.ncbi.nlm.nih.gov/compound/2-_1-methyl-1H-imidazol-4-yl_acetic-acid#section=Synonyms . live .
  7. Development of a HILIC-MS/MS method for the quantification of histamine and its main metabolites in human urine samples . 10.1016/j.talanta.2020.121328 . 2020 . Talanta . 220 . 32928382 . Nelis M, Decraecker L, Boeckxstaens G, Augustijns P, Cabooter D .
  8. Web site: Acid 1,4–metil-imidazolacetic (Metabolit histamina) . 18 August 2024 . 16 April 2024 . https://web.archive.org/web/20240416223457/https://www.synevo.ro/shop/acid-14-metil-imidazolacetic-metabolit-histamina/ . live .
  9. New approach for the diagnosis of histamine intolerance based on the determination of histamine and methylhistamine in urine . 10.1016/j.jpba.2017.06.029 . 2017 . Journal of Pharmaceutical and Biomedical Analysis . 145 . 379–385 . 28715791 . Comas-Basté O, Latorre-Moratalla M, Bernacchia R, Veciana-Nogués M, Vidal-Carou M . 18 August 2024 . 18 August 2024 . https://web.archive.org/web/20240818203311/https://www.sciencedirect.com/unsupported_browser . live .
  10. Gas chromatographic analysis of histamine metabolites in urine . 10.1016/S0021-9673(01)98675-3 . 1966 . Journal of Chromatography A . 23 . 2 . 207–216 . 4165374 . Tham R . 18 August 2024 . 18 August 2024 . https://web.archive.org/web/20240818203222/https://www.sciencedirect.com/unsupported_browser . live .
  11. New approach for the diagnosis of histamine intolerance based on the determination of histamine and methylhistamine in urine . 10.1016/j.jpba.2017.06.029 . 2017 . Journal of Pharmaceutical and Biomedical Analysis . 145 . 379–385 . 28715791 . Comas-Basté O, Latorre-Moratalla M, Bernacchia R, Veciana-Nogués M, Vidal-Carou M . 18 August 2024 . 18 August 2024 . https://web.archive.org/web/20240818203311/https://www.sciencedirect.com/unsupported_browser . live .
  12. Stimulated Release of Urine Histamine in Interstitial Cystitis . 10.1016/S0022-5347(17)36844-1 . 1992 . Journal of Urology . 148 . 4 . 1145–1148 . 1404625 . Yun SK, Laub DJ, Weese DL, Lad PM, Leach GE, Zimmern PE . 18 August 2024 . 18 August 2024 . https://web.archive.org/web/20240818203231/https://www.auajournals.org/doi/10.1016/S0022-5347%2817%2936844-1 . live .
  13. Increased Urine Histamine and Methylhistamine in Interstitial Cystitis . 10.1016/S0022-5347(17)32737-4 . 1994 . Journal of Urology . 152 . 2 Part 1 . 350–353 . 8015069 . El-Mansoury M, Boucher W, Sant G, Theoharides T . subscription .
  14. Arih K, Đorđević N, Košnik M, Rijavec M . Evaluation of Serum Diamine Oxidase as a Diagnostic Test for Histamine Intolerance . Nutrients . 15 . 19 . October 2023 . 4246 . 37836530 . 10574399 . 10.3390/nu15194246 . free .
  15. Manzotti G, Breda D, Di Gioacchino M, Burastero SE . Serum diamine oxidase activity in patients with histamine intolerance . International Journal of Immunopathology and Pharmacology . 29 . 1 . 105–11 . March 2016 . 26574488 . 5806734 . 10.1177/0394632015617170 .
  16. 3354134. 2011. Music E, Silar M, Korosec P, Kosnik M, Rijavec M . Serum diamine oxidase (DAO) activity as a diagnostic test for histamine intolerance. Clinical and Translational Allergy. 1. Suppl 1. 115. 10.1186/2045-7022-1-S1-P115 . free .
  17. Zeiger RS, Colten HR . Histaminase release from human eosinophils . Journal of Immunology . 118 . 2 . 540–3 . February 1977 . 10.4049/jimmunol.118.2.540 . 402420 . 36128339 . free . 2 July 2016 . 8 March 2024 . https://web.archive.org/web/20240308023324/https://journals.aai.org/cgi/pmidlookup . live .
  18. Agúndez JA, Ayuso P, Cornejo-García JA, Blanca M, Torres MJ, Doña I, Salas M, Blanca-López N, Canto G, Rondon C, Campo P, Laguna JJ, Fernández J, Martínez C, García-Martín E . The diamine oxidase gene is associated with hypersensitivity response to non-steroidal anti-inflammatory drugs . PLOS ONE . 7 . 11 . e47571 . 2012 . 23152756 . 3495953 . 10.1371/journal.pone.0047571 . 2012PLoSO...747571A . free .
  19. Maintz L, Schwarzer V, Bieber T, van der Ven K, Novak N . Effects of histamine and diamine oxidase activities on pregnancy: a critical review . Hum Reprod Update . 14 . 5 . 485–95 . 2008 . 18499706 . 10.1093/humupd/dmn014. free .
  20. Velicky P, Windsperger K, Petroczi K, Pils S, Reiter B, Weiss T, Vondra S, Ristl R, Dekan S, Fiala C, Cantonwine DE, McElrath TF, Jilma B, Knöfler M, Boehm T, Pollheimer J . Pregnancy-associated diamine oxidase originates from extravillous trophoblasts and is decreased in early-onset preeclampsia . Scientific Reports . 8 . 1 . 6342 . April 2018 . 29679053 . 5910386 . 10.1038/s41598-018-24652-0 . 2018NatSR...8.6342V .
  21. Hakl R, Litzman J . Histamine intolerance . Vnitr Lek . 69 . 1 . 37–40 . 2023 . 36931880 . 10.36290/vnl.2023.005 . 257604532 . free .
  22. Izquierdo-Casas J, Comas-Basté O, Latorre-Moratalla ML, Lorente-Gascón M, Duelo A, Soler-Singla L, Vidal-Carou MC . Diamine oxidase (DAO) supplement reduces headache in episodic migraine patients with DAO deficiency: A randomized double-blind trial . Clin Nutr . 38 . 1 . 152–158 . February 2019 . 29475774 . 10.1016/j.clnu.2018.01.013 . 2445/162978 . 3511305 . free .
  23. Okutan G, Sánchez Niño GM, Terrén Lora A, López Oliva S, San Mauro Martín I . Exogenous Supplementation with DAO Enzyme in Women with Fibromyalgia: A Double-Blind Placebo-Controlled Clinical Trial . J Clin Med . 12 . 20 . October 2023 . 6449 . 37892588 . 10.3390/jcm12206449 . 10607251 . free .
  24. Schnedl WJ, Enko D . Histamine Intolerance Originates in the Gut . Nutrients . 13 . 4 . April 2021 . 1262 . 33921522 . 8069563 . 10.3390/nu13041262 . free .
  25. Comas-Basté O, Sánchez-Pérez S, Veciana-Nogués MT, Latorre-Moratalla M, Vidal-Carou MC . Histamine Intolerance: The Current State of the Art . Biomolecules . 10 . 8 . August 2020 . 1181 . 32824107 . 7463562 . 10.3390/biom10081181 . free .
  26. Hrubisko M, Danis R, Huorka M, Wawruch M . Histamine Intolerance-The More We Know the Less We Know. A Review . Nutrients . 13 . 7 . June 2021 . 2228 . 34209583 . 8308327 . 10.3390/nu13072228 . free .
  27. Web site: regulations.gov search for diamine oxidase. 29 October 2023. 29 October 2023. https://web.archive.org/web/20231029170939/https://www.regulations.gov/search?filter=diamine%20oxidase. live.
  28. Reese I, Ballmer-Weber B, Beyer K, Dölle-Bierke S, Kleine-Tebbe J, Klimek L, Lämmel S, Lepp U, Saloga J, Schäfer C, Szepfalusi Z, Treudler R, Werfel T, Zuberbier T, Worm M . Guideline on management of suspected adverse reactions to ingested histamine: Guideline of the German Society for Allergology and Clinical Immunology (DGAKI), the Society for Pediatric Allergology and Environmental Medicine (GPA), the Medical Association of German Allergologists (AeDA) as well as the Swiss Society for Allergology and Immunology (SGAI) and the Austrian Society for Allergology and Immunology (ÖGAI) . Allergol Select . 5 . 305–314 . 2021 . 34651098 . 8511827 . 10.5414/ALX02269E.
  29. 38447930 . 2024 . Is calcitonin gene-related peptide (CGRP) the missing link in food histamine-induced migraine? A review of functional gut-to-trigeminovascular system connections . Drug Discovery Today . 29 . 4 . 10.1016/j.drudis.2024.103941 . De Mora F, Messlinger K . free .

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