The Tetradetoxin (TTX) is an aminoperhydroquinazoline poison found mainly in the liver and ovaries of fish in the order of the Tetraodontiformes.
It is a potent marine neurotoxin, named after the order of the fish of which it is most commonly associated, the Tetraodontiformes (tetras-four and odontos-tooth) or balloon fish.
He Tetraodon Is equipped with four large, almost fused teeth forming a beak-like structure used to crack molluscs and other invertebrates, as well as scraping coral and general reef grazing.
Members of this order include the fahaka balloonfish (Tetraodon fahaka), the Congo balloonfish (Tetraodon miurus), and the giant mbu balloonfish (Tetraodon mbu).
The balloon fish of the genus Fugu (F. flavidus, F. poecilonotus and F. niphobles), Arothron (A. nigropunctatus), Chelonodon (Chelonodon spp.) And Takifugu (Takifugu rubripes) also store TTX and related analogues in their tissues , SF).
Tetrodotoxin (TTX) is a natural toxin that has been responsible for human poisoning and death. The most common form of intoxication is through the ingestion of this type of contaminated fish, considered a deli In certain culinary cultures.
TTX is believed to be limited to Southeast Asian regions, but recent studies have shown that the toxin has spread to regions in the Pacific and the Mediterranean. There is no known antidote for TTX that is a potent sodium channel inhibitor (Vaishali Bane, 2014).
Properties
The empirical formula of tetrodotoxin is C11H17N3O8 and its molecular weight is 319.268 g / mol. It is a colorless crystalline solid that darkens when heated above 220 ° C (The National Institute for Occupational Safety and Health (NIOSH), 2014).
The molecule is very soluble in water, being able to dissolve 1 x 106 grams per liter. It has a pKa of 8.76 and is thermally stable except in alkaline medium, where it releases toxic fumes of nitrogen oxide (National Center for Biotechnology Information, 2017).
The tetrodotoxin safety sheet specifies that the median oral lethal dose (LD50) for mice is 334 μg per kg. Assuming that the lethal dose for humans is similar, 25 milligrams of tetrodotoxin is expected to kill a 75 kg person.
The amount required to reach a lethal injection dose is much lower, 8 μg per kg, or a little over half a milligram to kill a 75 kg (170 lb) person (Gilbert, 2012).
A recent study using tetrodotoxin therapeutically shows that tetrodotoxin used in conjunction with bupivacaine prolongs the local anesthetic effect.
Tetrodotoxin is being investigated by Wex Pharmaceuticals for the treatment of chronic pain and in studies in patients with advanced cancer, as well as for the treatment of opioid dependence (Benzer, 2015).
Pathophysiology
The flow of sodium ions into nerve cells is a necessary step in conducting nerve impulses in excitable nerve fibers and along axons. Normal axonal cells have high concentrations of K + ions and low concentrations of Na + ions and have a negative potential.
Stimulation of the axon results in an action potential arising from a flow of Na + ions within the cell and the generation of a positive membrane potential. The propagation of this depolarization along the nerve terminal presages all other events.
Na + ions flow through the cell membrane using the sodium ion channel, a channel that is selective for sodium ions on potassium ions on an order of magnitude.
The channel consists of a single peptide chain with four repeating units, each unit consisting of six trans-membrane propellers. The trans-membrane pore is formed when the four units are folded into a cluster with the pore in the center (figure 3).
Peptides that make up the sodium channel (left and center) and view of the sodium channel from outside the cell (right).
Tetrodotoxin acts by blocking the conduction of nerve impulses along nerve fibers and axons. The victim finally dies from respiratory paralysis.
The molecule is quite specific for blocking the Na + ion channel and therefore the flow of Na + ions without having no effect on K + ions. The binding to the channel is relatively narrow (Kd = 10-10 nM). While the hydrated sodium ion is reversibly bound on a nanosecond time scale, the tetrodotoxin is bound for tens of seconds.
Membrane with ion channel. With hydrated sodium ion (left) and with tetrodotoxin (der.).
Tetrodotoxin, much larger than the sodium ion, acts like a cork in a bottle, preventing the flow of sodium until it diffuses slowly. A deadly dose of tetrodotoxin is only one milligram.
The tetrodotoxin competes with the hydrated sodium cation and enters the Na + channel to which it binds. It is proposed that this binding results from the interaction of the positively charged guanidino group on the tetrodotoxin and negatively charged carboxylate groups on side chains at the mouth of the channel. Saxitoxin, a natural product of dinoflagellates, acts similarly and is also a powerful neurotoxin.
The sodium ion channel in the host should be different from that of the victim, since they should not be susceptible to the toxin. It has been shown that for balloon fish, the sodium ion channel protein has undergone a mutation that changes the amino acid sequence making the channel insensitive to tetrodotoxin.
The spontaneous mutation that caused this structural change is beneficial for the balloon fish, as it allowed it to incorporate the symbiotic bacteria and to use the toxin that it produces to its best advantage.
Stages of intoxication and toxicity
The first symptom of intoxication is a slight numbness of the lips and tongue, which appears between 20 minutes and three hours after eating the balloon fish.
The next symptom is the growing Paresthesia On the face and limbs, which can be followed by feelings of lightness or floating. You can also experience headache , Epigastric pain, nausea, diarrhea and / or vomiting.
Occasionally, some drumming or difficulty walking may occur. The second stage of intoxication is growing paralysis. Many victims are unable to move and even sitting can be difficult.
Increased respiratory distress occurs where speech is affected, and the victim usually presents dyspnea, cyanosis, and hypotension. Paralysis increases and may occur Convulsions , Mental deterioration And cardiac arrhythmia.
The victim, although completely paralyzed, may be conscious and in some cases completely lucid until shortly before death. Death usually occurs within 4 to 6 hours, with a known range of about 20 minutes to 8 hours.
From 1974 to 1983 there were 646 cases of Fugu intoxication in Japan, with 179 deaths. Estimates of up to 200 cases per year have been reported with a mortality rate close to 50%.
Outbreaks outside the countries of the Indo-Pacific region are rare, with only a few reported in the United States. Sushi chefs who wish to prepare fugu must be authorized by the Japanese government.
Tetrodotoxin is ten times more lethal than krait poison from Southeast Asia, which in turn is 10 to 100 times more deadly than black widow spider venom when administered to mice and more than 10,000 times more deadly than cyanide.
It has the same toxicity as saxitoxin that causes paralytic seafood intoxication (both TTX and saxitoxin block the Na + channel and both are found in balloon fish tissues).
The"zombie powders"
One particularly curious detail regarding the TTX is its use in the so-called zombie powder. According to numerous reports, voodoo priests known as bokor create a white and dusty compound called coupé poudre. The ingredients of this powder can supposedly turn a person into a zombie. In the 1980s, Harvard ethnobotanist Wade Davis traveled to Haiti to investigate zombies and"zombie dust".
Although different bokor used different ingredients in their powders, Davis found that"there are five constant animal ingredients: burned and buried human remains (usually bone), a small tree frog, a polychaete worm, a great New World toad and one or more species Of globe fish. The most potent ingredients are balloon fish, which contain deadly neurotoxins known as tetrodotoxin,"Davis wrote in Harper's Magazine.
Although the scientific community has criticized Davis's research, it is undeniable that his identification of tetrodotoxin as an active ingredient in zombie dust has considerable scientific merit (Lallanilla, 2013).
References
- Benzer, T. (2015, December 28). Tetrodotoxin Toxicity. Retrieved from emedicine.medscape.com.
- Gilbert, S. (2012, May 13). Tetrodotoxin. Retrieved from toxipedia.org.
- Johnson, J. (S.F.). Tetrodotoxin... an ancient alkaloid from the sea... Retrieved from chm.bris.ac.uk.
- Lallanilla, M. (2013, October 24). How to Make a Zombie (Seriously). Retrieved from livescience.com.
- National Center for Biotechnology Information. (2017, March 4). PubChem Compound Database; CID = 11174599. Recovered from PubChem.
- Tetrodotoxin: Mode of Action. (2001). Recovered from life.umd.edu.
- The National Institute for Occupational Safety and Health (NIOSH). (2014, November 20). TETRODOTOXIN: Biotoxin. Retrieved from cdc.gov.
- Vaishali Bane, M.L. (2014). Tetrodotoxin: Chemistry, Toxicity, Source, Distribution and Detection. Toxins 6 (2), 693-755.