Tyramine

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Tyramine
Tyramine.svg
Tyramine 3D ball.png
Clinical data
ATC code none
Pharmacokinetic data
Metabolism CYP2D6, FMO3, MAO-A, MAO-B, PNMT, DBH, others
Metabolites 4-hydroxyphenylacetaldehyde, dopamine, N-methyltyramine, octopamine
Identifiers
Systematic (IUPAC) name: 4-(2-aminoethyl)phenol
CAS Number 51-67-2 YesY
PubChem (CID) 5610
IUPHAR/BPS 2150
ChemSpider 5408 YesY
UNII X8ZC7V0OX3 YesY
KEGG C00483 YesY
ChEBI CHEBI:15760 YesY
ChEMBL CHEMBL11608 YesY
Chemical and physical data
Formula C8H11NO
Molar mass 137.179
3D model (Jmol) Interactive image
Melting point 164.5 °C (328.1 °F) [1]
Boiling point 206 °C (403 °F) at 25 mmHg; 166 °C at 2 mmHg[1]

Tyramine (/ˈtrəmin/ TY-rə-meen), also known by several other names, is a naturally occurring trace amine derived from the amino acid tyrosine.[2] 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 monoamine oxidase inhibitors (MAOIs).

Occurrence[edit]

Tyramine occurs widely in plants[3] 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 containing considerable amounts of tyramine include meats that are potentially spoiled or pickled, aged, smoked, fermented, or marinated (some fish, poultry, and beef); most pork (except cured ham). Other foods containing considerable amounts of tyramine are chocolate; alcoholic beverages; and fermented foods, such as most cheeses (except ricotta, cottage, cream and Neufchâtel cheeses), sour cream, yogurt, shrimp paste, soy sauce, soybean condiments, teriyaki sauce, tempeh, miso soup, sauerkraut, kimchi, broad (fava) beans, green bean pods, Italian flat (Romano) beans, snow peas, edamame, avocados, bananas, pineapple, eggplants, figs, red plums, raspberries, peanuts, Brazil nuts, coconuts, processed meat, yeast, an array of cacti and the holiday plant mistletoe.

Physical effects and pharmacology[edit]

Evidence for the presence of tyramine in the human brain has been confirmed by postmortem analysis.[4] Additionally, the possibility that tyramine acts directly as a neurotransmitter was revealed by the discovery of a G protein-coupled receptor with high affinity for tyramine, called TAAR1.[5][6] The TAAR1 receptor is found in the brain, as well as peripheral tissues, including the kidneys.[7]

Tyramine is physiologically metabolized by monoamine oxidases (primarily MAO-A), FMO3, PNMT, DBH, and CYP2D6.[8][9][10][11][12] In humans, 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.

The first signs of this were discovered by a British pharmacist who noticed his wife, who at the time was on MAOI medication, had severe headaches when eating cheese.[13] For this reason, the crisis is still called the "cheese effect" or "cheese crisis", though other foods can cause the same problem.[14]:30–31

Most processed cheeses do not contain enough tyramine to cause hypertensive effects, although some aged cheeses (such as Stilton) do.[15][16]

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 displacement of norepinephrine (noradrenaline) from neuronal storage vesicles by acute tyramine ingestion is thought to cause the vasoconstriction and increased heart rate and blood pressure of the pressor response. In severe cases, adrenergic crisis can occur.[medical citation needed] Although the mechanism is unclear, tyramine ingestion also triggers migraines in sensitive individuals. Vasodilation, dopamine, and circulatory factors are all implicated in migraine. Double-blind trials suggest that the effects of tyramine on migraines may be adrenergic.[17] Migraineurs are over-represented among those with inadequate natural monoamine oxidase, resulting in similar problems individuals taking MAO inhibitors. Many migraine triggers are high in tyramine.[18]

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.[medical citation needed]

When using a MAO inhibitor (MAOI), the 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.[medical citation needed]

Research reveals a possible link between migraine and elevated levels of tyramine. A 2007 review published in Neurological Sciences[19] presented data showing migraine and cluster headaches are characterised by an increase of circulating neurotransmitters and neuromodulators (including tyramine, octopamine and synephrine) in the hypothalamus, amygdala and dopaminergic system.

Biosynthesis[edit]

Biochemically, tyramine is produced by the decarboxylation of tyrosine via the action of the enzyme tyrosine decarboxylase.[20] Tyramine can, in turn, be converted to methylated alkaloid derivatives N-methyltyramine, N,N-dimethyltyramine (hordenine), and N,N,N-trimethyltyramine (candicine).

In humans, tyramine is produced from tyrosine, as shown in the following diagram.

Chemistry[edit]

In the laboratory, tyramine can be synthesized in various ways, in particular by the decarboxylation of tyrosine.[21][22][23]

Tyrosine decarboxylation

Legal status[edit]

United States[edit]

Tyramine is not scheduled at the federal level in the United States and is therefore legal to buy, sell, or possess.[24]

Status in Florida[edit]

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 whatever. 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".[25] 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.[citation needed] Given that tyramine occurs naturally in many foods and drinks (most commonly as a by-product of bacterial fermentation e.g. wine, cheese, chocolate), Florida's total ban on the substance may prove difficult to enforce.[26]

Names[edit]

Tyramine has also been called 4-hydroxyphenethylamine, para-tyramine, mydrial, or uteramin. The latter two names are not common. The IUPAC name is 4-(2-aminoethyl)phenol.

See also[edit]

References[edit]

  1. ^ a b The Merck Index, 10th Ed. (1983), p.1405, Rahway: Merck & Co.
  2. ^ PubChem
  3. ^ T. A. Smith (1977) Phytochem. 16 9-18.
  4. ^ Philips, Rozdilsky Boulton (Feb 1978). "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): 51–57. PMID 623853. 
  5. ^ Navarro, Gilmour Lewin (10 July 2006). "A Rapid Functional Assay for the Human Trace Amine-Associated Receptor 1 Based on the Mobilization of Internal Calcium". J Biomol Screen. 11 (6): 668–693. doi:10.1177/1087057106289891. PMID 16831861. 
  6. ^ Liberles, Buck (10 August 2006). "A second class of chemosensory receptors in the olfactory epithelium". Nature. 441 (7103): 645–650. doi:10.1038/nature05066. PMID 16878137. 
  7. ^ Xie, Westmoreland Miller (May 2008). "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.". J. Pharm. 441 (2): 629–640. doi:10.1124/jpet.107.135079. PMID 18310473. 
  8. ^ "Trimethylamine monooxygenase (Homo sapiens)". BRENDA. Technische Universität Braunschweig. July 2016. Retrieved 18 September 2016. 
  9. ^ Krueger SK, Williams DE (June 2005). "Mammalian flavin-containing monooxygenases: structure/function, genetic polymorphisms and role in drug metabolism". Pharmacol. Ther. 106 (3): 357–387. doi:10.1016/j.pharmthera.2005.01.001. PMC 1828602Freely accessible. PMID 15922018. 
    Table 5: N-containing drugs and xenobiotics oxygenated by FMO
  10. ^ a b 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. 
  11. ^ a b Lindemann L, Hoener MC (May 2005). "A renaissance in trace amines inspired by a novel GPCR family". Trends Pharmacol. Sci. 26 (5): 274–281. doi:10.1016/j.tips.2005.03.007. PMID 15860375. 
  12. ^ a b Wang X, Li J, Dong G, Yue J (February 2014). "The endogenous substrates of brain CYP2D". Eur. J. Pharmacol. 724: 211–218. doi:10.1016/j.ejphar.2013.12.025. PMID 24374199. The highest level of brain CYP2D activity was found in the substantia nigra (Bromek et al., 2010). The in vitro and in vivo studies have shown the contribution of the alternative CYP2D-mediated dopamine synthesis to the concentration of this neurotransmitter although the classic biosynthetic route to dopamine from tyrosine is active. CYP2D6 protein level is approximately 40% lower in the frontal cortex, cerebellum, and hippocampus in PD patients, even when controlling for CYP2D6 genotype (Mann et al., 2012). ... Tyramine levels are especially high in the basal ganglia and limbic system, which are thought to be related to individual behavior and emotion (Yu et al., 2003c). Studies have demonstrated that dopamine is formed from p-tyramine as well as m-tyramine via tyramine 3-hydroxylation or 4-hydroxylation by rat CYP2D2, 2D4, and 2D18 as well as human CYP2D6. ... Both rat CYP2D and human CYP2D6 have a higher affinity for m-tyramine compared with p-tyramine for the generation of dopamine. Rat CYP2D isoforms (2D2/2D4/2D18) are less efficient than human CYP2D6 for the generation of dopamine from p-tyramine. The Km values of the CYP2D isoforms are as follows: CYP2D6 (87–121 μm) ≈ CYP2D2 ≈ CYP2D18 > CYP2D4 (256 μm) for m-tyramine and CYP2D4 (433 μm) > CYP2D2 ≈ CYP2D6 > CYP2D18 (688 μm) for p-tyramine (Bromek et al., 2010; Thompson et al., 2000). 
  13. ^ Sathyanarayana Rao TS and Vikram K. Yeragani VK (2009) Hypertensive crisis and cheese Indian J Psychiatry. 51(1): 65–66.
  14. ^ E. Siobhan Mitchell Antidepressants, chapter in Drugs, the Straight Facts, edited by David J. Triggle. 2004, Chelsea House Publishers
  15. ^ Stahl SM, Felker A (2008). "Monoamine oxidase inhibitors: a modern guide to an unrequited class of antidepressants". Cns Spectrums. 13 (10): 855–870. PMID 18955941. 
  16. ^ Tyramine-restricted Diet 1998, W.B. Saunders Company.
  17. ^ http://www.bmj.com/content/1/6070/1191?variant=abstract
  18. ^ http://www.headaches.org/headache-sufferers-diet/
  19. ^ D'Andrea, G; Nordera, GP; Perini, F; Allais, G; Granella, F (May 2007). "Biochemistry of neuromodulation in primary headaches: focus on anomalies of tyrosine metabolism". Neurological Sciences. 28, Supplement 2 (S2): S94–S96. doi:10.1007/s10072-007-0758-4. PMID 17508188 
  20. ^ Tyrosine metabolism - Reference pathway, Kyoto Encyclopedia of Genes and Genomes (KEGG)
  21. ^ G. Barger (1909). "CXXVII.?Isolation and synthesis of p-hydroxyphenylethylamine, an active principle of ergot soluble in water". J. Chem. Soc. 95: 1123. doi:10.1039/ct9099501123. 
  22. ^ Waser, Ernst (1925). "Untersuchungen in der Phenylalanin-Reihe VI. Decarboxylierung des Tyrosins und des Leucins". Helvetica Chimica Acta. 8: 758–773. doi:10.1002/hlca.192500801106. 
  23. ^ Buck, Johannes S. (1933). "Reduction of Hydroxymandelonitriles. A New Synthesis of Tyramine". Journal of the American Chemical Society. 55 (8): 3388–3390. doi:10.1021/ja01335a058. 
  24. ^ §1308.11 Schedule I
  25. ^ Florida Statutes - Chapter 893 - DRUG ABUSE PREVENTION AND CONTROL
  26. ^ http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4435245/