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Diamine oxidase

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Not to be confused with D-amino acid oxidase or D-aspartate oxidase.

Diamine oxidase
Diamine oxidase dimer, Human
Identifiers
EC no.1.4.3.22
Databases
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BRENDABRENDA entry
ExPASyNiceZyme view
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MetaCycmetabolic pathway
PRIAMprofile
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Diamine oxidase (DAO), also known "amine oxidase, copper-containing, 1" (AOC1), formerly called histaminase,[1] is an enzyme (EC 1.4.3.22) 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

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Histamine metabolites

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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 imidazole acetaldehyde.[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

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DAO metabolizes histamine into imidazole-4-acetaldehyde:

R−CH2−NH2 + H2O + O2 → R−CHO + NH3 + H2O2

Imidazole-4-acetaldehyde is then further oxidized by a NAD-dependent aldehyde dehydrogenase, leading to imidazole-4-acetic acid.[5]

Biological role

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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.[6][7][8]

Expression

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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.[9][10]

The role in human pregnancy

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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.[11]

During pregnancy, DAO plays a crucial role in maintaining fetal growth and development by regulating histamine levels.[11] DAO levels in the blood circulation increases vastly in pregnant women suggesting a protective mechanism against adverse histamine.[12] 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.[12]

Supplementation

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Exogenous DAO (supplements) are being studied as complementary treatment[13] for the relief of symptoms associated with histamine intolerance, and for the relief of other conditions, such as migraine[14] or fibromyalgia.[15] However, the results are inconclusive because studies to date have involved small study populations and short intervention periods.[16][17][18]

In the United States, DAO supplements are available over the counter but are not FDA-approved.[19]

In Europe, two investigations, financially backed by the manufacturer of the oral DAO supplementation, have posited that DAO supplementation could alleviate patient symptoms.[20] 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".[20] 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.[20] 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.[20] The chosen design was not suitable to demonstrate causal effects and carried a high risk of attributing placebo effects.[20] The effectiveness of DAO supplementation has not been scientifically validated and is not recommended by the medical associations in Germany, Austria and Switzerland.[20]

Research directions

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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.[21]

References

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  1. ^ Wolvekamp MC, de Bruin RW (1994). "Diamine oxidase: an overview of historical, biochemical and functional aspects". Digestive Diseases. 12 (1): 2–14. doi:10.1159/000171432. PMID 8200121.
  2. ^ a b c d e f g h Keyzer J, Wolthers B, Breukelman H, Kauffman H, De Monchy J (1982). "Determination of Nτ-methylimidazoleacetic acid (A histamine metabolite) in urine by gas chromatography using nitrogen-phosphorus detection". Clinica Chimica Acta. 121 (3): 379–387. doi:10.1016/0009-8981(82)90247-9. PMID 6955073.
  3. ^ Mohammed T (2010). "Biological and Pharmacological Aspects of Histamine Receptors and Their Ligands". Biomedical Aspects of Histamine. Springer. pp. 61–100. doi:10.1007/978-90-481-9349-3_4. ISBN 978-90-481-9348-6.
  4. ^ Peters LJ, Kovacic JP (2009). "Histamine: Metabolism, physiology, and pathophysiology with applications in veterinary medicine". Journal of Veterinary Emergency and Critical Care. 19 (4): 311–328. doi:10.1111/j.1476-4431.2009.00434.x. PMID 25164630.
  5. ^ Bähre H, Kaever V (2017). "Analytical Methods for the Quantification of Histamine and Histamine Metabolites". Handbook of Experimental Pharmacology. 241: 3–19. doi:10.1007/164_2017_22. ISBN 978-3-319-58192-7. PMID 28321587.
  6. ^ Arih K, Đorđević N, Košnik M, Rijavec M (October 2023). "Evaluation of Serum Diamine Oxidase as a Diagnostic Test for Histamine Intolerance". Nutrients. 15 (19): 4246. doi:10.3390/nu15194246. PMC 10574399. PMID 37836530.
  7. ^ Manzotti G, Breda D, Di Gioacchino M, Burastero SE (March 2016). "Serum diamine oxidase activity in patients with histamine intolerance". International Journal of Immunopathology and Pharmacology. 29 (1): 105–11. doi:10.1177/0394632015617170. PMC 5806734. PMID 26574488.
  8. ^ Music E, Silar M, Korosec P, Kosnik M, Rijavec M (2011). "Serum diamine oxidase (DAO) activity as a diagnostic test for histamine intolerance". Clinical and Translational Allergy. 1 (Suppl 1): 115. doi:10.1186/2045-7022-1-S1-P115. PMC 3354134.
  9. ^ Zeiger RS, Colten HR (February 1977). "Histaminase release from human eosinophils". Journal of Immunology. 118 (2): 540–3. doi:10.4049/jimmunol.118.2.540. PMID 402420. S2CID 36128339. Archived from the original on 8 March 2024. Retrieved 2 July 2016.
  10. ^ Agúndez JA, Ayuso P, Cornejo-García JA, Blanca M, Torres MJ, Doña I, et al. (2012). "The diamine oxidase gene is associated with hypersensitivity response to non-steroidal anti-inflammatory drugs". PLOS ONE. 7 (11): e47571. Bibcode:2012PLoSO...747571A. doi:10.1371/journal.pone.0047571. PMC 3495953. PMID 23152756.
  11. ^ a b Maintz L, Schwarzer V, Bieber T, van der Ven K, Novak N (2008). "Effects of histamine and diamine oxidase activities on pregnancy: a critical review". Hum Reprod Update. 14 (5): 485–95. doi:10.1093/humupd/dmn014. PMID 18499706.
  12. ^ a b Velicky P, Windsperger K, Petroczi K, Pils S, Reiter B, Weiss T, et al. (April 2018). "Pregnancy-associated diamine oxidase originates from extravillous trophoblasts and is decreased in early-onset preeclampsia". Scientific Reports. 8 (1): 6342. Bibcode:2018NatSR...8.6342V. doi:10.1038/s41598-018-24652-0. PMC 5910386. PMID 29679053.
  13. ^ Hakl R, Litzman J (2023). "Histamine intolerance". Vnitr Lek. 69 (1): 37–40. doi:10.36290/vnl.2023.005. PMID 36931880. S2CID 257604532.
  14. ^ Izquierdo-Casas J, Comas-Basté O, Latorre-Moratalla ML, Lorente-Gascón M, Duelo A, Soler-Singla L, et al. (February 2019). "Diamine oxidase (DAO) supplement reduces headache in episodic migraine patients with DAO deficiency: A randomized double-blind trial". Clin Nutr. 38 (1): 152–158. doi:10.1016/j.clnu.2018.01.013. hdl:2445/162978. PMID 29475774. S2CID 3511305.
  15. ^ Okutan G, Sánchez Niño GM, Terrén Lora A, López Oliva S, San Mauro Martín I (October 2023). "Exogenous Supplementation with DAO Enzyme in Women with Fibromyalgia: A Double-Blind Placebo-Controlled Clinical Trial". J Clin Med. 12 (20): 6449. doi:10.3390/jcm12206449. PMC 10607251. PMID 37892588.
  16. ^ Schnedl WJ, Enko D (April 2021). "Histamine Intolerance Originates in the Gut". Nutrients. 13 (4): 1262. doi:10.3390/nu13041262. PMC 8069563. PMID 33921522.
  17. ^ Comas-Basté O, Sánchez-Pérez S, Veciana-Nogués MT, Latorre-Moratalla M, Vidal-Carou MC (August 2020). "Histamine Intolerance: The Current State of the Art". Biomolecules. 10 (8): 1181. doi:10.3390/biom10081181. PMC 7463562. PMID 32824107.
  18. ^ Hrubisko M, Danis R, Huorka M, Wawruch M (June 2021). "Histamine Intolerance-The More We Know the Less We Know. A Review". Nutrients. 13 (7): 2228. doi:10.3390/nu13072228. PMC 8308327. PMID 34209583.
  19. ^ "regulations.gov search for diamine oxidase". Archived from the original on 29 October 2023. Retrieved 29 October 2023.
  20. ^ a b c d e f Reese I, Ballmer-Weber B, Beyer K, Dölle-Bierke S, Kleine-Tebbe J, Klimek L, et al. (2021). "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. doi:10.5414/ALX02269E. PMC 8511827. PMID 34651098. This article incorporates text from this source, which is available under the CC BY 4.0 license.
  21. ^ De Mora F, Messlinger K (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). doi:10.1016/j.drudis.2024.103941. PMID 38447930.
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