Tetrodotoxin

Structural formula
General
Surname	Tetrodotoxin
Molecular formula	C 11 H 17 N 3 O 8
Brief description	colorless and odorless solid
External identifiers / databases
CAS number 4368-28-9 EC number 224-458-8 ECHA InfoCard 100.022.236 PubChem 20382 ChemSpider 21248349 DrugBank DB05232 Wikidata Q379842
properties
Molar mass	319.27 g · mol -1
Physical state	firmly
solubility	heavy in water
safety instructions
GHS labeling of hazardous substances danger H and P phrases H: 300-310-330-319 P: 280-302 + 350-330-304 + 340-310-361
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

The tetrodotoxin (to lat. Tetraodontidae , Vierzähner '), short- TTX , is a neurotoxin , which is a zwitterionic alkaloid with guanidine is partial structure. In 1964 the structure of the tetrodotoxin was elucidated by Robert B. Woodward . It is good in acetone , but poorly soluble in water . Anhydro-TTX is a molecularly slightly different variant of this poison .

Poison carrier

TTX and Anhydro-TTX occur in some, mostly marine, poisonous animals . Puffer fish , porcupine fish and other families of the Tetraodontiformes , western American newts , stump foot frogs , some crabs , snails , starfish and blue-ringed octopus ( Hapalochlaena ) are carriers of this poison. Well-known land animals in which TTX could be detected include the flatworm species Bipalium adventitium and Bipalium kewense .

Tetrodotoxin could be isolated from puffer fish ovaries for the first time in 1950 , after the isolation attempts had already started in 1909.

education

Because of the enormous diversity of known TTX-containing animals , it is believed that they do not produce it themselves, but rather sequester it from external sources .

Strains from four genera of marine bacteria that produce TTX or Anhydro-TTX and thus could serve as sources have been identified: Pseudomonas ( Pseudomonas spp.), Vibrio ( Listonella pelagia or Vibrio pelagius ), Shewanella ( Shewanella alga ) and Alteromonas ( Alteromonas tetraodoni and Pseudoalteromonas haloplanktis or Alteromonas haloplanktis ). As a hint, when Takifugu poecilonotus Pseudomonas was identified on the skin of the puffer fish .

Since then, members of the Vibrionaceae have been the focus of the investigations, after other members of Vibrio could be made likely as sources of TTX. Thus were Vibrio fischeri (now aliivibrio fischeri ) in olive greens stone crab ( Atergatis floridus ) and Vibrio alginolyticus from the stomach of puffer fish vermicularis Takifugu isolated. It is therefore assumed that TTX is not produced by the animals, but that they receive it through ingestion of Vibrio bacteria or through a symbiosis with them.

The biosynthesis of tetrodotoxin is not fully understood. A Japanese research group of the University of Nagoya to Tohru Fukuyama managed a total synthesis of the compound from 1,4-benzoquinone over 31 synthetic steps.

effect

Tetrodotoxin blocks voltage-activated sodium channels , which are also found in neurons . A distinction must be made between the TTX-sensitive (Na _v 1.1 - Na _v 1.7, with the exception of Na _v 1.5) and TTX-resistant (Na _v 1.5, Na _v 1.8, Na _v 1.9) sodium channels. By blocking the channels, action potentials can no longer be triggered, as a result of which nerve and muscle excitation is hindered or prevented. The result is motor and sensory paralysis. Tetrodotoxin is one of the strongest non-protein poisons and is only surpassed in terms of toxicity by a few other poisons such as maitotoxin . The lethal dose of tetrodotoxin is approximately 10 micrograms per kilogram of body weight.

The symptoms of poisoning after ingestion of the poison (e.g. when eating the skin , liver or ovaries of the fugu ) begin within a very short time of about 45 minutes. The patient shows various symptoms of paralysis, including paralysis of the skeletal muscles and thus also of the respiratory muscles ; coordination and perception problems are also apparent. Ventilation and oral medication of charcoal may help. If the patient survives the first 24 hours after ingesting the poison, the prognosis is very good.

Example: If the lethal dose of 0.5 to 1 milligram is taken orally , the fatal effect only occurs after a certain period of time, so that it is usually still possible to rescue the victims. If the poison but intravenously injected , the whole is due to fast propagation nervous system paralyzed, and the person succumbs after a short time of a respiratory paralysis .

Oral tetrodotoxin poisoning can be divided into four degrees of severity, which are differentiated based on the symptoms:

• Grade 1: Sensory disturbances in the mouth and throat, possibly digestive problems
• Grade 2: extensive paresthesia and numbness, incipient symptoms of paralysis, coordination disorders
• Grade 3: extensive flaccid paralysis with respiratory insufficiency, aphonia , autonomic deficits (hypotension, mydriasis )
• Grade 4: severe respiratory insufficiency, circulatory failure, impaired consciousness, brady arrhythmias

use

Since tetrodotoxin has an analgesic effect in very small amounts, it is also being considered for use in cancer therapies.

It is also the antidote to the alkaloid toxin batrachotoxin in poison dart frogs .

In biological and neurological research, TTX is used to selectively block sodium channels experimentally .

Cinematic mention

Tetrodotoxin is for example in the US action - thriller Law Abiding shown (2009), in which the resulting paralysis is made as a way to support the torture to Use and in the Wes Craven film The Serpent and the Rainbow .from 1988 in which the extraction of the poison used in Voodoo plays a central role.

literature

• Kyosuke Tsuda: tetrodotoxin, poison in bowl fish. In: Natural Sciences . 1966, 53 (7), pp. 171-176.
• Gerhard G. Habermehl, Hans Chr. Krebs: poison animals and their weapons. In: Natural Sciences. 1986, 73 (2), pp. 459-470.
• DF Hwang, O. Arakawa et al. a .: Tetrodotoxin-producing bacteria from the blue-ringed octopus Octopus maculosus. In: Marine Biology. , 1989, 100 (39), pp. 327-332.
• DF Hwang, KP Tai u. a .: Tetrodotoxin and derivatives in several species of the gastropod Naticidae. In: Toxicon , 1991, 29 (8), pp. 1019-1024.

Web links

• Bernhard Peter: Tetrodotoxin

Individual evidence

1. ↑ ^{a b} Tetrodotoxin data sheet (PDF) from Carl Roth , accessed on January 27, 2019.
2. ↑ ^{a b} Entry on tetrodotoxin in the GESTIS substance database of the IFA , accessed on January 9, 2019(JavaScript required) .
3. ↑ RB Woodward, J. Zanos. Gougoutas: The Structure of Tetrodotoxin. In: Journal of the American Chemical Society. 86, 1964, p. 5030, doi : 10.1021 / ja01076a076 .
4. ↑ Becky L. Williams, Charles T. Hanifin, Edmund D. Brodie Jr., Roy L. Caldwell: Ontogeny of tetrodotoxin levels in blue-ringed octopuses: Maternal investment and apparent independent production in offspring of Hapalochlaena lunulata. In: Journal of Chemical Ecology , Volume 37, No. 1, 2011, pp. 10-17, doi : 10.1007 / s10886-010-9901-4 .
5. ↑ Amber N. Stokes et al .: Confirmation and Distribution of Tetrodotoxin for the First Time in Terrestrial Invertebrates: Two Terrestrial Flatworm Species (Bipalium adventitium and Bipalium kewense). PLoS ONE 9 (6): e100718, 2014, doi: 10.1371 / journal.pone.0100718 .
6. ↑ Usio Simidu, Kumiko Kita-Tsukamoto, Takeshi Yasumoto, Mari Yotsu: Taxonomy of four marine bacterial strains that produce tetrodotoxin. In: International journal of systematic bacteriology. Volume 40, Number 4, October 1990, pp. 331-336, doi : 10.1099 / 00207713-40-4-331 , PMID 2275851 .
7. ↑ Takeshi Yasumoto, Daisuke Yasumura, Mari Yotsu, Tooru Michishita, Amane Endo, Yuichi Kotaki: Bacterial production of tetrodotoxin and anhydrotetrodotoxin. In: Agricultural and Biological Chemistry , Vol. 50, No. 3, 1986, pp. 793-795. doi : 10.1080 / 00021369.1986.10867470 (free full text)
8. ↑ ^{a b} U. Simidu, T. Noguchi, DF Hwang, Y. Shida, K. Hashimoto: Marine bacteria which produce tetrodotoxin. In: Applied and Environmental Microbiology. Volume 53, Number 7, July 1987, pp. 1714-1715, PMID 3310884 , PMC 203940 (free full text).
9. ↑ T. Noguchi, DF Hwang, O. Arakawa, H. Sugita, Y. Deguchi, Y. Shida, K. Hashimoto: Vibrio alginolyticus, a tetrodotoxin-producing bacterium, in the intestines of the fish Fugu vermicularis vermicularis. In: Marine Biology , Vol. 94, No. 4, 1987, pp. 625-630, doi : 10.1007 / BF00431409 .
10. ↑ Tomoaki Maehara; Keisuke Motoyama; Tatsuya Toma; Satoshi Yokoshima; Tohru Fukuyama: Total Synthesis of (-) - Tetrodotoxin and 11 ‐ norTTX ‐ 6 (R) ‐ol in Angew. Chem. 129 (2017) 1571-1574, doi : 10.1002 / anie.201611574 .
11. ↑ Keigo Murakami; Tatsuya Toma; Tohru Fukuyama; Satoshi Yokoshima: Total Synthesis of Tetrodotoxin in Angew. Chem. 132 (2020) 6312-6316, doi : 10.1002 / ange.201916611 .
12. ↑ sodium channels . ( Spektrum.de [accessed on July 6, 2018]).
13. ↑ Vaishali Bane, Mary Lehane, Madhurima Dikshit, Alan O'Riordan, Ambrose Furey: Tetrodotoxin: Chemistry, Toxicity, Source, Distribution and Detection. In: Toxins. 6, 2014, p. 693, doi : 10.3390 / toxins6020693 .
14. ↑ Jorge Lago, Laura Rodríguez, Lucía Blanco, Juan Vieites, Ana Cabado: Tetrodotoxin, an Extremely Potent Marine Neurotoxin: Distribution, Toxicity, Origin and Therapeutical Uses. In: Marine Drugs. 13, 2015, p. 6384, doi : 10.3390 / md13106384 .
15. ↑ NA Hagen, P. du Souich u. a .: Tetrodotoxin for moderate to severe cancer pain: a randomized, double blind, parallel design multicenter study. In: Journal of pain and symptom management. Volume 35, Number 4, April 2008, pp. 420-429, doi : 10.1016 / j.jpainsymman.2007.05.011 . PMID 18243639 .