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Tetrodotoxin Niharika Mandal et al. / Journal of Pharmacy Research 2012,5(7),3567-3570 Review Article Available online through ISSN: 0974-6943 http://jprsolutions.info Tetrodotoxin: An intriguing molecule Niharika Mandal*, Samanta Sekhar Khora, Kanagaraj Mohanapriya, and Soumya Jal School of Biosciences and Technology, VIT University, Vellore-632013 Tamil Nadu, India Received on:07-04-2012; Revised on: 12-05-2012; Accepted on:16-06-2012 ABSTRACT Tetrodotoxin (TTX) is one of the most potent neurotoxin of biological origin. It was first isolated from puffer fish and it has been discovered in various arrays of organism since then. Its origin is still unclear though some reports indicate towards microbial origin. TTX selectively blocks the sodium channel, inhibiting action potential thereby, leading to respiratory paralysis. TTX toxicity is mainly caused due to consumption of puffer fish. No Known antidote for TTX exists. Treatment is symptomatic. The present review is therefore, an effort to give an idea about the distribution, origin, structure, pharmacol- ogy, toxicity, symptoms, treatment, resistance and application of TTX. Key words: Tetrodotoxin, Neurotoxin, Puffer fish. INTRODUCTION One of the most intriguing biotoxins isolated and described in the twentieth cantly more toxic than TTX. Palytoxin and maitotoxin have potencies nearly century is the neurotoxin, Tetrodotoxin (TTX, CAS Number [4368-28-9]). 100 times that of TTX and Saxitoxin, and all four toxins are unusual in being A neurotoxin is a toxin that acts specifically on neurons usually by interact- non-proteins. Interestingly, there is also some evidence for a bacterial bio- ing with membrane proteins and ion channels mostly resulting in paralysis. genesis of saxitoxin, palytoxin, and maitotoxin in living animals the toxin TTX is a poison so lethal that the US Food and Drug Administration warn acts primarily on myelinated (sheathed) peripheral nerves and does not it can lead to “rapid and violent death”. It is named after the order of fish appear to cross the blood-brain barrier.” from which it is most commonly associated, the Tetraodontiformes. The member of this order includes the various types of puffer fish. It was first Distribution isolated in 1909 from Spheroides rubripes (puffer fish).[1] Pure crystalline A total of 22 species of puffers in the family tetraodontidae are reported to form of TTX was isolated in 1950 from the overies of Fugu rubripes contain TTX, [8] while the closely related porcupine fish and boxfish does (puffer fish).[2] TTX was believed to occur only in puffer fish for a long not contain TTX. TTX is accumulated in the liver, gonads, intestine, muscle time, however the toxin has been found in a variety of animals. The toxin is and skin of the puffer fish.[9-10] The distribution of TTX in puffer fish varies variously used as a defensive biotoxin to ward off predation as in case of between species and at different seasons and geographic localities. Other puffer fish,[3] or as both defensive and predatory venom like in the case of marine organisms which contain TTX are worms such as Lineus Fuscoviridis blue ringed octopus.[4-6] annelids like Pseudopolamilla occelata, Snails like Charonia and Niotha, Crustaceans like horseshoe crab (Carcinoscorpius rotundicauda) as well TTX is a non protienaceous low molecular weight (319.28 amu) neuro- as Xanthid Crabs of different genera, starfish of genus Astropecte, goby fish toxin. TTX is highly polar and hygroscopic and is only sparingly soluble in (Yongeichthys criniger) etc. Some blue-ringed octopuses of genus acidified water. It has a pk of 8.5. A single milligram or less of TTX - an Hapalochlaena contain TTX in their posterior salivary glands and soft amount that can be placed on the head of a pin, is enough to kill an adult . tissues.[6] Some terrestrial vertebrates like Californian newts (Taricha torosa) The LD50 of TTX for human is 10.2µg/kg. [7] and frogs from genus Atelopus were also reported to contain TTX.[11-12] This highly potent neurotoxin is found in a diverse array of organisms, including According to William H. Light, “Tetrodotoxin is ten times as deadly as the bacteria, dinoflagellates, arthropods, nematodes, mollusks, fish, and am- venom of the many-banded krait of Southeast Asia. It is 10 to 100 times as phibians. The number of species containing TTX continues to grow. lethal as black widow spider venom (depending upon the species) when administered to mice, and more than 10,000 times deadlier than cyanide. It Origin has the same toxicity as saxitoxin which causes paralytic shellfish poison- The metabolic source of TTX is still uncertain. Until now TTX was be- ing ([both TTX and saxitoxin block the Na+ channel - and both are found in lieved to be produced by the animal (or the host). However, recent reports the tissues of puffer fish]) A recently discovered, naturally occurring con- point towards the bacterial origin of this toxin TTX is considered likely to gener of tetrodotoxin has proven to be four to five times as potent as TTX. be produced by marine bacteria associated with marine animals. The most Except for a few bacterial protein toxins, only palytoxin, a bizarre molecule common TTX producing bacteria are Vibrio bacteria, with Vibrio isolated from certain zoanthideans (small, colonial, marine organisms re- alginolvticus being the most common species. Puffer fish,[13] sembling sea anemones) of the genus Palythoa, and maitotoxin, found in Chaetognathas,[14] and Nemerteans,[15] have been shown to contain and Vibrio certain fishes associated with ciguatera poisoning, are known to be signifi- alginolvticus TTX. These TTX producing bacteria are primarily marine species,[16-19] although a few freshwater species have also been identified.[20] [21-23] *Corresponding author. A vast array of taxonomic groups is known to possess TTX. This is unusual for animal toxins, as they are usually very specific for a particular Niharika Mandal Research Associate group. In marine organisms the accepted hypothesis is that the TTX present School of Biosciences and Technology in metazoans results from either dietary uptake of bacterially produced [22-26] Medical Biotechnology Laboratory TTX or symbiosis with TTX producing bacteria. However this hy- [21, 27-30] SMV 203, VIT University, pothesis is not acceptable for TTX present in terrestrial taxa. This is Vellore 632013,Tamil Nadu, India probably because TTX in terrestrial metazoans appears to be limited to a Journal of Pharmacy Research Vol.5 Issue 7.July 2012 3567-3570 Niharika Mandal et al. / Journal of Pharmacy Research 2012,5(7),3567-3570 single class of vertebrates (Amphibia) with limited distributions within the Tetrodotoxin Toxicity class, unlike marine species in which TTX is found in a wide array of taxa. The first recorded case of tetrodotoxin poisoning was on 7 September Moreover, the presence of multiple analogs of TTX are common in the 1774,[1] when Captain James Cook recorded his crew eating some local TTX profiles of some TTX bearing amphibians, but are absent or a very tropic fish (puffer fish), then feeding the remains to the pigs kept on board. minor component in the TTX profiles of marine taxa or TTX producing The crew experienced numbness and shortness of breath, while the pigs bacteria.[31-37] Therefore, several genera of bacteria have been identified as were all found dead the next morning. It was clear that the crew received a TTX producers,[19, 26, 38] but these findings are controversial.[39-41]The pro- mild dose of tetrodotoxin, while the pigs ate the puffer fish body parts that duction of TTX in animals has not been firmly established, and there re- contain most of the toxin, thus being fatally poisoned. Tetrodotoxin toxic- mains much debate in the literature as to whether the bacteria are truly the ity mostly occurs due to the consumption of puffer fish. The organs (e.g. source of TTX in animals. liver) of the puffer fish can contain levels of tetrodotoxin sufficient to pro- duce paralysis of the diaphragm and death due to respiratory failure,[1] On Structure the other hand, puffer fish is considered as a notorious delicacy in Japan. It The structure of TTX was first elucidated in 1964 at the Natural Product is prepared by chefs who are specially trained and certified by the govern- Symposium of the International Union of Pure applied Chemistry by four ment. Despite these precautions, many cases of tetrodotoxin poisoning are different Lab groups including K. Tsuda, T. Goto, R.B. Woodward and H.S. reported each year in patients ingesting puffer fish. Mosher.[42] TTX has a guanidium ion with a complex oxygenated cyclohex- ane framework with both guanidine and orth-oacid functional groups. [43-45] TTX is not always fatal, but at near-lethal doses, it can leave a person in a Numerous natural, synthetic and semi-synthetic analogs of TTX have been state of near-death for several days, while the person remains conscious. reported. Amphibians have been a plentiful source of TTX analogs.[31-32, 46- That is why, TTX has been used an ingredient in Haitian Vodou and the 48] The hemilactal forms of TTX are more common naturally occurring closest approximation of zombieism, an idea popularized by Harvard- analogs. These analogs are very potent and have toxicities equivalent or trained ethnobotanist Wade Davis in a 1983 paper, and in his 1985 book, greater than TTX itself. [47-51] The structure and analogs of TTX are shown The Serpent and the Rainbow. This idea was dismissed by the scientific in Fig1. community in the 1980s, as the descriptions of voodoo zombies do not match the symptoms displayed by victims of tetrodotoxin poisoning, and Pharmacology the alleged incidents of zombies created in this manner could not be sub- The pharmacology of TTX was studied by Takahashi in 1889,[42] but, it stantiated.[58] was not until 1950’s that more detailed understanding of the pharmacology of TTX began to emerge.
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