Chemistry:Tyramine

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Short description: Chemical compound
Tyramine
Tyramine.svg
Skeletal formula of tyramine
Tyramine-neutral-from-xtal-view-1-3D-bs-17.png
Ball-and-stick model of the neutral (non-zwitterionic) form of tyramine found in the crystal structure[1]
Clinical data
ATC code
  • none
Pharmacokinetic data
MetabolismCYP2D6, flavin-containing monooxygenase 3, monoamine oxidase A, monoamine oxidase B, phenylethanolamine N-methyltransferase, DBH, others
Metabolites4-hydroxyphenylacetaldehyde, dopamine, N-methyltyramine, octopamine
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC8H11NO
Molar mass137.179 g·mol−1
3D model (JSmol)
Density1.103 g/cm3 predicted[2]
Melting point164.5 °C (328.1 °F) [3]
Boiling point206 °C (403 °F) at 25 mmHg; 166 °C at 2 mmHg[3]

Tyramine (/ˈtaɪrəmiːn/ TY-rə-meen) (also spelled tyramin), also known under several other names,[note 1] is a naturally occurring trace amine derived from the amino acid tyrosine.[4] Tyramine acts as a catecholamine releasing agent. Notably, it is unable to cross the blood-brain barrier, resulting in only non-psychoactive peripheral sympathomimetic effects following ingestion. A hypertensive crisis can result, however, from ingestion of tyramine-rich foods in conjunction with the use of monoamine oxidase inhibitors (MAOIs).

Occurrence

Tyramine occurs widely in plants[5] and animals, and is metabolized by various enzymes, including monoamine oxidases. In foods, it often is produced by the decarboxylation of tyrosine during fermentation or decay. Foods that are fermented, cured, pickled, aged, or spoiled have high amounts of tyramine. Tyramine levels go up when foods are at room temperature or go past their freshness date.

Specific foods containing considerable amounts of tyramine include:[6][7]

  • strong or aged cheeses: cheddar, Swiss, Parmesan, Stilton, Gorgonzola or blue cheeses, Camembert, feta, Muenster
  • meats that are cured, smoked, or processed, such as salami, pepperoni, dry sausages, hot dogs, bologna, bacon, corned beef, pickled or smoked fish, caviar, aged chicken livers, soups or gravies made from meat extract
  • pickled or fermented foods: sauerkraut, kimchi, tofu (especially stinky tofu), pickles, miso soup, bean curd, tempeh, sourdough breads
  • condiments: soy, shrimp, fish, miso, teriyaki, and bouillon-based sauces
  • drinks: beer (especially tap or home-brewed), vermouth, red wine, sherry, liqueurs
  • beans, vegetables, and fruits: fermented or pickled vegetables, overripe fruits
  • chocolate[8]

Scientists more and more consider tyramine in food as an aspect of safety.[9] They propose projects of regulations aimed to enact control of biogenic amines in food by various strategies, including usage of proper fermentation starters, or preventing their decarboxylase activity.[10] Some authors wrote that this has already given positive results, and tyramine content in food is now lower than it has been in the past.[11]

In plants

Mistletoe (toxic and not used by humans as a food, but historically used as a medicine).[12]

In animals

Tyramine also plays a role in animals including: In behavioral and motor functions in Caenorhabditis elegans;[13] Locusta migratoria swarming behaviour;[14] and various nervous roles in Rhipicephalus, Apis, Locusta, Periplaneta, Drosophila, Phormia, Papilio, Bombyx, Chilo, Heliothis, Mamestra, Agrotis, and Anopheles.[15]

Physical effects and pharmacology

Evidence for the presence of tyramine in the human brain has been confirmed by postmortem analysis.[16] Additionally, the possibility that tyramine acts directly as a neuromodulator was revealed by the discovery of a G protein-coupled receptor with high affinity for tyramine, called TAAR1.[17][18] The TAAR1 receptor is found in the brain, as well as peripheral tissues, including the kidneys.[19] Tyramine binds to TAAR1 as an agonist in humans.[20]

Tyramine is physiologically metabolized by monoamine oxidases (primarily MAO-A), FMO3, PNMT, DBH, and CYP2D6.[21][22][23][24][25] Human monoamine oxidase enzymes metabolize tyramine into 4-hydroxyphenylacetaldehyde.[26] If monoamine metabolism is compromised by the use of monoamine oxidase inhibitors (MAOIs) and foods high in tyramine are ingested, a hypertensive crisis can result, as tyramine also can displace stored monoamines, such as dopamine, norepinephrine, and epinephrine, from pre-synaptic vesicles. Tyramine is considered a "false neurotransmitter", as it enters noradrenergic nerve terminals and displaces large amounts of norepinephrine, which enters the blood stream and causes vasoconstriction.

Additionally, cocaine has been found to block blood pressure rise that is originally attributed to tyramine, which is explained by the blocking of adrenaline by cocaine from reabsorption to the brain.[27]

The first signs of this effect were discovered by a British pharmacist who noticed that his wife, who at the time was on MAOI medication, had severe headaches when eating cheese.[28] For this reason, it is still called the "cheese reaction" or "cheese crisis", although other foods can cause the same problem.[29]

Most processed cheeses do not contain enough tyramine to cause hypertensive effects, although some aged cheeses (such as Stilton) do.[30][31]

A large dietary intake of tyramine (or a dietary intake of tyramine while taking MAO inhibitors) can cause the tyramine pressor response, which is defined as an increase in systolic blood pressure of 30 mmHg or more. The increased release of norepinephrine (noradrenaline) from neuronal cytosol or storage vesicles is thought to cause the vasoconstriction and increased heart rate and blood pressure of the pressor response. In severe cases, adrenergic crisis can occur. Although the mechanism is unclear, tyramine ingestion also triggers migraine attacks in sensitive individuals and can even lead to stroke.[32] Vasodilation, dopamine, and circulatory factors are all implicated in the migraines. Double-blind trials suggest that the effects of tyramine on migraine may be adrenergic.[33]

Research reveals a possible link between migraines and elevated levels of tyramine. A 2007 review published in Neurological Sciences[34] presented data showing migraine and cluster diseases are characterized by an increase of circulating neurotransmitters and neuromodulators (including tyramine, octopamine, and synephrine) in the hypothalamus, amygdala, and dopaminergic system. People with migraine are over-represented among those with inadequate natural monoamine oxidase, resulting in similar problems to individuals taking MAO inhibitors. Many migraine attack triggers are high in tyramine.[35]

If one has had repeated exposure to tyramine, however, there is a decreased pressor response; tyramine is degraded to octopamine, which is subsequently packaged in synaptic vesicles with norepinephrine (noradrenaline).[citation needed] Therefore, after repeated tyramine exposure, these vesicles contain an increased amount of octopamine and a relatively reduced amount of norepinephrine. When these vesicles are secreted upon tyramine ingestion, there is a decreased pressor response, as less norepinephrine is secreted into the synapse, and octopamine does not activate alpha or beta adrenergic receptors.

When using a MAO inhibitor (MAOI), an intake of approximately 10 to 25 mg of tyramine is required for a severe reaction, compared to 6 to 10 mg for a mild reaction.[36]

Biosynthesis

Biochemically, tyramine is produced by the decarboxylation of tyrosine via the action of the enzyme tyrosine decarboxylase.[37] Tyramine can, in turn, be converted to methylated alkaloid derivatives N-methyltyramine, N,N-dimethyltyramine (hordenine), and N,N,N-trimethyltyramine (candicine).

  • Tyramine

  • N-Methyltyramine

  • N,N-Dimethyltyramine (hordenine)

  • N,N,N-Trimethyltyramine (candicine)

In humans, tyramine is produced from tyrosine, as shown in the following diagram.{{Annotated image 4 | caption = {{{caption|In humans, catecholamines and phenethylaminergic trace amines are derived from the amino acid {{nowrap|L-phenylalanine}}.}}} | header_background = #F0F8FF | header = Biosynthetic pathways for catecholamines and trace amines in the human brain<ref name="Trace amine template 1">Broadley KJ (March 2010). "The vascular effects of trace amines and amphetamines". Pharmacol. Ther. 125 (3): 363–375. doi:10.1016/j.pharmthera.2009.11.005. PMID 19948186. </ref>[24][25] | alt = Graphic of catecholamine and trace amine biosynthesis | image = Catecholamine and trace amine biosynthesis.png | image-width = 580 | image-left = 5 | image-top = 0 | align = center | width = 590 | height = 585 | annot-font-size = 14 | annot-text-align = center | annotations =

{{annotation|50|565|{{if pagename|Adrenaline=Adrenaline|Epinephrine=Epinephrine|Catecholamine=Epinephrine|other=Epinephrine}}}}

{{annotation|245|60|{{if pagename|Phenethylamine=Phenethylamine|Trace amine=Phenethylamine|Neurobiological effects of physical exercise={{highlight|Phenethylamine}}|other=Phenethylamine}}}}

p-Tyramine

{{annotation|245|565|{{if pagename|Norepinephrine=Norepinephrine|Adrenaline=Noradrenaline|Catecholamine=Norepinephrine|other=Norepinephrine}}}}

{{annotation|440|295|p-Octopamine}}}}

primary
pathway
brain
CYP2D6
minor
pathway

Chemistry

In the laboratory, tyramine can be synthesized in various ways, in particular by the decarboxylation of tyrosine.[38][39][40]

Tyrosine decarboxylation

Legal status

United States

Tyramine is a Schedule I controlled substance, categorized as a hallucinogen, making it illegal to buy, sell, or possess in the state of Florida without a license at any purity level or any form whatsoever. The language in the Florida statute says tyramine is illegal in "any material, compound, mixture, or preparation that contains any quantity of [tyramine] or that contains any of [its] salts, isomers, including optical, positional, or geometric isomers, and salts of isomers, if the existence of such salts, isomers, and salts of isomers is possible within the specific chemical designation."[41]

This ban is likely the product of lawmakers overly eager to ban substituted phenethylamines, which tyramine is, in the mistaken belief that ring-substituted phenethylamines are hallucinogenic drugs like the 2C series of psychedelic substituted phenethylamines. The further banning of tyramine's optical isomers, positional isomers, or geometric isomers, and salts of isomers where they exist, means that meta-tyramine and phenylethanolamine, a substance found in every living human body, and other common, non-hallucinogenic substances are also illegal to buy, sell, or possess in Florida.[41] Given that tyramine occurs naturally in many foods and drinks (most commonly as a by-product of bacterial fermentation), e.g. wine, cheese, and chocolate, Florida's total ban on the substance may prove difficult to enforce.[42]

Notes

  1. ↑ Synonyms and alternative names include: 4-hydroxyphenethylamine, para-tyramine, mydrial, and uteramin; the latter two names are not commonly used. The IUPAC name is 4-(2-aminoethyl)phenol.

References

  1. ↑ "Tautomeric and ionisation forms of dopamine and tyramine in the solid state". J. Mol. Struct. 1051: 132–136. 2013. doi:10.1016/j.molstruc.2013.08.002. Bibcode: 2013JMoSt1051..132C. 
  2. ↑ SciFinder, Calculated using Advanced Chemistry Development (ACD/Labs) Software V11.02 (© 1994-2021 ACD/Labs)
  3. ↑ 3.0 3.1 The Merck Index, 10th Ed. (1983), p. 1405, Rahway: Merck & Co.
  4. ↑ "tyramine | C8H11NO" (in en). https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=5610. 
  5. ↑ T. A. Smith (1977) Phytochemistry 16 9–18.
  6. ↑ "Avoid the combination of high-tyramine foods and MAOIs" (in en). 18 December 2018. https://www.mayoclinic.org/diseases-conditions/depression/expert-answers/maois/faq-20058035. 
  7. ↑ "Tyramine-Rich Foods As A Migraine Trigger & Low Tyramine Diet" (in en). 21 June 2020. https://www.webmd.com/migraines-headaches/tyramine-and-migraines. 
  8. ↑ "Tyramine" (in en). https://pubchem.ncbi.nlm.nih.gov/compound/Tyramine#section=Mechanism-of-Action. 
  9. ↑ "Biogenic Amines' Content in Safe and Quality Food". Foods 10 (1): 100. January 2021. doi:10.3390/foods10010100. PMID 33418895. 
  10. ↑ "Scientific Opinion on risk based control of biogenic amine formation in fermented foods". EFSA Journal 9 (10): 2393. 2011. doi:10.2903/j.efsa.2011.2393. 
  11. ↑ "Selective inhibitors of monoamine oxidase type B and the "cheese effect"". Monoamine Oxidase and their Inhibitors. International Review of Neurobiology. 100. 2011. pp. 169–190. doi:10.1016/B978-0-12-386467-3.00009-1. ISBN 978-0-12-386467-3. 
  12. ↑ "Tyramine" (in en). 19 December 2005. https://www.acs.org/content/acs/en/molecule-of-the-week/archive/t/tyramine.html. 
  13. ↑ "Tyramine Functions Independently of Octopamine in the Caenorhabditis elegans Nervous System". Neuron (Cell Press (Elsevier BV)) 46 (2): 247–60. April 2005. doi:10.1016/j.neuron.2005.02.024. PMID 15848803. 
  14. ↑ "Octopamine and tyramine respectively regulate attractive and repulsive behavior in locust phase changes". Scientific Reports (Nature/Springer) 5 (1): 8036. January 2015. doi:10.1038/srep08036. PMID 25623394. Bibcode: 2015NatSR...5E8036M. 
  15. ↑ "Molecular Signalling, Pharmacology, and Physiology of Octopamine and Tyramine Receptors as Potential Insect Pest Control Targets". Advances in Insect Physiology. 46. Elsevier. 2014. pp. 73–166. doi:10.1016/b978-0-12-417010-0.00002-1. ISBN 978-0-12-417010-0. 
  16. ↑ "Evidence for the presence of m-tyramine, p-tyramine, tryptamine, and phenylethylamine in the rat brain and several areas of the human brain". Biological Psychiatry 13 (1): 51–7. February 1978. PMID 623853. 
  17. ↑ "A rapid functional assay for the human trace amine-associated receptor 1 based on the mobilization of internal calcium". Journal of Biomolecular Screening 11 (6): 688–93. September 2006. doi:10.1177/1087057106289891. PMID 16831861. 
  18. ↑ "A second class of chemosensory receptors in the olfactory epithelium". Nature 442 (7103): 645–50. August 2006. doi:10.1038/nature05066. PMID 16878137. Bibcode: 2006Natur.442..645L. 
  19. ↑ "Modulation of monoamine transporters by common biogenic amines via trace amine-associated receptor 1 and monoamine autoreceptors in human embryonic kidney 293 cells and brain synaptosomes". The Journal of Pharmacology and Experimental Therapeutics 325 (2): 629–640. May 2008. doi:10.1124/jpet.107.135079. PMID 18310473. 
  20. ↑ "The emerging roles of human trace amines and human trace amine-associated receptors (hTAARs) in central nervous system". Biomedicine & Pharmacotherapy 83: 439–449. October 2016. doi:10.1016/j.biopha.2016.07.002. PMID 27424325. 
  21. ↑ "Trimethylamine monooxygenase (Homo sapiens)". Trimethylamine monooxygenase (Homo sapiens). Technische Universität Braunschweig. July 2016. http://www.brenda-enzymes.info/enzyme.php?ecno=1.14.13.148&Suchword=&reference=&organism%5B%5D=Homo+sapiens&show_tm=0. Retrieved 18 September 2016. 
  22. ↑ "Mammalian flavin-containing monooxygenases: structure/function, genetic polymorphisms and role in drug metabolism". Pharmacology & Therapeutics 106 (3): 357–87. June 2005. doi:10.1016/j.pharmthera.2005.01.001. PMID 15922018. 
    Table 5: N-containing drugs and xenobiotics oxygenated by FMO
  23. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named Trace amine template 1
  24. ↑ 24.0 24.1 "A renaissance in trace amines inspired by a novel GPCR family". Trends Pharmacol. Sci. 26 (5): 274–281. May 2005. doi:10.1016/j.tips.2005.03.007. PMID 15860375. 
  25. ↑ 25.0 25.1 "The endogenous substrates of brain CYP2D". Eur. J. Pharmacol. 724: 211–218. February 2014. doi:10.1016/j.ejphar.2013.12.025. PMID 24374199. 
  26. ↑ "4-Hydroxyphenylacetaldehyde". University of Alberta. 2019-07-23. http://www.hmdb.ca/metabolites/HMDB0003767. 
  27. ↑ "REVIEW --- Books: What Sets Your Heart Pounding". Wall Street Journal: p. C.6. 27 April 2013. ProQuest 1346292101. 
  28. ↑ "Hypertensive crisis and cheese". Indian Journal of Psychiatry 51 (1): 65–6. January 2009. doi:10.4103/0019-5545.44910. PMID 19742203. 
  29. ↑ "Drugs, The Straight Facts: Antidepressants". Chelsea House Publishers. 2004. pp. 30–31. http://iftandcs.org/Addictions/Drugs%20The%20Straight%20Facts,%20Antidepressants.pdf. 
  30. ↑ "Monoamine oxidase inhibitors: a modern guide to an unrequited class of antidepressants". CNS Spectrums 13 (10): 855–870. October 2008. doi:10.1017/S1092852900016965. PMID 18955941. 
  31. ↑ "Tyramine-restricted Diet". W.B. Saunders Company. 1998. http://web.squ.edu.om/med-lib/med_cd/e_cds/Griffith's%20Instructions%20Patients/pdf/Pg570.pdf. 
  32. ↑ "Tyramine" (in en). Biochemistry. Encyclopedia Britannica. https://www.britannica.com/science/tyramine. Retrieved 2021-11-12. 
  33. ↑ "Intravenous tyramine response in migraine before and during treatment with indoramin". British Medical Journal 1 (6070): 1191–3. May 1977. doi:10.1136/bmj.1.6070.1191. PMID 324566. 
  34. ↑ "Biochemistry of neuromodulation in primary headaches: focus on anomalies of tyrosine metabolism". Neurological Sciences 28 (S2): S94-6. May 2007. doi:10.1007/s10072-007-0758-4. PMID 17508188. 
  35. ↑ "Headache Sufferer's Diet | National Headache Foundation" (in en-US). National Headache Foundation. http://www.headaches.org/headache-sufferers-diet/. 
  36. ↑ "Dietary tyramine and other pressor amines in MAOI regimens: a review". Journal of the American Dietetic Association 86 (8): 1059–64. August 1986. doi:10.1016/S0002-8223(21)04074-8. PMID 3525654. 
  37. ↑ "Tyrosine metabolism - Reference pathway". Kyoto Encyclopedia of Genes and Genomes (KEGG). http://www.genome.jp/kegg/pathway/map/map00350.html. 
  38. ↑ "CXXVII.?Isolation and synthesis of p-hydroxyphenylethylamine, an active principle of ergot soluble in water". J. Chem. Soc. 95: 1123–1128. 1909. doi:10.1039/ct9099501123. https://zenodo.org/record/1429723. 
  39. ↑ "Untersuchungen in der Phenylalanin-Reihe VI. Decarboxylierung des Tyrosins und des Leucins". Helvetica Chimica Acta 8: 758–773. 1925. doi:10.1002/hlca.192500801106. 
  40. ↑ "Reduction of Hydroxymandelonitriles. A New Synthesis of Tyramine". Journal of the American Chemical Society 55 (8): 3388–3390. 1933. doi:10.1021/ja01335a058. 
  41. ↑ 41.0 41.1 "Statutes & Constitution :View Statutes : Online Sunshine". http://leg.state.fl.us/statutes/index.cfm?App_mode=Display_Statute&URL=0800-0899/0893/0893.html. 
  42. ↑ "Editorial: Biogenic amines in foods". Frontiers in Microbiology 6: 472. 2015-05-18. doi:10.3389/fmicb.2015.00472. PMID 26042107. 



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