The tetrodotoxin (TTX) is a poisonous aminoperhydroquinazoline, found in the liver and ovaries of fish of the order tetraodontiformes; including the puffer fish. Likewise, it is in the newt, flatworms (flatworms), crabs, blue-ringed octopus, and a large number of bacteria.
Among the bacterial species in which tetrodotoxin (abbreviated as TTX) is found, are: Vibrio algynolyticus, Pseudoalteromonas tetraodonis, as well as in other bacteria of the genus Vibrio and Pseudomonas. From here it can be intuited that its origin is bacterial..
However, the presence of exocrine glands for the secretion of TTX in puffer fish, as well as its storage in salivary glands of the blue-ringed octopus, showed that certain animals may also have the ability to synthesize it.
TTX exerts its action on the body by blocking the sodium channels of neuronal axons and skeletal and smooth muscle cells; except for cardiac muscle cells, which have TTX resistant “gates”.
The main cause of sudden death in man mediated by TTX is its paralyzing action on the diaphragm and intercostal muscles; muscles needed for breathing. Therefore, death occurs within a few hours, after ingestion of TTX.
The median lethal oral dose (LD50) of tetrodotoxin for mice is 334 µg / kg body weight. Meanwhile, the LD50 for potassium cyanide is 8.5 mg / kg. This means that TTX is a poison about 25 times more potent than potassium cyanide..
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The upper image shows the molecular structure of tetrodotoxin with a spheres and rods model. The red spheres correspond to oxygen atoms, the blue spheres to nitrogen atoms, and the white and black spheres to hydrogens and carbons, respectively..
If you stop for a moment at the O atoms, you will see that six of them are found as hydroxyl groups, OH; therefore, there are six OH groups on the periphery of the molecule. Meanwhile, the two remaining atoms are as oxygenated bridges within condensed cyclic units..
On the other hand, there are barely three nitrogen atoms, but they belong to a unique group: guanidino. This group can carry a positive charge if C = NH gains a hydrogen ion, transforming into C = NHtwo+; it would therefore be located in the lower part of the molecule. While at the top, the -OH on top can be deprotonated and be like -O-.
Thus, tetrodotoxin can have two ionic charges at the same time in different regions of its structure; which, although it may seem intricate, is simplified by considering it a cage.
Tetrodotoxin can then be visualized as a cage, since its fused cycles represent a compact structure. Above it was said that it has six OH groups in its periphery (if it does not have a negative charge), in addition to three NH groups belonging to the guanidino group (if it does not have a positive charge)..
In total, then, the molecule is capable of donating up to nine hydrogen bonds; and likewise, it can accept the same number of bridges, and two more because of the internal oxygen atoms in its cycles. Therefore, said cage is quite active in terms of intermolecular interactions; he cannot "walk" around without being noticed.
This means that it is enough that there is a nitrogen or oxygenated surface for the tetrodotoxin to anchor due to the strong interactions. In fact, this is the reason why it blocks sodium channels, behaving like a cork-cage that prevents the passage of Na ions.+ inside cells.
Some characteristics or properties of tetrodotoxin are mentioned below:
-Its molecular formula CelevenH17N3OR8 and a molecular weight of 319.27 g / mol.
-TTX can be prepared from the ovaries of puffer fish. After homogenization, the proteins are precipitated, and the supernatant is subjected to chromatography on activated carbon; obtaining 8-9 g of pure TTX per 1,000 g of fish roe.
-Dehydrated TTX is a white powder, soluble in water and dilute acetic acid; but practically insoluble in organic solvents.
-It is heat stable, except in an alkaline medium. It is also unstable when heated to 100 ° C in an acid medium.
-When heated to 220 ° C, it darkens without decomposing.
-TTX is destroyed by strong acids and alkalis.
-It has a dissociation constant, pKa = 8.76 in water, and pKa = 9.4 in 50% alcohol.
-It is a monoacidic base, stable between a pH 3 - 8.5.
-The toxicity of TTX is eliminated by the action of 2% sodium hydroxide for 90 minutes..
-A TTX density of 1.3768 g / cm has been estimated3. Likewise, a boiling point of 458.31 ºC has been estimated..
TTX blocks Na channels+, preventing the propagation of action potentials or nerve impulses in excitable cells.
By preventing the spread of action potentials, TTX leads to a paralysis of muscle cells leading to the death of animals in a short time.
Na channels+, Like other ion channels, they are proteins that cross the plasma membrane. These are voltage-dependent; that is, they are capable of responding to an adequate variation of membrane potential with their opening.
TTX is a molecule of approximately 8 Å in diameter, which is placed on the outside of the Na channel+; exactly in the mouth that gives access to the canal, preventing the entry of Na+ through it. It is considered that a single molecule of TTX is sufficient to block a Na channel+.
TTX by blocking the entry of Na+ it prevents the formation of the action potential in the neuronal cell, as well as its propagation along the axon. In the same way, the formation of action potentials in muscle cells, a requirement for their contraction, is prevented..
Therefore, as the muscle cells do not contract, their paralysis occurs. In the case of the diaphragm muscle and the intercostal muscles, their paralysis blocks breathing, causing death within a few hours.
Low-dose TTX has analgesic action in patients with severe pain not relieved by conventional treatments. 24 patients suffering from terminal cancer were treated, subjecting them to 31 treatment cycles with doses of TTX between 15 and 90 µg / day.
As a result, a clinically significant reduction in pain intensity was observed in 17 of the 31 cycles. Pain relief persisted for two or more weeks. TTX effectively mitigated severe and refractory pain in most cancer patients.
Additionally, the Wex Pharmaceuticals company studies the use of tetrodotoxin for the treatment of pain in patients with advanced cancer. And also in opium users, in order to reduce the consumed dose of the drug.
A low dose of TTX produces paresthesia, which is a tingling and numbness around the mouth and fingers and toes. These symptoms are also part of the general symptoms of TTX poisoning..
There are contractions of the skeletal muscle as a whole, manifested by a difficulty in articulating words and swallowing. The pupils of poisoned people are fixed and dilated. The most dramatic thing is that people are completely paralyzed, but aware.
Cardiovascular signs and symptoms are characterized by chest pain, hypotension, and cardiac arrhythmia. The respiratory disturbance is manifested by shortness of breath and cyanosis; that is, bluish color of the skin and oral cavity.
Nausea, vomiting, and diarrhea are common in the gastrointestinal system..
The death rate of people who ingested TTX, and have not been treated, is greater than 50%. Death occurs within 4 to 6 hours after poisoning.
In some cases death can occur in as little as 20 minutes. TTX can kill a person at a dose as low as 1 to 4 mg..
In the past, most TTX poisonings were caused by ingestion of fugus. Fugus is a dish that is considered a delicacy of Japanese food and is prepared with puffer fish; which has its highest concentration of TTX in the liver and gonads.
Currently, controls have been established to reduce the risk of poisoning from this cause. The people who process the puffer fish and who prepare the fugus require a training of several years to obtain the dexterity that allows them to prepare the dish.
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