Tetrodotoxin

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Tetrodotoxin
Tetrodotoxin.svg
Tetrodotoxin-based-on-xtal-1970-3D-balls.png
Names
IUPAC name
(4R,4aR,5R,6S,7S,8S,8aR,10S,12S)-2-azaniumylidene-4,6,8,12-tetrahydroxy-6-(hydroxymethyl)-2,3,4,4a,5,6,7,8-octahydro-1H-8a,10-methano-5,7-(epoxymethanooxy)quinazolin-10-olate
Other names
anhydrotetrodotoxin, 4-epitetrodotoxin, tetrodonic acid, TTX
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.022.236 OOjs UI icon edit-ltr-progressive.svg
KEGG
PubChem CID
UNII
  • InChI=1S/C11H17N3O8/c12-8-13-6(17)2-4-9(19,1-15)5-3(16)10(2,14-8)7(18)11(20,21-4)22-5/h2-7,15-20H,1H2,(H3,12,13,14)/t2-,3-,4-,5+,6-,7+,9+,10-,11+/m1/s1 X mark.svgN
    Key: CFMYXEVWODSLAX-QOZOJKKESA-N X mark.svgN
  • InChI=1/C11H17N3O8/c12-8-13-6(17)2-4-9(19,1-15)5-3(16)10(2,14-8)7(18)11(20,21-4)22-5/h2-7,15-20H,1H2,(H3,12,13,14)/t2-,3-,4-,5+,6-,7+,9+,10-,11+/m1/s1
    Key: CFMYXEVWODSLAX-QOZOJKKEBM
  • O1[C@@H]4[C@@](O)([C@@H]3O[C@@]1(O)[C@@H](O)[C@]2(N\C(N/[C@H](O)[C@H]23)=N)[C@@H]4O)CO
  • zwitterion:O1[C@@H]4[C@@](O)([C@@H]3O[C@@]1([O-])[C@@H](O)[C@]2(N\C(N/[C@H](O)[C@H]23)=[NH2+])[C@@H]4O)CO
Properties
C11H17N3O8
Molar mass 319.270 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)

Tetrodotoxin (TTX) is a potent neurotoxin. Its name derives from Tetraodontiformes, an order that includes pufferfish, porcupinefish, ocean sunfish, and triggerfish; several of these species carry the toxin. Although tetrodotoxin was discovered in these fish, it is found in several other animals (e.g., in blue-ringed octopuses, rough-skinned newts, and moon snails). It is also produced by certain infectious or symbiotic bacteria like Pseudoalteromonas , Pseudomonas , and Vibrio as well as other species found in symbiotic relationships with animals and plants. [1] [2]

Contents

Although it produces thousands of intoxications annually and several deaths, [3] it has shown efficacy for the treatment of cancer-related pain in phase II and III clinical trials. [4]

Tetrodotoxin is a sodium channel blocker. It inhibits the firing of action potentials in neurons by binding to the voltage-gated sodium channels in nerve cell membranes and blocking the passage of sodium ions (responsible for the rising phase of an action potential) into the neuron. This prevents the nervous system from carrying messages and thus muscles from contracting in response to nervous stimulation. [5]

Its mechanism of action— selective blocking of the sodium channel— was shown definitively in 1964 by Toshio Narahashi and John W. Moore at Duke University, using the sucrose gap voltage clamp technique. [6]

Sources in nature

Apart from their bacterial species of most likely ultimate biosynthetic origin (see below), tetrodotoxin has been isolated from widely differing animal species, including: [1]

Tarichatoxin was shown to be identical to TTX in 1964 by Mosher et al., [12] [13] and the identity of maculotoxin and TTX was reported in Science in 1978, [14] and the synonymity of these two toxins is supported in modern reports (e.g., at Pubchem [15] and in modern toxicology textbooks [16] ) though historic monographs questioning this continue in reprint. [17]

The toxin is variously used by animals as a defensive biotoxin to ward off predation, or as both a defensive and predatory venom (e.g., in octopuses, chaetognaths, and ribbon worms). [18] Even though the toxin acts as a defense mechanism, some predators such as the common garter snake have developed insensitivity to TTX, which allows them to prey upon toxic newts. [19]

The association of TTX with consumed, infecting, or symbiotic bacterial populations within the animal species from which it is isolated is relatively clear; [1] presence of TTX-producing bacteria within an animal's microbiome is determined by culture methods, the presence of the toxin by chemical analysis, and the association of the bacteria with TTX production by toxicity assay of media in which suspected bacteria are grown. [2] As Lago et al. note, "there is good evidence that uptake of bacteria producing TTX is an important element of TTX toxicity in marine animals that present this toxin." [2] TTX-producing bacteria include Actinomyces , Aeromonas , Alteromonas , Bacillus , Pseudomonas , and Vibrio species; [2] in the following animals, specific bacterial species have been implicated: [lower-alpha 1]

Association of animals with TTX-producing bacteria
AnimalBacteriaRef
Takifugu obscurus , obscure pufferfish
  • Aeromonas sp. Ne-1
  • Bacillus sp. W-3
 [2] [5]
Nassarius semiplicatus , a gastropod
  • Vibrio spp., including V. alginolyticus, V. cf. shilonii, and unassigned ones
  • Marinomonas sp.
  • Tenacibaculum cf. aestuarii
 [1]
Hapalochlaena maculosa, the Southern blue-ringed octopus
  • Alteromonas spp.
  • Bacillus spp.
  • Pseudomonas spp.
  • Vibrio spp.
 [1] [2] [5] [20]
Astropecten polyacanthus , a starfish Vibrio alginolyticus [2] [5]
Takifugu vermicularis , a pufferfish
  • Vibrio spp., including V. alginolyticus
 [1] [2] [5] [21]
Four species of Chaetognatha (arrow worms)
  • V. alginolyticus
 [22]
Species of Nemertea (ribbon worms)Vibrio spp. [1] [23]

The association of bacterial species with the production of the toxin is unequivocal – Lago and coworkers state, "[e]ndocellular symbiotic bacteria have been proposed as a possible source of eukaryotic TTX by means of an exogenous pathway", [2] and Chau and coworkers note that the "widespread occurrence of TTX in phylogenetically distinct organisms... strongly suggests that symbiotic bacteria play a role in TTX biosynthesis" [1] – although the correlation has been extended to most but not all animals in which the toxin has been identified. [1] [2] [5] To the contrary, there has been a failure in a single case, that of newts ( Taricha granulosa ), to detect TTX-producing bacteria in the tissues with highest toxin levels (skin, ovaries, muscle), using PCR methods, [24] although technical concerns about the approach have been raised. [1] Critically for the general argument, Takifugu rubripes puffers captured and raised in laboratory on controlled, TTX-free diets "lose toxicity over time," while cultured, TTX-free Takifugu niphobles puffers fed on TTX-containing diets saw TTX in the livers of the fishes increase to toxic levels. [1] Hence, as bacterial species that produce TTX are broadly present in aquatic sediments, a strong case is made for ingestion of TTX and/or TTX-producing bacteria, with accumulation and possible subsequent colonization and production. [1] Nevertheless, without clear biosynthetic pathways (not yet found in animals, but shown for bacteria), [25] it remains uncertain whether it is simply via bacteria that each animal accumulates TTX; the question remains as to whether the quantities can be sufficiently explained by ingestion, ingestion plus colonization, or some other mechanism. [1] [2] [5]

Biochemistry

Tetrodotoxin binds to what is known as site 1 of the fast voltage-gated sodium channel. [26] Site 1 is located at the extracellular pore opening of the ion channel. Any molecule bound to this site will block sodium ions from going into the nerve cell through this channel (which is ultimately necessary for nerve conduction). Saxitoxin, neosaxitoxin, and several of the conotoxins also bind the same site. [27]

The use of this toxin as a biochemical probe has elucidated two distinct types of voltage-gated sodium channels (VGSCs) present in mammals: tetrodotoxin-sensitive voltage-gated sodium channels (TTX-s Na+ channels) and tetrodotoxin-resistant voltage-gated sodium channels (TTX-r Na+ channels). Tetrodotoxin inhibits TTX-s Na+ channels at concentrations of around 1–10 nM, [28] whereas micromolar concentrations of tetrodotoxin are required to inhibit TTX-r Na+ channels. [29] Nerve cells containing TTX-r Na+ channels are located primarily in cardiac tissue, while nerve cells containing TTX-s Na+ channels dominate the rest of the body.

TTX and its analogs have historically been important agents for use as chemical tool compounds, for use in channel characterization and in fundamental studies of channel function. [30] [31] The prevalence of TTX-s Na+ channels in the central nervous system makes tetrodotoxin a valuable agent for the silencing of neural activity within a cell culture.

Biosynthesis

The biosynthetic route to TTX is only partially understood. It is long known that the molecule is related to saxitoxin, and as of 2011 it is believed that there are separate routes for aquatic (bacterial) and terrestrial (newt) TTX. [32] In 2020, new intermediates found in newts suggest that the synthesis starts with geranyl guanidine in the amphibian; these intermediates were not found in aquatic TTX-containing animals, supporting the separate-route theory. [33] In 2021, the first genome of a TTX-producing bacterium was produced. This "Bacillus sp. 1839" was identified as Cytobacillus gottheilii using its rRNA sequence. The researcher responsible for this study has not yet identified a coherent pathway but hopes to do so in the future. [34]

Resistance

Animals that accumulate TTX as a defense mechanism as well as their predators must evolve to be resistant to the effects of TTX. Mutations in the VGSC genes, especially the genes for Nav 1.4 (skeletal muscle VGSC, "TTX-s" [35] ), are found in many such animals. [36] These mutations have independently arisen several times, even multiple times in different populations of the same species as seen in the garter snake. They consist of different amino acid substitutions in similar positions, a weak example of convergent evolution caused by how TTX binds to the unmutated VGSC. [36]

Another path to TTX resistance is toxin-binding proteins that hold onto TTX tightly enough to prevent it reaching the vulnerable VGSCs. Various proteins that bind TTX have been found in pufferfish, crabs, and gastropods. There are also proteins that bind saxitoxin (STX), a toxin with a similar mode of action. [36]

Chemical synthesis

In 1964, a team of scientists led by Robert B. Woodward elucidated the structure of tetrodotoxin. [37] The structure was confirmed by X-ray crystallography in 1970. [38] Yoshito Kishi and coworkers reported the first total synthesis of racemic tetrodotoxin in 1972. [39] [40] M. Isobe and coworkers [41] [42] [43] and J. Du Bois reported the asymmetric total synthesis of tetrodotoxin in 2003. [44] The two 2003 syntheses used very different strategies, with Isobe's route based on a Diels-Alder approach and Du Bois's work using C–H bond activation. Since then, methods have rapidly advanced, with several new strategies for the synthesis of tetrodotoxin having been developed. [45] [46]

Poisoning

Toxicity

TTX is extremely toxic. The Material Safety Data Sheet for TTX lists the oral median lethal dose (LD50) for mice as 334  μg per kg. [47] For comparison, the oral LD50 of potassium cyanide for mice is 8,500 μg per kg, [48] demonstrating that even orally, TTX is more poisonous than cyanide. TTX is even more dangerous if administered intravenously; the amount needed to reach a lethal dose by injection is 8 μg per kg in mice. [49]

The toxin can enter the body of a victim by ingestion, injection, or inhalation, or through abraded skin. [50]

Poisoning occurring as a consequence of consumption of fish from the order Tetraodontiformes is extremely serious. The organs (e.g. liver) of the pufferfish can contain levels of tetrodotoxin sufficient to produce the described paralysis of the diaphragm and corresponding death due to respiratory failure. [51] Toxicity varies between species and at different seasons and geographic localities, and the flesh of many pufferfish may not be dangerously toxic. [5]

The mechanism of toxicity is through the blockage of fast voltage-gated sodium channels, which are required for the normal transmission of signals between the body and brain. [52] As a result, TTX causes loss of sensation, and paralysis of voluntary muscles including the diaphragm and intercostal muscles, stopping breathing. [53]

History

A Chinese pharmacopoeia, 1930. Zh pharmacopoeia 1.JPG
A Chinese pharmacopoeia, 1930.

The therapeutic uses of puffer fish (tetraodon) eggs were mentioned in the first Chinese pharmacopoeia Pen-T’so Ching (The Book of Herbs, allegedly 2838–2698 BC by Shennong; but a later date is more likely), where they were classified as having "medium" toxicity, but could have a tonic effect when used at the correct dose. The principal use was "to arrest convulsive diseases". [30] In the Pen-T’so Kang Mu (Index Herbacea or The Great Herbal by Li Shih-Chen, 1596) some types of the fish Ho-Tun (the current Chinese name for tetraodon) were also recognized as both toxic yet, at the right dose, useful as part of a tonic. Increased toxicity in Ho-Tun was noted in fish caught at sea (rather than river) after the month of March. It was recognized that the most poisonous parts were the liver and eggs, but that toxicity could be reduced by soaking the eggs. [30] (Tetrodotoxin is slightly water-soluble, and soluble at 1 mg/ml in slightly acidic solutions.) [54]

The German physician Engelbert Kaempfer, in his "A History of Japan" (translated and published in English in 1727), described how well known the toxic effects of the fish were, to the extent that it would be used for suicide and that the Emperor specifically decreed that soldiers were not permitted to eat it. [55] There is also evidence from other sources that knowledge of such toxicity was widespread throughout southeast Asia and India. [30]

The first recorded cases of TTX poisoning affecting Westerners are from the logs of Captain James Cook from 7 September 1774. [51] On that date Cook recorded his crew eating some local tropic fish (pufferfish), then feeding the remains to the pigs kept on board. The crew experienced numbness and shortness of breath, while the pigs were all found dead the next morning. In hindsight, it is clear that the crew survived a mild dose of tetrodotoxin, while the pigs ate the pufferfish body parts that contain most of the toxin, thus being fatally poisoned.

The toxin was first isolated and named in 1909 by Japanese scientist Dr. Yoshizumi Tahara. [2] [56] [51] It was one of the agents studied by Japan's Unit 731, which evaluated biological weapons on human subjects in the 1930s. [57]

Symptoms and treatment

The diagnosis of pufferfish poisoning is based on the observed symptomatology and recent dietary history. [58]

Symptoms typically develop within 30 minutes of ingestion, but may be delayed by up to four hours; however, if the dose is fatal, symptoms are usually present within 17 minutes of ingestion. [51] Having pins and needles of the lips and tongue is followed by developing it in the extremities, hypersalivation, sweating, headache, weakness, lethargy, incoordination, tremor, paralysis, bluish skin, loss of voice, difficulty swallowing, and seizures. The gastrointestinal symptoms are often severe and include nausea, vomiting, diarrhoea, and abdominal pain; death is usually secondary to respiratory failure. [53] [58] There is increasing respiratory distress, speech is affected, and the victim usually exhibits shortness of breath, excess pupil dilation, and abnormally low blood pressure. Paralysis increases, and convulsions, mental impairment, and irregular heartbeats may occur. The victim, although completely paralysed, may be conscious and in some cases completely understandable until shortly before death, which generally occurs within 4 to 6 hours (range ~20 minutes to ~8 hours). However, some victims enter a coma. [53] [59]

If the patient survives 24 hours, recovery without any aftereffects will usually occur over a few days. [58]

Therapy is supportive and based on symptoms, with aggressive early airway management. [51] If consumed, treatment can consist of emptying the stomach, feeding the victim activated charcoal to bind the toxin, and taking standard life-support measures to keep the victim alive until the effect of the poison has worn off. [51] Alpha adrenergic agonists are recommended in addition to intravenous fluids to increase the blood pressure; anticholinesterase agents "have been proposed as a treatment option but have not been tested adequately". [59]

No antidote has been developed and approved for human use, but a primary research report (preliminary result) indicates that a monoclonal antibody specific to tetrodotoxin is in development by USAMRIID that was effective, in the one study, for reducing toxin lethality in tests on mice. [60]

Worldwide distribution of toxicity

Poisonings from tetrodotoxin have been almost exclusively associated with the consumption of pufferfish from waters of the Indo-Pacific Ocean regions, primarily because equally toxic pufferfishes from other regions are much less commonly eaten. Several reported cases of poisonings, including fatalities, nonetheless involved pufferfish from the Atlantic Ocean, Gulf of Mexico, and Gulf of California. There have been no confirmed cases of tetrodotoxicity from the Atlantic pufferfish, Sphoeroides maculatus , but three studies found extracts from fish of this species highly toxic in mice. Several recent intoxications from these fishes in Florida were due to saxitoxin, which causes paralytic shellfish poisoning with very similar symptoms and signs. The trumpet shell Charonia sauliae has been implicated in food poisonings, and evidence suggests it contains a tetrodotoxin derivative. There have been several reported poisonings from mislabelled pufferfish, and at least one report of a fatal episode in Oregon when an individual swallowed a rough-skinned newt Taricha granulosa on a dare. [61]

In 2009, a major scare in the Auckland Region of New Zealand was sparked after several dogs died eating Pleurobranchaea maculata (grey side-gilled seaslug) on beaches. [62] Children and pet owners were asked to avoid beaches, and recreational fishing was also interrupted for a time. After exhaustive analysis, it was found that the sea slugs must have ingested tetrodotoxin. [63]

Statistical factors

Statistics from the Tokyo Bureau of Social Welfare and Public Health indicate 20–44 incidents of fugu poisoning per year between 1996 and 2006 in the entire country, leading to 34–64 hospitalizations and 0–6 deaths per year, for an average fatality rate of 6.8%. [64] Of the 23 incidents recorded within Tokyo between 1993 and 2006, only one took place in a restaurant, while the others all involved fishermen eating their catch. [64] From 2006 through 2009 in Japan there were 119 incidents involving 183 people but only seven people died. [65]

Only a few cases have been reported in the United States, and outbreaks in countries outside the Indo-Pacific area are rare. In Haiti, tetrodotoxin was thought to have been used in voodoo preparations, in so-called zombie poisons. Subsequent careful analysis has however repeatedly called early studies into question on technical grounds, and failed to identify the toxin in any preparation. [66] [67] [68] Discussion of the matter has therefore all but disappeared from the primary literature since the early 1990s. Kao and Yasumoto concluded in the first of their papers in 1986 that "the widely circulated claim in the lay press to the effect that tetrodotoxin is the causal agent in the initial zombification process is without factual foundation." [66] : 748 

Genetic background is not a factor in susceptibility to tetrodotoxin poisoning. This toxicosis may be avoided by not consuming animal species known to contain tetrodotoxin, principally pufferfish; other tetrodotoxic species are not usually consumed by humans.

Fugu as a food

Poisoning from tetrodotoxin is of particular public health concern in Japan, where fugu is a traditional delicacy. It is prepared and sold in special restaurants where trained and licensed chefs carefully remove the viscera to reduce the danger of poisoning. [69] There is potential for misidentification and mislabelling, particularly of prepared, frozen fish products.

Food analysis

The mouse bioassay developed for paralytic shellfish poisoning (PSP) can be used to monitor tetrodotoxin in pufferfish and is the current method of choice. An HPLC method with post-column reaction with alkali and fluorescence has been developed to determine tetrodotoxin and its associated toxins. The alkali degradation products can be confirmed as their trimethylsilyl derivatives by gas chromatography/mass spectrometry.[ citation needed ]

Detection in body fluids

Tetrodotoxin may be quantified in serum, whole blood or urine to confirm a diagnosis of poisoning in hospitalized patients or to assist in the forensic investigation of a case of fatal overdosage. Most analytical techniques involve mass spectrometric detection following gas or liquid chromatographic separation. [70]

Modern therapeutic research

Tetrodotoxin has been investigated as a possible treatment for cancer-associated pain. Early clinical trials demonstrate significant pain relief in some patients. [71] [72]

It has also been studied in relation to migraine headaches. Mutations in one particular TTX-sensitive Na+ channel are associated with some migraine headaches, [73] although it is unclear as to whether this has any therapeutic relevance for most people with migraine. [74]

Tetrodotoxin has been used clinically to relieve negative affects associated with heroin withdrawal. [75]

Regulation

In the U.S., tetrodotoxin appears on the select agents list of the Department of Health and Human Services, [76] and scientists must register with HHS to use tetrodotoxin in their research. However, investigators possessing less than 500 mg are exempt from regulation. [77]

Tetrodotoxin serves as a plot device for characters to fake death, as in the films Hello Again (1987), The Serpent and the Rainbow (1988), The A-Team (2010) and Captain America: The Winter Soldier (2014), War (2019), and in episodes of "Jane the Virgin", Miami Vice (1985), [78] Nikita , MacGyver Season 7, Episode 6, where the antidote is Datura stramonium leaf, CSI: NY (Season 4, episode 9 "Boo") and Chuck . In Law Abiding Citizen (2009) and Alex Cross (2012), its paralysis is presented as a method of assisting torture. The toxin was also referenced in "synthetic form" in the S1E2 of the series "FBI". The toxin is used as a weapon in both the second season of Archer , in Covert Affairs and in the Inside No. 9 episode "The Riddle of the Sphinx". [79] [80] In Columbo, Episode 2 of Season 7, fugu is used to kill the antagonists victim. Columbo (season 7) In The Apothecary Diaries light novel, as well as the respective manga [81] [82] and anime [83] [84] adaptations, fugu toxin is encountered across multiple mystery arcs.

Based on the presumption that tetrodotoxin is not always fatal, but at near-lethal doses can leave a person extremely unwell with the person remaining conscious, [58] tetrodotoxin has been alleged to result in zombieism, and has been suggested as an ingredient in Haitian Vodou preparations. [85] This idea first appeared in the 1938 non-fiction book Tell My Horse by Zora Neale Hurston in which there were multiple accounts of purported tetrodotoxin poisoning in Haiti by a voodoo sorcerer called the bokor. [86] These stories were later popularized by Harvard-trained ethnobotanist Wade Davis [85] in his 1985 book and Wes Craven's 1988 film, both titled The Serpent and the Rainbow . James Ellroy includes "blowfish toxin" as an ingredient in Haitian Vodou preparations to produce zombieism and poisoning deaths in his dark, disturbing, violent novel Blood's a Rover . But this theory has been questioned by the scientific community since the 1990s based on analytical chemistry-based tests of multiple preparations and review of earlier reports (see above). [66] [67] [68]

See also

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Zosimus aeneus, also known as the devil crab, toxic reef crab, and devil reef crab is a species of crab that lives on coral reefs in the Indo-Pacific from East Africa to Hawaii. It grows to a size of 60 mm × 90 mm and has distinctive patterns of brownish blotches on a paler background. It is potentially lethal due to the presence of the neurotoxins tetrodotoxin and saxitoxin in its flesh and shell.

<span class="mw-page-title-main">Neosaxitoxin</span> Chemical compound

Neosaxitoxin (NSTX) is included, as other saxitoxin-analogs, in a broad group of natural neurotoxic alkaloids, commonly known as the paralytic shellfish toxins (PSTs). The parent compound of PSTs, saxitoxin (STX), is a tricyclic perhydropurine alkaloid, which can be substituted at various positions, leading to more than 30 naturally occurring STX analogues. All of them are related imidazoline guanidinium derivatives.

Pao turgidus is a species of freshwater pufferfish native to the Mekong basin. It may also occur in the Chao Phraya basin in Thailand. This species grows to a length of 18.5 centimetres (7.3 in) SL.

<span class="mw-page-title-main">Decarbamoylsaxitoxin</span> Chemical compound

Decarbamoylsaxitoxin, abbreviated as dcSTX, is a neurotoxin which is naturally produced in dinoflagellate. DcSTX is one of the many analogues of saxitoxin (STX).

<span class="mw-page-title-main">Zetekitoxin AB</span> Chemical compound

Zetekitoxin AB (ZTX) is a guanidine alkaloid found in the Panamanian golden frog Atelopus zeteki. It is an extremely potent neurotoxin.

References

  1. ↑ For a more comprehensive list of TTX-producing bacterial species associated with animals from which the toxin has been isolated or toxicity observed, and for a thorough discussion of the research literature regarding bacterial origins (and the remaining contrary perspectives, e.g., in newts), as well as for a thorough speculative discussion regarding biosynthesis, see [1]
  1. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Chau R, Kalaitzis JA, Neilan BA (Jul 2011). "On the origins and biosynthesis of tetrodotoxin" (PDF). Aquatic Toxicology. 104 (1–2): 61–72. Bibcode:2011AqTox.104...61C. doi:10.1016/j.aquatox.2011.04.001. PMID   21543051. Archived from the original (PDF) on 2016-03-05. Retrieved 2016-02-29.
  2. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Lago J, Rodríguez LP, Blanco L, Vieites JM, Cabado AG (2015). "Tetrodotoxin, an Extremely Potent Marine Neurotoxin: Distribution, Toxicity, Origin and Therapeutical Uses". Marine Drugs. 13 (10): 6384–406. doi: 10.3390/md13106384 . PMC   4626696 . PMID   26492253.
  3. ↑ Guardone L, Maneschi A, Meucci V, Gasperetti L, Nucera D, Armani A (2020-10-02). "A Global Retrospective Study on Human Cases of Tetrodotoxin (TTX) Poisoning after Seafood Consumption". Food Reviews International. 36 (7): 645–667. doi:10.1080/87559129.2019.1669162. hdl: 11568/1013333 . ISSN   8755-9129. S2CID   204144112.
  4. ↑ Huerta MÁ, de la Nava J, Artacho-Cordón A, Nieto FR (May 2023). "Efficacy and Security of Tetrodotoxin in the Treatment of Cancer-Related Pain: Systematic Review and Meta-Analysis". Marine Drugs. 21 (5): 316. doi: 10.3390/md21050316 . ISSN   1660-3397. PMC   10221257 . PMID   37233510.
  5. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Bane V, Lehane M, Dikshit M, O'Riordan A, Furey A (February 2014). "Tetrodotoxin: Chemistry, Toxicity, Source, Distribution and Detection". Toxins. 6 (2): 693–755. doi: 10.3390/toxins6020693 . PMC   3942760 . PMID   24566728.
  6. ↑ Narahashi T, Moore JW, Scott WR (May 1964). "Tetrodotoxin blockage of sodium conductance increase in lobster giant axons". The Journal of General Physiology. 47 (5): 965–974. doi:10.1085/jgp.47.5.965. PMC   2195365 . PMID   14155438.
  7. ↑ Sigma-Aldrich Tetrodotoxin (T8024) – Product Information Sheet.
  8. ↑ Hwang DF, Tai KP, Chueh CH, Lin LC, Jeng SS (1991). "Tetrodotoxin and derivatives in several species of the gastropod Naticidae". Toxicon. 29 (8): 1019–24. doi:10.1016/0041-0101(91)90084-5. PMID   1949060.
  9. ↑ Stokes AN, Ducey PK, Neuman-Lee L, Hanifin CT, French SS, Pfrender ME, Brodie ED, Brodie ED (2014). "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. Bibcode:2014PLoSO...9j0718S. doi: 10.1371/journal.pone.0100718 . PMC   4070999 . PMID   24963791.
  10. ↑ Pires, O.R. Jr., A. Sebben, E.F. Schwartz, R.A.V. Morales, C. Bloch Jr., C.A. Schwartz (2005). "Further report of the occurrence of tetrodotoxin and new analogues in the Anuran family Brachycephalidae". Toxicon. 45 (1): 73–79. doi:10.1016/j.toxicon.2004.09.016. PMID   15581685.
  11. ↑ Marion Z, Hay M (2011). "Chemical Defense of the Eastern Newt (Notophthalmus viridescens): Variation in Efficiency against Different Consumers and in Different Habitats". PLOS ONE. 6 (12): e27581. Bibcode:2011PLoSO...627581M. doi: 10.1371/journal.pone.0027581 . PMC   3229496 . PMID   22164212.
  12. ↑ Scheuer PJ (1970). "Toxins from fish and other marine organisms". Advances in Food Research. 18: 141–61. doi:10.1016/S0065-2628(08)60369-9. ISBN   9780120164189. PMID   4929140.
  13. ↑ Mosher HS, Fuhrman FA, Buchwald HD, Fischer HG (May 1964). "Tarichatoxin – tetrodotoxin: a potent neurotoxin". Science. 144 (3622): 1100–10. Bibcode:1964Sci...144.1100M. doi:10.1126/science.144.3622.1100. PMID   14148429.
  14. ↑ Sheumack DD, Howden ME, Spence I, Quinn RJ (Jan 1978). "Maculotoxin: a neurotoxin from the venom glands of the octopus Hapalochlaena maculosa identified as tetrodotoxin". Science. 199 (4325): 188–89. Bibcode:1978Sci...199..188S. doi:10.1126/science.619451. PMID   619451. Maculotoxin, a potent neurotoxin isolated from the posterior salivary glands of the blue-ringed octopus. Hapalochlaena maculosa, has now been identified as tetrodotoxin. This is the first reported case in which tetrodotoxin has been found to occur in a venom.
  15. ↑ "Tetrodotoxin". PubChem. National Center for Biotechnology Information (NCBI).
  16. ↑ Stine KE, Brown TM (2015). Principles of Toxicology (3rd ed.). Boca Raton, FL: CRC Press. pp. 196, 390. ISBN   978-1466503434.
  17. ↑ Gage PW, Dulhunty AF (2012) [1973]. "Effects of Toxin from the Blue-Ringed Octopus (Hapalochlaena maculosa) [Chapter III]". In Martin D, Padilla G (eds.). Marine Pharmacognosy: Action of Marine Biotoxins at the Cellular Level. Philadelphia, PA [New York, NY]: Elsevier [Academic Press]. pp. 85–106. ISBN   978-0323155601.
  18. ↑ Spafford J, Spencer AN, Gallin WJ (27 March 1998). "A Putative Voltage-Gated Sodium Channel α Subunit (PpSCN1) from the Hydrozoan Jellyfish, Polyorchis penicillatus: Structural Comparisons and Evolutionary Considerations". Biochemical and Biophysical Research Communications. 244 (3): 772–80. doi:10.1006/bbrc.1998.8332. PMID   9535741.
  19. ↑ Brodie ED, Brodie ED Jr (May 1990). "Tetrodotoxin Resistance in Garter Snakes: An Evolutionary Response of Predators to Dangerous Prey". Evolution. 44 (3): 651–659. doi:10.2307/2409442. JSTOR   2409442. PMID   28567972.
  20. ↑ Hwang DF, Arakawa O, Saito T, Noguchi T, Simidu U, Tsukamoto K, Shida Y, Hashimoto K (1988). "Tetrodotoxin-producing bacteria from the blue-ringed octopus Octopus maculosus [sic.]". Marine Biology. 100 (3): 327–32. doi:10.1007/BF00391147. S2CID   84188968.
  21. ↑ Noguchi T, Hwang D, Arakawa O, Sugita H, Deguchi Y, Shida Y, Hashimoto K (1987). "Vibrio alginolyticus, a tetrodotoxin-producing bacterium, in the intestines of the fish Fugu vermicularis vermicularis". Marine Biology. 94 (4): 625–30. Bibcode:1987MarBi..94..625N. doi:10.1007/BF00431409. S2CID   84437298.
  22. ↑ Thuesen EV, Kogure K (1989). "Bacterial production of tetrodotoxin in four species of Chaetognatha" (PDF). Biological Bulletin. 176 (2): 191–94. doi:10.2307/1541587. JSTOR   1541587.
  23. ↑ Carroll S, McEvoy E, Gibson R (2003). "The production of tetrodotoxin-like substances by nemertean worms in conjunction with bacteria". Journal of Experimental Marine Biology and Ecology. 288 (1): 51–63. doi:10.1016/S0022-0981(02)00595-6.
  24. ↑ Lehman EM, Brodie ED, Brodie ED (1 September 2004). "No evidence for an endosymbiotic bacterial origin of tetrodotoxin in the newt Taricha granulosa". Toxicon. 44 (3): 243–49. doi:10.1016/j.toxicon.2004.05.019. PMID   15302530.
  25. ↑ As Chau et al., op. cit., note, "Despite its long history and a thorough knowledge of its toxicity and pharmacology, neither the pathway to TTX nor even the biogenic origin of TTX is known. The debate into whether TTX is derived from bacteria or is endogenous to the host animals is on-going and the only published study into the substrates of TTX biosynthesis proved inconclusive."
  26. ↑ Moczydlowski EG (Mar 2013). "The molecular mystique of tetrodotoxin". Toxicon. 63: 165–83. doi:10.1016/j.toxicon.2012.11.026. PMID   23261990.
  27. ↑ Shen H, Li Z, Jiang Y, Pan X, Wu J, Cristofori-Armstrong B, Smith JJ, Chin Y, Lei J, Zhou Q, King GF, Yan N (19 October 2018). "Structural basis for the modulation of voltage-gated sodium channels by animal toxins". Science. 362 (6412). doi: 10.1126/science.aau2596 . PMID   30049784.
  28. ↑ "Tetrodotoxin | Ligand page | IUPHAR/BPS Guide to Pharmacology". Guide to Pharmacology. International Union of Pharmacologists.
  29. ↑ Narahashi T (2008). "Tetrodotoxin: A brief history". Proc Jpn Acad Ser B Phys Biol Sci. 84 (5): 147–54. doi:10.2183/pjab.84.147. PMC   2858367 . PMID   18941294.
  30. 1 2 3 4 Kao CY (Jun 1966). "Tetrodotoxin, saxitoxin and their significance in the study of excitation phenomena". Pharmacological Reviews. 18 (2): 997–1049. PMID   5328391.
  31. ↑ Blankenship, J.E. (1976). "Tetrodotoxin: From Poison to Powerful Tool". Perspectives in Biology and Medicine. 19 (4, Summer): 509–26. doi:10.1353/pbm.1976.0071. PMID   785373. S2CID   6117457.
  32. ↑ Chau R, Kalaitzis JA, Neilan BA (July 2011). "On the origins and biosynthesis of tetrodotoxin". Aquatic Toxicology (Amsterdam, Netherlands). 104 (1–2): 61–72. Bibcode:2011AqTox.104...61C. doi:10.1016/j.aquatox.2011.04.001. PMID   21543051.
  33. ↑ Kudo Y, Hanifin CT, Kotaki Y, Yotsu-Yamashita M (25 September 2020). "Structures of N-Hydroxy-Type Tetrodotoxin Analogues and Bicyclic Guanidinium Compounds Found in Toxic Newts". Journal of Natural Products. 83 (9): 2706–17. doi: 10.1021/acs.jnatprod.0c00623 . PMID   32896120.
  34. ↑ Melnikova DI, Nijland R, Magarlamov TY (9 June 2021). "The First Data on the Complete Genome of a Tetrodotoxin-Producing Bacterium". Toxins. 13 (6): 410. doi: 10.3390/toxins13060410 . PMC   8228330 . PMID   34207879.
  35. ↑ Maruta S, Yamaoka K, Yotsu-Yamashita M (March 2008). "Two critical residues in p-loop regions of puffer fish Na+ channels on TTX sensitivity". Toxicon. 51 (3): 381–387. doi:10.1016/j.toxicon.2007.10.014. PMID   18067939.
  36. 1 2 3 van Thiel J, Khan MA, Wouters RM, Harris RJ, Casewell NR, Fry BG, Kini RM, Mackessy SP, Vonk FJ, Wüster W, Richardson MK (October 2022). "Convergent evolution of toxin resistance in animals". Biological Reviews of the Cambridge Philosophical Society. 97 (5): 1823–1843. doi:10.1111/brv.12865. PMC   9543476 . PMID   35580905.
  37. ↑ Woodward RB (1964). "The Structure of Tetrodotoxin" (PDF). Pure Appl. Chem. 9 (1): 49–75. doi:10.1351/pac196409010049. S2CID   98806870. Archived from the original (PDF) on 2016-03-04. Retrieved 2013-11-11.
  38. ↑ Furusaki A, Tomiie Y, Nitta I (1970). "The Crystal and Molecular Structure of Tetrodotoxin Hydrobromide". Bulletin of the Chemical Society of Japan . 43 (11): 3332–41. doi:10.1246/bcsj.43.3332.
  39. ↑ Kishi Y, Aratani M, Fukuyama T, Nakatsubo F, Goto T (Dec 1972). "Synthetic studies on tetrodotoxin and related compounds. 3. A stereospecific synthesis of an equivalent of acetylated tetrodamine". Journal of the American Chemical Society. 94 (26): 9217–19. doi:10.1021/ja00781a038. PMID   4642370.
  40. ↑ Kishi Y, Fukuyama T, Aratani M, Nakatsubo F, Goto T (Dec 1972). "Synthetic studies on tetrodotoxin and related compounds. IV. Stereospecific total syntheses of DL-tetrodotoxin". Journal of the American Chemical Society. 94 (26): 9219–21. doi:10.1021/ja00781a039. PMID   4642371.
  41. ↑ Taber D (2005-05-02). "Synthesis of (-)-Tetrodotoxin". Organic Chemistry Portal. organic-chemistry.org.
  42. ↑ Ohyabu N, Nishikawa T, Isobe M (Jul 2003). "First asymmetric total synthesis of tetrodotoxin". Journal of the American Chemical Society. 125 (29): 8798–805. doi:10.1021/ja0342998. PMID   12862474.
  43. ↑ Nishikawa T, Urabe D, Isobe M (Sep 2004). "An efficient total synthesis of optically active tetrodotoxin". Angewandte Chemie. 43 (36): 4782–85. doi:10.1002/anie.200460293. PMID   15366086.
  44. ↑ Hinman A, Du Bois J (Sep 2003). "A stereoselective synthesis of (–)-tetrodotoxin". Journal of the American Chemical Society. 125 (38): 11510–11. doi:10.1021/ja0368305. PMID   13129349.
  45. ↑ Chau J, Ciufolini MA (2011). "The chemical synthesis of tetrodoxin: an ongoing quest". Marine Drugs. 9 (10): 2046–74. doi: 10.3390/md9102046 . PMC   3210618 . PMID   22073009.
  46. ↑ Sato K, Akai S, Yoshimura J (Jul 2013). "Stereocontrolled total synthesis of tetrodotoxin from myo-inositol and D-glucose by three routes: aspects for constructing complex multi-functionalized cyclitols with branched-chain structures". Natural Product Communications. 8 (7): 987–98. doi: 10.1177/1934578X1300800726 . PMID   23980434. S2CID   23840469.
  47. ↑ "Material Safety Data Sheet Tetrodotoxin ACC# 01139". Acros Organics N.V.
  48. ↑ "Cyanides (as CN)". Immediately Dangerous to Life or Health Concentrations (IDLH). National Institute for Occupational Safety and Health (NIOSH).
  49. ↑ Gilman AG, Goodman LS, Gilman AZ (1980). Goodman & Gilman's The pharmacological Basis of Therapeutics. New York: McGraw-Hill. p. 310. ISBN   0-07-146891-9.
  50. ↑ Patockaa J, Stredab L (April 23, 2002). Price R (ed.). "Brief Review of Natural Nonprotein Neurotoxins". ASA Newsletter. 02–2 (89). Applied Science and Analysis inc.: 16–23. ISSN   1057-9419 . Retrieved 26 May 2012.
  51. 1 2 3 4 5 6 Clark RF, Williams SR, Nordt SP, Manoguerra AS (1999). "A review of selected seafood poisonings". Undersea & Hyperbaric Medicine. 26 (3): 175–84. PMID   10485519. Archived from the original on October 7, 2008.{{cite journal}}: CS1 maint: unfit URL (link)
  52. ↑ Rang H, Ritter J, Flower R, Henderson G (2015). Rang & Dale's Pharmacology (8th ed.). Churchill Livingstone. ISBN   9780702053627.
  53. 1 2 3 "CDC – The Emergency Response Safety and Health Database: Biotoxin: Tetrodotoxin – NIOSH". www.cdc.gov. Retrieved 2016-01-03.
  54. ↑ "T8024 Sigma Tetrodotoxin". Catalogue. Sigma-Aldrich. Retrieved 23 August 2015.
  55. ↑ Kaempfer E, Scheuchzer Johannes Caspar, trans. (1727). The History of Japan …. Historia imperii Japonici. Vol. 1. London, England: J.C. Scheuchzer (ed.). pp. 134–135.{{cite book}}: CS1 maint: multiple names: authors list (link)
  56. ↑ Suehiro M (1994). "[Historical review on chemical and medical studies of globefish toxin before World War II]". Yakushigaku Zasshi. 29 (3): 428–34. PMID   11613509.
  57. ↑ Eric Croddy, James J. Wirtz, eds. (2005). Weapons of Mass Destruction: Chemical and biological weapons. ABC-CLIO. ISBN   9781851094905.
  58. 1 2 3 4 Butterton J, Calderwell S (1998). "Acute infectious diarrhoea disease and bacterial food poisoning". In Fauci AS, Braunwald E, Isselbacher KJ, Wilson JD, Martin JB, Kasper DL, Hauser SL, Longo DL (eds.). Harrison's principles of internal medicine (14th ed.). New York: McGraw-Hill, Health Professions Division. pp.  796–601. ISBN   0070202915.
  59. 1 2 Benzer T. "Tetrodotoxin Toxicity". Medscape. Retrieved 23 August 2015.
  60. ↑ Rivera VR, Poli MA, Bignami GS (Sep 1995). "Prophylaxis and treatment with a monoclonal antibody of tetrodotoxin poisoning in mice". Toxicon. 33 (9): 1231–37. doi:10.1016/0041-0101(95)00060-Y. PMID   8585093. Closed Access logo transparent.svg
  61. ↑ Bradley SG, Klika LJ (Jul 1981). "A fatal poisoning from the Oregon rough-skinned newt (Taricha granulosa)". JAMA. 246 (3): 247. doi:10.1001/jama.1981.03320030039026. PMID   7241765. Closed Access logo transparent.svg
  62. ↑ McNabb P, Mackenzie L, Selwood A, Rhodes L, Taylor D, Cornelison C (2009). "Review of tetrodotoxins in the sea slug Pleurobranchaea maculata and coincidence of dog deaths along Auckland Beaches" (PDF). Auckland Regional Council Technical Report 2009/108. Cawthron Institute for the Auckland Regional Council. Archived from the original (PDF) on 2015-09-23. Retrieved 2010-02-23.
  63. ↑ Gibson E (15 August 2009). "Puffer fish toxin blamed for deaths of two dogs". The New Zealand Herald . Retrieved 19 November 2011.
  64. 1 2 危険がいっぱい ふぐの素人料理 [Danger in fugu amateur cuisine] (in Japanese). Tokyo Bureau of Social Welfare and Public Health. Archived from the original on 28 January 2010.
  65. ↑ 自然毒のリスクプロファイル：魚類：フグ毒 [Fish: fugu poison risk profile of natural poison] (in Japanese). 厚生労働省 (Ministry of Health Labour and Welfare (Japan)). Archived from the original on 27 September 2011.
  66. 1 2 3 Yasumoto T, Kao CY (1986). "Tetrodotoxin and the Haitian zombie". Toxicon. 24 (8): 747–49. doi:10.1016/0041-0101(86)90098-x. PMID   3775790.
  67. 1 2 Kao CY, Yasumoto T (1990). "Tetrodotoxin in "zombie powder"". Toxicon. 28 (2): 129–32. doi:10.1016/0041-0101(90)90330-a. PMID   2339427.
  68. 1 2 Hines T (May–June 2008). "Zombies and Tetrodotoxin". Skeptical Inquirer. 32 (3): 60–62. Archived from the original on 2016-07-09. Retrieved 2015-08-23.
  69. ↑ Warin RH, Steventon GB, Mitchell SC (2007). Molecules of death. Imperial College Press. p. 390. ISBN   978-1-86094-814-5.
  70. ↑ Baselt RC (2008). Disposition of toxic drugs and chemicals in man (8th ed.). Foster City, California: Biomedical Publications. pp. 1521–22. ISBN   978-0-9626523-7-0.
  71. ↑ Hagen NA, Lapointe B, Ong-Lam M, Dubuc B, Walde D, Gagnon B, Love R, Goel R, Hawley P, Ngoc AH, du Souich P (Jun 2011). "A multicentre open-label safety and efficacy study of tetrodotoxin for cancer pain". Current Oncology. 18 (3): e109–16. doi:10.3747/co.v18i3.732. PMC   3108870 . PMID   21655148.
  72. ↑ Hagen NA, du Souich P, Lapointe B, Ong-Lam M, Dubuc B, Walde D, Love R, Ngoc AH (Apr 2008). "Tetrodotoxin for moderate to severe cancer pain: a randomized, double blind, parallel design multicenter study". Journal of Pain and Symptom Management. 35 (4): 420–49. doi: 10.1016/j.jpainsymman.2007.05.011 . PMID   18243639.
  73. ↑ Nieto FR, Cobos EJ, Tejada MÁ, Sánchez-Fernández C, González-Cano R, Cendán CM (Feb 2012). "Tetrodotoxin (TTX) as a therapeutic agent for pain". Marine Drugs. 10 (2): 281–305. doi: 10.3390/md10020281 . PMC   3296997 . PMID   22412801.
  74. ↑ Stimmel B (2002). "12: Heroin Addiction". Alcoholism, drug addiction, and the road to recovery: life on the edge. New York: Haworth Medical Press. ISBN   0-7890-0553-0. Tetrodotoxin blocks the sodium currents and is believed to have potential as a potent analgesic and as an effective agent in detoxoification from heroin addiction without withdrawal symptoms and without producing physical dependence.
  75. ↑ Song H, Li J, Lu CL, Kang L, Xie L, Zhang YY, Zhou XB, Zhong S (Aug 2011). "Tetrodotoxin alleviates acute heroin withdrawal syndrome: a multicentre, randomized, double-blind, placebo-controlled study". Clinical and Experimental Pharmacology & Physiology. 38 (8): 510–14. doi:10.1111/j.1440-1681.2011.05539.x. PMID   21575032. S2CID   11221499.
  76. ↑ "HHS and USDA Select Agents and Toxins 7 CFR Part 331, 9 CFR Part 121, and 42 CFR Part 73" (PDF). Archived from the original (PDF) on 17 January 2009. Retrieved 17 March 2013.
  77. ↑ "Permissible Toxin Amounts". Federal Select Agent Program. United States Centers for Disease Control and Prevention. Retrieved 20 Feb 2017.
  78. ↑ Miami Vice (1984–1990) Tale of the Goat. IMDb
  79. ↑ Miranda K (26 November 2014). "Covert Affairs Recap: Starlings of the Slipstream". Movie News Guide. Archived from the original on 6 August 2018. Retrieved 25 July 2015.
  80. ↑ "Covert Affairs: Starlings of the Slipstream (season 5, episode 12, original air date 13 November 2014)". USA Networks. 2015. Retrieved 25 July 2015.
  81. ↑ "The Apothecary Diaries, Vol. 5, Chapter 25". Square Enix. Archived from the original on June 16, 2023. Retrieved July 13, 2022.
  82. ↑ "The Apothecary Diaries, Vol. 7, Chapter 33". Square Enix. Archived from the original on February 2, 2023. Retrieved November 19, 2022.
  83. ↑ Silverman R (January 21, 2024). "The Apothecary Diaries Episode 15". Anime News Network . Archived from the original on January 21, 2024. Retrieved 2024-02-27.
  84. ↑ Silverman R (February 25, 2024). "The Apothecary Diaries Episode 20". Anime News Network . Archived from the original on February 25, 2024. Retrieved 2024-02-27.
  85. 1 2 Davis W (1985). 'The Serpent and the Rainbow (1st Touchstone ed.). New York: Simon and Schuster. ISBN   978-0671502478.
  86. ↑ Hurston ZN (2009). Reed I, Louis H (eds.). Tell my horse: Voodoo and life in Haiti and Jamaica (1st Harper Perennial Modern Classics ed.). New York: Harper Perennial. p. 336. ISBN   978-0061695131.

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