Editing Histamine (section)

== Degradation ==
Histamine is released by mast cells as an immune response and is later degraded primarily by two enzymes: [[diamine oxidase]] (DAO), coded by AOC1 genes, and [[histamine-N-methyltransferase]] (HNMT), coded by the HNMT gene. The presence of [[Single-nucleotide polymorphism|single nucleotide polymorphisms]] (SNPs) at these genes are associated with a wide variety of disorders, from [[ulcerative colitis]] to [[Autism spectrum|autism spectrum disorder]] (ASD).<ref name="Altered expression of histamine sig">{{cite journal | vauthors = Wright C, Shin JH, Rajpurohit A, Deep-Soboslay A, Collado-Torres L, Brandon NJ, Hyde TM, Kleinman JE, Jaffe AE, Cross AJ, Weinberger DR | display-authors = 6 | title = Altered expression of histamine signaling genes in autism spectrum disorder | journal = Translational Psychiatry | volume = 7 | issue = 5 | pages = e1126 | date = May 2017 | pmid = 28485729 | pmc = 5534955 | doi = 10.1038/tp.2017.87 }}</ref> Histamine degradation is crucial to the prevention of allergic reactions to otherwise harmless substances.

DAO is typically expressed in [[Epithelium|epithelial cells]] at the tip of the [[Intestinal villus|villus]] of the small intestine mucosa.<ref>{{cite journal | vauthors = Thompson JS | title = Significance of the intestinal gradient of diamine oxidase activity | language = english | journal = Digestive Diseases | volume = 8 | issue = 3 | pages = 163–8 | date = 1990 | pmid = 2110876 | doi = 10.1159/000171249 }}</ref> Reduced DAO activity is associated with gastrointestinal disorders and widespread food intolerances. This is due to an increase in histamine absorption through [[enterocyte]]s, which increases histamine concentration in the bloodstream.<ref name="Histamine N-Methyltransferase i">{{cite journal | vauthors = Yoshikawa T, Nakamura T, Yanai K | title = Histamine ''N''-Methyltransferase in the Brain | journal = International Journal of Molecular Sciences | volume = 20 | issue = 3 | pages = 737 | date = February 2019 | pmid = 30744146 | pmc = 6386932 | doi = 10.3390/ijms20030737 | doi-access = free }}</ref> One study found that [[migraine]] patients with [[Non-celiac gluten sensitivity|gluten sensitivity]] were positively correlated with having lower DAO serum levels.<ref>{{cite journal | vauthors = Griauzdaitė K, Maselis K, Žvirblienė A, Vaitkus A, Jančiauskas D, Banaitytė-Baleišienė I, Kupčinskas L, Rastenytė D | display-authors = 6 | title = Associations between migraine, celiac disease, non-celiac gluten sensitivity and activity of diamine oxidase | journal = Medical Hypotheses | volume = 142 | pages = 109738 | date = September 2020 | pmid = 32416409 | doi = 10.1016/j.mehy.2020.109738 | s2cid = 216303896 }}</ref> Low DAO activity can have more severe consequences as mutations in the ABP1 alleles of the AOC1 gene have been associated with ulcerative colitis.<ref>{{cite journal | vauthors = García-Martin E, Mendoza JL, Martínez C, Taxonera C, Urcelay E, Ladero JM, de la Concha EG, Díaz-Rubio M, Agúndez JA | display-authors = 6 | title = Severity of ulcerative colitis is associated with a polymorphism at diamine oxidase gene but not at histamine N-methyltransferase gene | journal = World Journal of Gastroenterology | volume = 12 | issue = 4 | pages = 615–20 | date = January 2006 | pmid = 16489678 | pmc = 4066097 | doi = 10.3748/wjg.v12.i4.615 | doi-access = free }}</ref> [[Zygosity|Heterozygous or homozygous]] recessive genotypes at the rs2052129, rs2268999, rs10156191 and rs1049742 [[allele]]s increased the risk for reduced DAO activity.<ref>{{cite journal | vauthors = Maintz L, Yu CF, Rodríguez E, Baurecht H, Bieber T, Illig T, Weidinger S, Novak N | display-authors = 6 | title = Association of single nucleotide polymorphisms in the diamine oxidase gene with diamine oxidase serum activities | journal = Allergy | volume = 66 | issue = 7 | pages = 893–902 | date = July 2011 | pmid = 21488903 | doi = 10.1111/j.1398-9995.2011.02548.x | s2cid = 205405463 | url = http://mediatum.ub.tum.de/doc/1099433/document.pdf }}{{Dead link|date=March 2024 |bot=InternetArchiveBot |fix-attempted=yes }}</ref> People with genotypes for reduced DAO activity can avoid foods high in histamine, such as alcohol, fermented foods, and aged foods, to attenuate any allergic reactions. Additionally, they should be aware whether any [[probiotic]]s they are taking contain any histamine-producing strains and consult with their doctor to receive proper support {{Citation needed|date=September 2023|reason=This implicitly assumes that digested histamine can enter the bloodstream, which hasn't been established in this section.}}.

HNMT is expressed in the [[central nervous system]], where deficiencies have been shown to lead to aggressive behavior and abnormal sleep-wake cycles in mice.<ref>{{cite journal | vauthors = Branco AC, Yoshikawa FS, Pietrobon AJ, Sato MN | title = Role of Histamine in Modulating the Immune Response and Inflammation | journal = Mediators of Inflammation | volume = 2018 | pages = 9524075 | date = 2018-08-27 | pmid = 30224900 | pmc = 6129797 | doi = 10.1155/2018/9524075 | doi-access = free }}</ref> Since brain histamine as a neurotransmitter regulates a number of neurophysiological functions, emphasis has been placed on the development of drugs to target histamine regulation. Yoshikawa et al. explores how the C314T, A939G, G179A, and T632C polymorphisms all impact HNMT enzymatic activity and the pathogenesis of various neurological disorders.<ref name="Histamine N-Methyltransferase i"/> These mutations can have either a positive or negative impact. Some patients with [[Attention deficit hyperactivity disorder|ADHD]] have been shown to exhibit exacerbated symptoms in response to food additives and preservatives, due in part to histamine release. In a [[Blinded experiment|double-blind]] placebo-controlled crossover trial, children with ADHD who responded with aggravated symptoms after consuming a challenge beverage were more likely to have HNMT polymorphisms at T939C and Thr105Ile.<ref>{{cite journal | vauthors = Stevenson J, Sonuga-Barke E, McCann D, Grimshaw K, Parker KM, Rose-Zerilli MJ, Holloway JW, Warner JO | display-authors = 6 | title = The role of histamine degradation gene polymorphisms in moderating the effects of food additives on children's ADHD symptoms | journal = The American Journal of Psychiatry | volume = 167 | issue = 9 | pages = 1108–15 | date = September 2010 | pmid = 20551163 | doi = 10.1176/appi.ajp.2010.09101529 }}</ref> Histamine's role in neuroinflammation and cognition has made it a target of study for many neurological disorders, including autism spectrum disorder (ASD). De novo deletions in the HNMT gene have also been associated with ASD.<ref name="Altered expression of histamine sig"/>

Mast cells serve an important immunological role by defending the body from [[antigen]]s and maintaining [[homeostasis]] in the [[Gut microbiota|gut microbiome]]. They act as an alarm to trigger inflammatory responses by the immune system. Their presence in the digestive system enables them to serve as an early barrier to [[pathogen]]s entering the body. People who suffer from widespread sensitivities and allergic reactions may have [[mast cell activation syndrome]] (MCAS), in which excessive amounts of histamine are released from [[mast cell]]s, and cannot be properly degraded. The abnormal release of histamine can be caused by either dysfunctional internal signals from defective mast cells or by the development of clonal mast cell populations through mutations occurring in the [[tyrosine kinase]] [[KIT (gene)|Kit]].<ref name=":0">{{cite journal | vauthors = Haenisch B, Nöthen MM, Molderings GJ | title = Systemic mast cell activation disease: the role of molecular genetic alterations in pathogenesis, heritability and diagnostics | journal = Immunology | volume = 137 | issue = 3 | pages = 197–205 | date = November 2012 | pmid = 22957768 | pmc = 3482677 | doi = 10.1111/j.1365-2567.2012.03627.x }}</ref> In such cases, the body may not be able to produce sufficient degradative enzymes to properly eliminate the excess histamine. Since MCAS is symptomatically characterized as such a broad disorder, it is difficult to diagnose and can be mislabeled as a variety of diseases, including [[irritable bowel syndrome]] and [[fibromyalgia]].<ref name=":0" />

Histamine is often explored as a potential cause for diseases related to hyper-responsiveness of the immune system. In patients with [[asthma]], abnormal histamine receptor activation in the lungs is associated with [[bronchospasm]], airway obstruction, and production of excess mucus. Mutations in histamine degradation are more common in patients with a combination of asthma and allergen hypersensitivity than in those with just asthma. The HNMT-464 TT and HNMT-1639 TT [[Polymorphism (biology)|polymorphisms]] are significantly more common among children with allergic asthma, the latter of which is overrepresented in African-American children.<ref>{{cite journal | vauthors = Anvari S, Vyhlidal CA, Dai H, Jones BL | title = Genetic Variation along the Histamine Pathway in Children with Allergic versus Nonallergic Asthma | journal = American Journal of Respiratory Cell and Molecular Biology | volume = 53 | issue = 6 | pages = 802–9 | date = December 2015 | pmid = 25909280 | pmc = 4742940 | doi = 10.1165/rcmb.2014-0493OC }}</ref>