Tetrodotoxin
Identifiers
CAS number	4368-28-9
PubChem	20382
Properties
Molecular formula	C11H17N3O8
Molar mass	319.268
Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa) Infobox disclaimer and references

Tetrodotoxin (anhydrotetrodotoxin 4-epitetrodotoxin, tetrodonic acid, TTX) is a potent neurotoxin with no known antidote, which blocks action potentials in nerves by binding to the pores of the voltage-gated, fast sodium channels in nerve cell membranes. The binding site of this toxin is located at the pore opening of the voltage-gated Na⁺ channel. Its name derives from Tetraodontiformes, the name of the order that includes the pufferfish, porcupinefish, ocean sunfish or mola, and triggerfish, several species of which carry the toxin. Although tetrodotoxin was discovered in these fish and found in several other animals, it is actually the product of certain bacteria such as Pseudoalteromonas tetraodonis, certain species of Pseudomonas and Vibrio, as well as some others. Image File history File links Size of this preview: 770 × 600 pixelsFull resolution (1100 × 857 pixel, file size: 50 KB, MIME type: image/png) File links The following pages on the English Wikipedia link to this file (pages on other projects are not listed): Tetrodotoxin ... Image File history File links Size of this preview: 634 × 599 pixelsFull resolution (1100 × 1040 pixel, file size: 294 KB, MIME type: image/png) File links The following pages on the English Wikipedia link to this file (pages on other projects are not listed): Tetrodotoxin ... CAS registry numbers are unique numerical identifiers for chemical compounds, polymers, biological sequences, mixtures and alloys. ... PubChem is a database of chemical molecules. ... This article or section does not cite any references or sources. ... This article does not cite any references or sources. ... In chemistry, the standard state of a material is its state at 1 bar (100 kilopascals) and 25 degrees Celsius (298. ... A neurotoxin is a toxin that acts specifically on nerve cells – neurons – usually by interacting with membrane proteins such as ion channels. ... A. A schematic view of an idealized action potential illustrates its various phases as the action potential passes a point on a cell membrane. ... Nerves (yellow) Nerves redirects here. ... A pore, in general, is some form of opening, usually very small. ... Voltage-gated ion channels are a class of transmembrane ion channels that are activated by changes in electrical potential difference near the channel; these types of ion channels are especially critical in neurons, but are common in many types of cells. ... Ion channels are pore-forming proteins that help to establish and control the small voltage gradient that exists across the plasma membrane of all living cells (see cell potential) by allowing the flow of ions down their electrochemical gradient. ... Drawing by Santiago Ramón y Cajal of neurons in the pigeon cerebellum. ... Look up cell membrane in Wiktionary, the free dictionary. ... A binding site is a region on a protein to which specific ligands bind. ... Families Balistidae - Triggerfishes Diodontidae - Porcupinefishes Molidae Monacanthidae - Filefishes Ostraciidae - Boxfishes Tetraodontidae - Pufferfishes Triacanthidae - Triplespines Triacanthodidae - Spikefishes Triodontidae - Three-toothed puffer The Tetraodontiformes are an order of highly derived ray-finned fish, also called the Plectognathi. ... Genera Amblyrhynchotes Arothron Auriglobus Canthigaster Carinotetraodon Chelonodon Colomesus Contusus Ephippion Feroxodon Fugu Gastrophysus Javichthys Lagocephalus Liosaccus Marilyna Monotretus Omegaphora Pelagocephalus Polyspina Reicheltia Sphoeroides Takifugu Tetractenos Tetraodon Torquigener Tylerius Xenopterus For species see Genera articles. ... Genera See text for genera and species. ... Binomial name (Linnaeus, 1758) The ocean sunfish (Mola mola) or common mola is the heaviest bony fish in the world, with an average weight of 1000 kilograms. ... Genera See text. ... Phyla Actinobacteria Aquificae Chlamydiae Bacteroidetes/Chlorobi Chloroflexi Chrysiogenetes Cyanobacteria Deferribacteres Deinococcus-Thermus Dictyoglomi Fibrobacteres/Acidobacteria Firmicutes Fusobacteria Gemmatimonadetes Lentisphaerae Nitrospirae Planctomycetes Proteobacteria Spirochaetes Thermodesulfobacteria Thermomicrobia Thermotogae Verrucomicrobia Bacteria (singular: bacterium) are unicellular microorganisms. ... Type species Pseudomonas aeruginosa Species group P. aeruginosa P. alcaligenes P. anguilliseptica P. argentinensis P. borbori P. citronellolis P. flavescens P. mendocina P. nitroreducens P. oleovorans P. pseudoalcaligenes P. resinovorans P. straminea group P. aurantiaca P. aureofaciens P. chlororaphis P. fragi P. lundensis P. taetrolens group P. antarctica P. azotoformans... Vibrio is a genus of bacteria, included in the gamma subgroup of the Proteobacteria. ...

Tetrodotoxin sources in nature

Tetrodotoxin has also been isolated from widely differing animal species, including western newts of the genus Taricha (where it was termed "tarichatoxin"), parrotfish, toads of the genus Atelopus, several species of blue-ringed octopodes of the genus Hapalochlaena (where it was called "maculotoxin"), several starfish, an angelfish, a polyclad flatworm, several species of Chaetognatha (arrow worms), several nemerteans (ribbonworms) and several species of xanthid crabs. The toxin is variously used as a defensive biotoxin to ward off predation, or as both a defensive and predatory venom (the octopodes, chaetognaths and ribbonworms). Tarichatoxin and maculotoxin were shown to be identical to tetrodotoxin in 1964 and 1978, respectively. Recent evidence has shown the toxin to be produced by bacteria within blue-ringed octopodes ^[1], and it is believed that pufferfish acquire the toxin through their diet. Evidence for the source of the toxin in other sources has not yet been determined ^{[citation needed]}. The most common source of bacteria associated with TTX production are 'Vibrio' bacteria, with Vibrio alginolyticus being the most common species. TTX has been found in nemerteans, Phylum nemertea, (sometimes called Ribbon worms), and both pufferfish and nemerteans have been shown to contain Vibrio alginolyticus and TTX. “Eft” redirects here. ... Species Taricha granulosa Taricha rivularis Taricha torosa The genus Taricha consists of three species and four subspecies of Western Newts (sometimes refered to as Pacific Newts). ... Genera Bolbometopon Calotomus Cetoscarus Chlorurus Cryptotomus Hipposcarus Leptoscarus Nicholsina Scarus Sparisoma Parrot fish are mostly tropical, perciform marine fish of the family Scaridae. ... Families At least 9, see article. ... Atelopus is a large genus of true toads natively distributed in Costa Rica to Bolivia and French Guiana. ... Species See text. ... Orders Brisingida (100 species[1]) Forcipulatida (300 species[2]) Paxillosida (255 species[3]) Notomyotida (75 species[4]) Spinulosida (120 species[5]) Valvatida (695 species[6]) Velatida (200 species[7]) For other uses, see Starfish (disambiguation). ... The name angelfish may refer to two unrelated types of fish: Freshwater angelfish, tropical cichlids of the genus Pterophyllum. ... Classes Monogenea Trematoda Cestoda Turbellaria Wikimedia Commons has media related to: Platyhelminthes Wikispecies has information related to: Platyhelminthes The flatworms (Phylum Platyhelminthes from the Greek platy, meaning flat and helminth, meaning worm) are a phylum of relatively simple soft-bodied invertebrate animals. ... Classes Archisagittoidea Sagittoidea Chaetognatha is a phylum of predatory marine worms that are a major component of plankton worldwide. ... Classes Anopla Enopla The phylum Nemertea (also Rhynchocoela, Nemertina, Nemertinea or Nemertini) contains the ribbon worms or proboscis worms, which are a group of unsegmented marine invertebrates. ... Phyla Actinobacteria Aquificae Chlamydiae Bacteroidetes/Chlorobi Chloroflexi Chrysiogenetes Cyanobacteria Deferribacteres Deinococcus-Thermus Dictyoglomi Fibrobacteres/Acidobacteria Firmicutes Fusobacteria Gemmatimonadetes Lentisphaerae Nitrospirae Planctomycetes Proteobacteria Spirochaetes Thermodesulfobacteria Thermomicrobia Thermotogae Verrucomicrobia Bacteria (singular: bacterium) are unicellular microorganisms. ...

Biochemistry

Tetrodotoxin binds to what is known as site 1 of the fast voltage-gated sodium channel. Site 1 is located at the extracellular pore opening of the ion channel. The binding of any molecules to this site will temporarily disable the function of the ion channel. Saxitoxin and several of the conotoxins also bind the same site. Sodium channels (also known as voltage-gated sodium channels) are integral membrane proteins that are localized in and conduct sodium ions (Na+) through a cells plasma membrane. ... Saxitoxin (STX) is a neurotoxin found in marine dinoflagellates (algae). ... A conotoxin is one of a group of neurotoxic peptides isolated from the venom of the marine cone snail. ...

The use of this toxin as a biochemical probe has elucidated two distinct types of voltage-gated sodium channels present in humans: the tetrodotoxin-sensitive voltage-gated sodium channel (TTX-s Na⁺ channel) and the tetrodotoxin-resistant voltage-gated sodium channel (TTX-r Na+ channel). Tetrodotoxin binds to TTX-s Na⁺ channels with a binding affinity of 5-15 nanomolar, while the TTX-r Na⁺ channels bind TTX with low micromolar affinity. 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. 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. In chemistry, concentration is the measure of how much of a given substance there is mixed with another substance. ... In chemistry, concentration is the measure of how much of a given substance there is mixed with another substance. ... This page is about the muscular organ, the Heart. ... A diagram showing the CNS: 1. ... Neurons (also called nerve cells) are the primary cells of the nervous system. ... Epithelial cells in culture, stained for keratin (red) and DNA (green) Cell culture is the process by which either prokaryotic or eukaryotic cells are grown under controlled conditions. ...

Physiology

The toxin blocks the fast Na+ current in human myocytes (the contractile cells of the muscles), thereby inhibiting their contraction. By contrast, the sodium channels in pacemaker cells of the heart are of the slow variety, so action potentials in the cardiac nodes are not inhibited by the compound. The poisoned individual therefore dies not because the electrical activity of the heart is compromised, but because the diaphragm is effectively paralyzed and breathing ceases. Myocyte is the technical term for a muscle cell. ...

Blocking of fast Na+ channels has medicinal use in treating some cardiac arrhythmias. Tetrodotoxin has also proved useful in the treatment of pain (originally used in Japan in the 1930's) from such diverse problems as terminal cancer, migraines, & heroin withdrawal.

Total synthesis

Y. Kishi et al Nagoya University, Nagoya, Japan, (now at Harvard University) reported the first total synthesis of D,L-tetrodotoxin in 1972.^[2] M. Isobe et al at Nagoya University, Japan and J. Du Bois et al at Stanford University, USA, reported the asymmetric total synthesis of tetrodotoxin in 2003.^[3][4] 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. A total synthesis is the complete chemical synthesis of complex organic molecules from simple, commercially available (petrochemical) precursors. ... Year 1972 (MCMLXXII) was a leap year starting on Saturday (link will display full calendar) of the Gregorian calendar. ... The two optical isomers of bromochlorofluoromethane Asymmetric synthesis, also called chiral synthesis, enantioselective synthesis or stereoselective synthesis, is organic synthesis which introduces one or more new and desired elements of chirality. ... The Diels-Alder reaction The Diels-Alder reaction is an organic chemical reaction (specifically, a cycloaddition) between a conjugated diene and a substituted alkene, commonly termed the dienophile, to form a substituted cyclohexene system. ...

Tetrodotoxin poisoning

Fish poisoning by consumption of members of the order Tetraodontiformes is extremely serious. The skin and organs of the pufferfish can contain levels of tetrodotoxin sufficient to produce paralysis of the diaphragm and death due to respiratory failure. Toxicity varies between species and at different seasons and geographic localities, and the flesh of many pufferfish may not usually be dangerously toxic. Families Balistidae - Triggerfishes Diodontidae - Porcupinefishes Molidae Monacanthidae - Filefishes Ostraciidae - Boxfishes Tetraodontidae - Pufferfishes Triacanthidae - Triplespines Triacanthodidae - Spikefishes Triodontidae - Three-toothed puffer The Tetraodontiformes are an order of highly derived ray-finned fish, also called the Plectognathi. ... Genera Amblyrhynchotes Arothron Auriglobus Canthigaster Carinotetraodon Chelonodon Colomesus Contusus Ephippion Feroxodon Fugu Gastrophysus Javichthys Lagocephalus Liosaccus Marilyna Monotretus Omegaphora Pelagocephalus Polyspina Reicheltia Sphoeroides Takifugu Tetractenos Tetraodon Torquigener Tylerius Xenopterus For species see Genera articles. ... In the anatomy of mammals, the diaphragm is a shelf of muscle extending across the bottom of the ribcage. ... Respiratory failure is a medical term for inadequate gas exchange by the respiratory system. ...

History

The first recorded cases of tetrodotoxin poisoning were from the logs of Captain James Cook. He 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 received a mild dose of tetrodotoxin, while the pigs ate the pufferfish body parts that contain most of the toxin, thus killing them. Captain is a rank or title with various meanings. ... This article is about the British explorer. ...

The toxin was first isolated and named in 1909 by Japanese scientist Dr. Yoshizumi Tahara. Year 1909 (MCMIX) was a common year starting on Friday (link will display full calendar) of the Gregorian calendar (or a common year starting on Thursday of the 13-day-slower Julian calendar). ...

Symptoms and diagnosis

The diagnosis of pufferfish poisoning is based on the observed symptomology and recent dietary history.

Symptoms typically develop within 30 min of ingestion but may be delayed by up to 4 h. Death has occurred within 17 min of ingestion. Paresthesias of the lips and tongue are followed by sialorrhea, sweating, headache, weakness, lethargy, ataxia, incoordination, tremor, paralysis, cyanosis, aphonia, dysphagia, seizures, dyspnea, bronchorrhea, bronchospasm, respiratory failure, coma, and hypotension. Gastroenteric symptoms are often severe and include nausea, vomiting, diarrhea, and abdominal pain. Cardiac arrhythmias may precede complete respiratory failure and cardiovascular collapse.

Treatment

Therapy is supportive and based on symptoms, with aggressive early airway management. Alpha adrenergic agonists are recommended in addition to intravenous fluids to combat hypotension. Anticholinesterase agents have been used with mixed success. Nothing equivalent to an antivenom has been developed--presumably because the toxin acts quickly and binds with an affinity that is not easily overcome. Antivenom (or antivenin, or antivenene) is a biological product used in the treatment of venomous bites or stings. ...

Course of tetrodotoxin poisoning and complications

The first symptom of intoxication is a slight numbness of the lips and tongue, appearing between 20 minutes to three hours after eating poisonous pufferfish. The next symptom is increasing paresthesia in the face and extremities, which may be followed by sensations of lightness or floating. Headache, epigastric pain, nausea, diarrhea, and/or vomiting may occur. Occasionally, some reeling or difficulty in walking may occur. The second stage of the intoxication is increasing paralysis. Many victims are unable to move; even sitting may be difficult. There is increasing respiratory distress. Speech is affected, and the victim usually exhibits dyspnea, cyanosis, and hypotension. Paralysis increases and convulsions, mental impairment, and cardiac arrhythmia may occur. 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. Paresthesia or paraesthesia (in British English) is a sensation of tingling, pricking, or numbness of a persons skin with no apparent long-term physical effect, more generally known as the feeling of pins and needles or of a limb being asleep (but not directly related to the phenomenon of... For other uses, see Nausea (disambiguation). ... Types 5-7 on the Bristol Stool Chart are often associated with diarrhea Diarrhea (in American English) or diarrhoea (in British English) is a condition in which the sufferer has frequent watery, loose bowel movements (from the Greek word διάρροια; literally meaning through-flowing). Acute infectious diarrhea is a common cause... Vomiting (also throwing up or emesis) is the forceful expulsion of the contents of ones stomach through the mouth and sometimes the nose. ... There are two forms of respiratory distress syndrome: ARDS, which is acute (or adult) respiratory distress syndrome or infant respiratory distress syndrome which is a complication of premature birth. ... Dyspnea (R06. ... Cyanosis refers to the bluish coloration of the skin due to the presence of deoxygenated hemoglobin in blood vessels near the skin surface. ... In physiology and medicine, hypotension refers to an abnormally low blood pressure. ... This article is about epileptic seizures. ... Cardiac arrhythmia is any of a group of conditions in which the electrical activity of the heart is irregular or is faster or slower than normal. ...

Geographic frequency of tetrodotoxin toxicity

Poisonings from tetrodotoxin have been almost exclusively associated with the consumption of pufferfish from waters of the Indo-Pacific ocean regions. Several reported cases of poisonings, including fatalities, 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. However, in three studies, extracts from fish of this species were 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 that 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. Gulf of Mexico in 3D perspective. ... The Gulf of California (also known as the Sea of Cortez or Sea of Cortés; locally known in the Spanish language as Mar de Cortés or, much less frequently, Golfo de California) is a body of water that separates the Baja California Peninsula from the Mexican mainland. ... Saxitoxin (STX) is a neurotoxin found in marine dinoflagellates (algae). ... 4 distinct shellfish-poisoning syndromes have been identified: Paralytic shellfish poisoning (PSP) Neurologic shellfish poisoning (NSP) Diarrheal shellfish poisoning (DSP) Amnestic shellfish poisoning (ASP) All 4 syndromes share some common features and primarily are associated with bivalve mollusks (eg, mussels, clams, oysters, scallops). ... [[{{{diversity_link}}}|Diversity]] {{{diversity}}} Binomial name Taricha granulosa Trinomial name {{{trinomial}}} Type Species {{{type_species}}} {{{subdivision_ranks}}} {{{subdivision}}} [[Image:{{{range_map}}}|{{{range_map_width}}}|]] Synonyms {{{synonyms}}} // Subspecies Species Granulosa is divided into two subspecies: Rough-Skinned newt (Taricha granulosa granulosa) Crater Lake Rough-Skinned newt (Taricha granulosa mazamae) A newt with pebbly, non-slimy skin, that...

Relative frequency of tetrodotoxin ingestive poisonings

From 1974 through 1983 there were 646 reported cases of pufferfish poisoning in Japan, with 179 fatalities. Estimates as high as 200 cases per year with mortality approaching 50% have been reported. Only a few cases have been reported in the United States, and outbreaks in countries outside the Indo-Pacific area are rare, except in Haiti, where Tetrodotoxin plays a key role in the creation of so called zombie poisons. Year 1974 (MCMLXXIV) was a common year starting on Tuesday (link will display full calendar) of the 1974 Gregorian calendar. ... Year 1983 (MCMLXXXIII) was a common year starting on Saturday (link displays the 1983 Gregorian calendar). ... This article is about the undead. ...

Target populations

Race is not a factor in susceptibility to tetrodotoxin poisoning. This toxicosis may be avoided by not consuming pufferfish or other animal species containing tetrodotoxin. Other animal species known to contain tetrodotoxin are not usually consumed by humans. Poisoning from tetrodotoxin is of significant public health concern primarily in Japan, where "Fugu" is a traditional delicacy. It is prepared and sold in special restaurants where trained and licensed individuals carefully remove the viscera to reduce the danger of poisoning. There is potential for misidentification and/or mislabelling, particularly of prepared, frozen fish products. For other uses, see Fugu (disambiguation). ...

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. These chromatographic methods have not yet been validated. 4 distinct shellfish-poisoning syndromes have been identified: Paralytic shellfish poisoning (PSP) Neurologic shellfish poisoning (NSP) Diarrheal shellfish poisoning (DSP) Amnestic shellfish poisoning (ASP) All 4 syndromes share some common features and primarily are associated with bivalve mollusks (eg, mussels, clams, oysters, scallops). ... Chemical structure of Tetramethylsilane Chemical structure of a Trimethylsilyl group The name Tetramethylsilane stands for a chemical compound whose molecular structure is essentially like a silane (SiH4) molecule with four methyl groups substituted for the four hydrogen atoms in it. ...

See also

• Conotoxin
• Saxitoxin
• Tectin

• Clairvius Narcisse, a Haitian alleged to have been buried alive under the effect of the drug

A conotoxin is one of a group of neurotoxic peptides isolated from the venom of the marine cone snail. ... Saxitoxin (STX) is a neurotoxin found in marine dinoflagellates (algae). ... Tectinâ„¢ is the brand name of a pain killing drug currently in development that is derived from the pufferfish. ... Clairvius Narcisse was reported to be zombie. ...

External links

• http://www.cbwinfo.com/Biological/Toxins/TTX.html
• http://vm.cfsan.fda.gov/~mow/chap39.html
• http://www.organic-chemistry.org/Highlights/2005/02May.shtm

References

1. ^ (a) Hwang, D. F., Arakawa, O., Saito, T., Noguchi, T., Simidu, U., Tsukamoto, K., Shida, Y., Hashimoto, K. Marine Biology 1989, 100, 327-332 (DOI 10.1007/BF00391147). (abstract)
2. ^ (a) Kishi, Y.; Aratani, M.; Fukuyama, T.; Nakatsubo, F.; Goto, T.; Inoue, S.; Tanino, H.; Sugiura, S.; Kakoi, H. J. Am. Chem. Soc. 1972, 94, 9217-9219. (b) Kishi, Y.; Fukuyama, T.; Aratani, M.; Nakatsubo, F.; Goto, T.; Inoue, S.; Tanino, H.; Sugiura, S.; Kakoi, H. J. Am. Chem. Soc. 1972, 94, 9219-9221.
3. ^ (a) Ohyabu, N.; Nishikawa, T.; Isobe, M. J. Am. Chem. Soc. 2003, 125, 8798-8805 (b) Angew. Chem. Int. Ed. 2004, 43, 4782 (DOI 10.1002/anie.200460293). See a free online review
4. ^ Hinman, A.; Du Bois, J. J. Am. Chem. Soc. 2003, 125, 11510 -11511. (DOI 10.1021/ja0368305)