Tyramine
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Tyramine ( ) (also spelled tyramin), also known under several other names, is a naturally occurring trace amine derived from the amino acid tyrosine. 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
plant Plants are the eukaryotes that form the Kingdom (biology), kingdom Plantae; they are predominantly Photosynthesis, photosynthetic. This means that they obtain their energy from sunlight, using chloroplasts derived from endosymbiosis with c ...
s and
animal Animals are multicellular, eukaryotic organisms in the Biology, biological Kingdom (biology), kingdom Animalia (). With few exceptions, animals heterotroph, consume organic material, Cellular respiration#Aerobic respiration, breathe oxygen, ...
s, and is metabolized by various
enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...
s, 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: * 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 Scientists more and more consider tyramine in food as an aspect of safety. 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. 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.


In plants

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


In animals

Tyramine also plays a role in animals including: In
behavior Behavior (American English) or behaviour (British English) is the range of actions of Individual, individuals, organisms, systems or Artificial intelligence, artificial entities in some environment. These systems can include other systems or or ...
al and motor functions in '' Caenorhabditis elegans''; '' Locusta migratoria'' swarming behaviour; and various nervous roles in '' Rhipicephalus'', '' Apis'', '' Locusta'', '' Periplaneta'', '' Drosophila'', '' Phormia'', '' Papilio'', '' Bombyx'', '' Chilo'', '' Heliothis'', '' Mamestra'', '' Agrotis'', and '' Anopheles''.


Biological activity

Tyramine is a norepinephrine and dopamine releasing agent (NDRA) and indirectly acting sympathomimetic. Evidence for the presence of tyramine in the human brain has been confirmed by postmortem analysis. 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 the
trace amine-associated receptor Trace amine-associated receptors (TAARs), sometimes referred to as trace amine receptors (TAs or TARs), are a class of G protein-coupled receptors that were discovered in 2001. TAAR1, the first of six functional human TAARs, has gained considerab ...
(TAAR1). The TAAR1 receptor is found in the
brain The brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head (cephalization), usually near organs for ...
, as well as peripheral tissues, including the kidneys. Tyramine is a full agonist of the TAAR1 in rodents and humans. Tyramine is physiologically metabolized by monoamine oxidases (primarily MAO-A), FMO3, PNMT, DBH, and CYP2D6.
Table 5: N-containing drugs and xenobiotics oxygenated by FMO
/ref> Human monoamine oxidase enzymes metabolize tyramine into 4-hydroxyphenylacetaldehyde. 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. 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. For this reason, it is still called the "cheese reaction" or "cheese crisis", although other foods can cause the same problem. Most processed cheeses do not contain enough tyramine to cause hypertensive effects, although some aged cheeses (such as Stilton) do. 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. 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. Research reveals a possible link between migraines and elevated levels of tyramine. A 2007 review published in Neurological Sciences 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. 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). 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. Tyramine, like phenethylamine, is a monoaminergic activity enhancer (MAE) of serotonin, norepinephrine, and dopamine in addition to its catecholamine-releasing activity. That is, it enhances the
action potential An action potential (also known as a nerve impulse or "spike" when in a neuron) is a series of quick changes in voltage across a cell membrane. An action potential occurs when the membrane potential of a specific Cell (biology), cell rapidly ri ...
-mediated release of these monoamine neurotransmitters. The compound is active as a MAE at much lower concentrations than the concentrations at which it induces the release of catecholamines. The MAE actions of tyramine and other MAEs may be mediated by TAAR1 agonism.


Biosynthesis

Biochemically, tyramine is produced by the decarboxylation of tyrosine via the action of the enzyme tyrosine decarboxylase. Tyramine can, in turn, be converted to methylated
alkaloid Alkaloids are a broad class of natural product, naturally occurring organic compounds that contain at least one nitrogen atom. Some synthetic compounds of similar structure may also be termed alkaloids. Alkaloids are produced by a large varie ...
derivatives ''N''-methyltyramine, ''N'',''N''-dimethyltyramine (hordenine), and ''N'',''N'',''N''-trimethyltyramine (candicine). File:Tyramine.svg, Tyramine File:Methyltyramine.svg, ''N''-Methyltyramine File:Dimethyltyramine.svg, ''N'',''N''-Dimethyltyramine (hordenine) File:Candicine.svg, ''N'',''N'',''N''-Trimethyltyramine (candicine) In humans, tyramine is produced from tyrosine, as shown in the following diagram.


Chemistry

In the laboratory, tyramine can be synthesized in various ways, in particular by the decarboxylation of tyrosine.


Society and culture


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 Florida ( ; ) is a U.S. state, state in the Southeastern United States, Southeastern region of the United States. It borders the Gulf of Mexico to the west, Alabama to the northwest, Georgia (U.S. state), Georgia to the north, the Atlantic ...
without a license at any purity level or any form whatsoever. The language in the Florida
statute A statute is a law or formal written enactment of a legislature. Statutes typically declare, command or prohibit something. Statutes are distinguished from court law and unwritten law (also known as common law) in that they are the expressed wil ...
says tyramine is illegal in "any material, compound, mixture, or preparation that contains any quantity of yramineor that contains any of ts 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." 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. 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.


Notes


References

{{Chocolate Antihypotensive agents Migraine Monoamine oxidase inhibitors Monoaminergic activity enhancers Norepinephrine-dopamine releasing agents Peripherally selective drugs Phenethylamine alkaloids Phenethylamines TAAR1 agonists Trace amines 4-Hydroxyphenyl compounds Aminoethyl compounds