Tetrodotoxin

Tetrodotoxin

Overview
Tetrodotoxin, also known as "tetrodox" and frequently abbreviated as TTX, sometimes colloquially referred to as "zombie powder" by those who practice Vodou, is a potent neurotoxin
Neurotoxin
A neurotoxin is a toxin that acts specifically on nerve cells , usually by interacting with membrane proteins such as ion channels. Some sources are more general, and define the effect of neurotoxins as occurring at nerve tissue...

 with no known antidote
Antidote
An antidote is a substance which can counteract a form of poisoning. The term ultimately derives from the Greek αντιδιδοναι antididonai, "given against"....

. There have been successful tests of a possible antidote in mice, but further tests must be carried out to determine efficacy in humans. Fampridine has been shown to reverse tetrodotoxin toxicity in animal experiments.
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Encyclopedia
Tetrodotoxin, also known as "tetrodox" and frequently abbreviated as TTX, sometimes colloquially referred to as "zombie powder" by those who practice Vodou, is a potent neurotoxin
Neurotoxin
A neurotoxin is a toxin that acts specifically on nerve cells , usually by interacting with membrane proteins such as ion channels. Some sources are more general, and define the effect of neurotoxins as occurring at nerve tissue...

 with no known antidote
Antidote
An antidote is a substance which can counteract a form of poisoning. The term ultimately derives from the Greek αντιδιδοναι antididonai, "given against"....

. There have been successful tests of a possible antidote in mice, but further tests must be carried out to determine efficacy in humans. Fampridine has been shown to reverse tetrodotoxin toxicity in animal experiments. Tetrodotoxin blocks action potential
Action potential
In physiology, an action potential is a short-lasting event in which the electrical membrane potential of a cell rapidly rises and falls, following a consistent trajectory. Action potentials occur in several types of animal cells, called excitable cells, which include neurons, muscle cells, and...

s in nerves by binding to the voltage-gated, fast sodium channels in nerve cell
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...

 membranes
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...

, essentially preventing any affected nerve cells from firing by blocking the channels used in the process. The binding site
Binding site
In biochemistry, a binding site is a region on a protein, DNA, or RNA to which specific other molecules and ions—in this context collectively called ligands—form a chemical bond...

 of this toxin is located at the pore opening of the voltage-gated Na+ channel. Its name derives from Tetraodontiformes
Tetraodontiformes
The Tetraodontiformes are an order of highly derived ray-finned fish, also called the Plectognathi. Sometimes these are classified as a suborder of the Perciformes...

, the name of the order that includes the pufferfish
Pufferfish
Tetraodontidae is a family of primarily marine and estuarine fish of the Tetraodontiformes order. The family includes many familiar species which are variously called pufferfish, balloonfish, blowfish, bubblefish, globefish, swellfish, toadfish, toadies, honey toads, sugar toads, and sea squab...

, porcupinefish
Porcupinefish
Porcupinefish are fish of the family Diodontidae, , also commonly called blowfish ....

, ocean sunfish
Ocean sunfish
The ocean sunfish, Mola mola, or common mola, is the heaviest known bony fish in the world. It has an average adult weight of . The species is native to tropical and temperate waters around the globe. It resembles a fish head with a tail, and its main body is flattened laterally...

 or mola, and triggerfish
Triggerfish
Triggerfishes are about 40 species of often brightly colored fishes of the family Balistidae. Often marked by lines and spots, they inhabit tropical and subtropical oceans throughout the world, with the greatest species richness in the Indo-Pacific...

, several species of which carry the toxin. Although tetrodotoxin was discovered in these fish and found in several other animals (e.g., blue-ringed octopus
Blue-ringed octopus
The blue-ringed octopuses are three octopus species that live in tide pools in the Pacific Ocean, from Japan to Australia . They are currently recognized as one of the world's most venomous marine animals...

, rough-skinned newt
Rough-skinned Newt
The rough-skinned newt is a North American newt known for its strong poison.- Toxicity :Many newts produce toxins to avoid predation, but the toxins of the genus Taricha are particularly potent...

, and Naticidae
Naticidae
Naticidae, common name the moon snails, is a family of minute to large-sized predatory sea snails, marine gastropod molluscs in the clade Littorinimorpha.Naticidae is the only family in the superfamily Naticoidea....

) it is actually produced by certain symbiotic
Symbiosis
Symbiosis is close and often long-term interaction between different biological species. In 1877 Bennett used the word symbiosis to describe the mutualistic relationship in lichens...

 bacteria
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...

, such as Pseudoalteromonas
Pseudoalteromonas
Pseudoalteromonas is a genus of marine bacterium.-Species:*Pseudoalteromonas agarivorans *Pseudoalteromonas antarctica *Pseudoalteromonas atlantica...

 tetraodonis
, certain species of Pseudomonas
Pseudomonas
Pseudomonas is a genus of gammaproteobacteria, belonging to the family Pseudomonadaceae containing 191 validly described species.Recently, 16S rRNA sequence analysis has redefined the taxonomy of many bacterial species. As a result, the genus Pseudomonas includes strains formerly classified in the...

and Vibrio
Vibrio
Vibrio is a genus of Gram-negative bacteria possessing a curved rod shape, several species of which can cause foodborne infection, usually associated with eating undercooked seafood. Typically found in saltwater, Vibrio are facultative anaerobes that test positive for oxidase and do not form...

, as well as some others that reside within these animals.

Its mechanism of action, selective blocking of the sodium channel, was shown definitively in 1964 by Toshio Narahashi and John Moore
John Moore
- Clergy :*John Moore , British Scholar*John Moore , English Baptist minister from Northampton*John Moore , Archbishop of Canterbury, Privy Counsellor...

at Duke University
Duke University
Duke University is a private research university located in Durham, North Carolina, United States. Founded by Methodists and Quakers in the present day town of Trinity in 1838, the school moved to Durham in 1892. In 1924, tobacco industrialist James B...

, using Moore's sucrose gap voltage clamp technique.

Sources in nature


Tetrodotoxin has been isolated from widely differing animal species, including western newt
Newt
A newt is an aquatic amphibian of the family Salamandridae, although not all aquatic salamanders are considered newts. Newts are classified in the subfamily Pleurodelinae of the family Salamandridae, and are found in North America, Europe and Asia...

s of the genus Taricha
Taricha
The genus Taricha consists of three species and four subspecies of Western Newts . All newts are part of the family Salamandridae...

(where it was formerly termed "tarichatoxin"), pufferfish
Pufferfish
Tetraodontidae is a family of primarily marine and estuarine fish of the Tetraodontiformes order. The family includes many familiar species which are variously called pufferfish, balloonfish, blowfish, bubblefish, globefish, swellfish, toadfish, toadies, honey toads, sugar toads, and sea squab...

, toad
Toad
A toad is any of a number of species of amphibians in the order Anura characterized by dry, leathery skin , short legs, and snoat-like parotoid glands...

s of the genus Atelopus
Atelopus
Atelopus, commonly known as harlequin frogs, is a large genus of true toads from Central and South America, ranging as far north as Costa Rica and as far south as Bolivia. Atelopus are small, generally brightly colored and diurnal. Most species are associated with mid- to high-elevation streams...

, several species of blue-ringed octopus
Blue-ringed octopus
The blue-ringed octopuses are three octopus species that live in tide pools in the Pacific Ocean, from Japan to Australia . They are currently recognized as one of the world's most venomous marine animals...

es of the genus Hapalochlaena (where it was called "maculotoxin"), several sea star
Sea star
Starfish or sea stars are echinoderms belonging to the class Asteroidea. The names "starfish" and "sea star" essentially refer to members of the class Asteroidea...

s, certain angelfish, a polyclad flatworm
Flatworm
The flatworms, known in scientific literature as Platyhelminthes or Plathelminthes are a phylum of relatively simple bilaterian, unsegmented, soft-bodied invertebrate animals...

, several species of Chaetognatha
Chaetognatha
Chaetognatha, meaning hair-jaws, and commonly known as arrow worms, are a phylum of predatory marine worms that are a major component of plankton worldwide. About 20% of the known species are benthic, that is belonging to the lowest zone of the ocean, or benthic zone, and can attach to algae and...

 (arrow worms), several nemertea
Nemertea
Nemertea is a phylum of invertebrate animals also known as "ribbon worms" or "proboscis worms". Alternative names for the phylum have included Nemertini, Nemertinea and Rhynchocoela. Although most are less than long, one specimen has been estimated at , which would make it the longest animal ever...

ns (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 octopuses, chaetognaths and ribbonworms). Tarichatoxin and maculotoxin were shown to be identical to tetrodotoxin in 1964 and 1978, respectively. The toxin is produced by bacteria
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...

 within blue-ringed octopuses. The most common bacteria associated with TTX production are Vibrio bacteria, with Vibrio alginolyticus
Vibrio alginolyticus
Vibrio alginolyticus is a Gram-negative marine bacterium. It is medically important since it causes otitis and wound infection. It is also present in the bodies of animals such as Puffer fish, where it is responsible for the production of the potent neurotoxin, tetrodotoxin....

being the most common species. Pufferfish, chaetognaths, and nemerteans have been shown to contain Vibrio alginolyticus and TTX. The link between these facts and production of TTX in animals has not been firmly established, and there remains much debate in the literature as to whether the bacteria are truly the source of TTX in animals.

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
Saxitoxin
Saxitoxin is a neurotoxin naturally produced by certain species of marine dinoflagellates and cyanobacteria Saxitoxin (STX) is a neurotoxin naturally produced by certain species of marine dinoflagellates (Alexandrium sp., Gymnodinium sp., Pyrodinium sp.) and cyanobacteria Saxitoxin (STX) is a...

 and several of the conotoxin
Conotoxin
A conotoxin is one of a group of neurotoxic peptides isolated from the venom of the marine cone snail, genus Conus.Conotoxins, which are peptides consisting of 10 to 30 amino acid residues, typically have one or more disulfide bonds. Conotoxins have a variety of mechanisms of actions, most of...

s also bind the same site.

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
Concentration
In chemistry, concentration is defined as the abundance of a constituent divided by the total volume of a mixture. Four types can be distinguished: mass concentration, molar concentration, number concentration, and volume concentration...

, while the TTX-r Na+ channels bind TTX with low micromolar
Concentration
In chemistry, concentration is defined as the abundance of a constituent divided by the total volume of a mixture. Four types can be distinguished: mass concentration, molar concentration, number concentration, and volume concentration...

 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
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...

 makes tetrodotoxin a valuable agent for the silencing of neural activity within a cell culture
Cell culture
Cell culture is the complex process by which cells are grown under controlled conditions. In practice, the term "cell culture" has come to refer to the culturing of cells derived from singlecellular eukaryotes, especially animal cells. However, there are also cultures of plants, fungi and microbes,...

.

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 myocytes in the atrium, which surround the main cardiac pacemaker, do express this fast Na+ current and therefore the electrical activity is blocked and the heart fails to beat.

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

Yoshito Kishi
Yoshito Kishi
Yoshito Kishi is the Morris Loeb Professor of Chemistry at Harvard University. He is known for his contributions to the sciences of organic synthesis and total synthesis....

 et al. Nagoya University
Nagoya University
Nagoya University is one of the most prestigious universities in Japan. It can be seen in the several rankings such as shown below.-General Rankings:...

, Nagoya, Japan
Japan
Japan is an island nation in East Asia. Located in the Pacific Ocean, it lies to the east of the Sea of Japan, China, North Korea, South Korea and Russia, stretching from the Sea of Okhotsk in the north to the East China Sea and Taiwan in the south...

, (now at Harvard University) reported the first total synthesis
Total synthesis
In organic chemistry, a total synthesis is, in principle, the complete chemical synthesis of complex organic molecules from simpler pieces, usually without the aid of biological processes. In practice, these simpler pieces are commercially available in bulk and semi-bulk quantities, and are often...

 of D,L-tetrodotoxin in 1972. M. Isobe et al. at Nagoya University, Japan and J. Du Bois et al. at Stanford University
Stanford University
The Leland Stanford Junior University, commonly referred to as Stanford University or Stanford, is a private research university on an campus located near Palo Alto, California. It is situated in the northwestern Santa Clara Valley on the San Francisco Peninsula, approximately northwest of San...

, U.S., reported the asymmetric total synthesis of tetrodotoxin in 2003. The two 2003 syntheses used very different strategies, with Isobe's route based on a Diels-Alder approach
Diels-Alder reaction
The Diels–Alder reaction is an organic chemical reaction between a conjugated diene and a substituted alkene, commonly termed the dienophile, to form a substituted cyclohexene system. The reaction can proceed even if some of the atoms in the newly formed ring are not carbon...

 and Du Bois's work using C-H bond activation.

Poisoning


Tetrodotoxin is roughly 10 times more poisonous than potassium cyanide
Potassium cyanide
Potassium cyanide is an inorganic compound with the formula KCN. This colorless crystalline compound, similar in appearance to sugar, is highly soluble in water. Most KCN is used in gold mining, organic synthesis, and electroplating. Smaller applications include jewelry for chemical gilding and...

. Fish poisoning by consumption of members of the order Tetraodontiformes
Tetraodontiformes
The Tetraodontiformes are an order of highly derived ray-finned fish, also called the Plectognathi. Sometimes these are classified as a suborder of the Perciformes...

 is extremely serious. The organs (e.g. liver) of the pufferfish
Pufferfish
Tetraodontidae is a family of primarily marine and estuarine fish of the Tetraodontiformes order. The family includes many familiar species which are variously called pufferfish, balloonfish, blowfish, bubblefish, globefish, swellfish, toadfish, toadies, honey toads, sugar toads, and sea squab...

 can contain levels of tetrodotoxin sufficient to produce paralysis of the diaphragm and death due to respiratory failure
Respiratory failure
The term respiratory failure, in medicine, is used to describe inadequate gas exchange by the respiratory system, with the result that arterial oxygen and/or carbon dioxide levels cannot be maintained within their normal ranges. A drop in blood oxygenation is known as hypoxemia; a rise in arterial...

. Toxicity varies between species and at different seasons and geographic localities, and the flesh of many pufferfish may not be dangerously toxic. It is not always fatal; but at near-lethal doses, it can leave a person in a state of near-death for several days, while the person remains conscious. For this reason, tetrodotoxin has been alleged an ingredient in Haitian Vodou and the closest approximation of zombie
Zombie
Zombie is a term used to denote an animated corpse brought back to life by mystical means such as witchcraft. The term is often figuratively applied to describe a hypnotized person bereft of consciousness and self-awareness, yet ambulant and able to respond to surrounding stimuli...

ism, an idea popularized by Harvard-trained ethnobotanist Wade Davis
Wade Davis
Edmund Wade Davis is a Canadian anthropologist, ethnobotanist, author and photographer whose work has focused on worldwide indigenous cultures, especially in North and South America and particularly involving the traditional uses and beliefs associated with psychoactive plants...

 in a 1983 paper, and in his 1985 book, The Serpent and the Rainbow
The Serpent and the Rainbow (book)
The Serpent and the Rainbow is a book by ethnobotanist and researcher Wade Davis. He investigated Haitian Vodou and the process of making zombies. He studied ethnobotanical poisons, discovering their use in a reported case of a contemporary zombie, Clairvius Narcisse.The book inspired a dramatic...

. This idea was dismissed by the scientific community in the 1980s, as the descriptions of voodoo zombies do not match the symptoms displayed by victims of tetrodotoxin poisoning, and the alleged incidents of zombies created in this manner could not be substantiated.

Toxicity


The Material Safety Data Sheet
Material safety data sheet
A Material Safety Data Sheet is a form with data regarding the properties of a particular substance....

 for tetrodotoxin lists the oral median lethal dose (LD50) for mice as 334 μg per kg. Assuming the lethal dose for humans is similar, 25 milligrams (0.000881 oz) of tetrodotoxin would be expected to kill a 75 kg (165.3 lb) person. The amount needed to reach a lethal dose by injection is much smaller, 8 μg per kg, or a little over one-half milligram (0.00002 oz) to kill a 75 kg (165.3 lb) person.

History


The first recorded cases of tetrodotoxin poisoning were from the logs of Captain
Captain (naval)
Captain is the name most often given in English-speaking navies to the rank corresponding to command of the largest ships. The NATO rank code is OF-5, equivalent to an army full colonel....

 James Cook
James Cook
Captain James Cook, FRS, RN was a British explorer, navigator and cartographer who ultimately rose to the rank of captain in the Royal Navy...

 from 7 September 1774 , on which 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 received 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.

Symptoms and treatment


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

Symptoms typically develop within 30 minutes of ingestion, but may be delayed by up to four hours; however, death once occurred within 17 minutes of ingestion. Paresthesia
Paresthesia
Paresthesia , spelled "paraesthesia" in British English, is a sensation of tingling, burning, pricking, or numbness of a person's skin with no apparent long-term physical effect. It is more generally known as the feeling of "pins and needles" or of a limb "falling asleep"...

 of the lips and tongue is followed by sialorrhea, sweating, headache, weakness, lethargy, incoordination
Ataxia
Ataxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...

, tremor, paralysis, cyanosis
Cyanosis
Cyanosis is the appearance of a blue or purple coloration of the skin or mucous membranes due to the tissues near the skin surface being low on oxygen. The onset of cyanosis is 2.5 g/dL of deoxyhemoglobin. The bluish color is more readily apparent in those with high hemoglobin counts than it is...

, aphonia
Aphonia
Aphonia is the inability to speak. It is considered more severe than dysphonia. A primary cause of aphonia is bilateral disruption of the recurrent laryngeal nerve, which supplies nearly all the muscles in the larynx...

, dysphagia
Dysphagia
Dysphagia is the medical term for the symptom of difficulty in swallowing. Although classified under "symptoms and signs" in ICD-10, the term is sometimes used as a condition in its own right. Sufferers are sometimes unaware of their dysphagia....

, seizures, dyspnea
Dyspnea
Dyspnea , shortness of breath , or air hunger, is the subjective symptom of breathlessness.It is a normal symptom of heavy exertion but becomes pathological if it occurs in unexpected situations...

, bronchorrhea
Bronchorrhea
Bronchorrhea is the production of more than 100 mL per day of watery sputum. Chronic bronchitis is a common cause, but it may also be caused by asthma, pulmonary contusion, bronchiectasis, tuberculosis, cancer, scorpion stings, and poisoning by organophosphates and other poisons...

, bronchospasm
Bronchospasm
Bronchospasm or a bronchial spasm is a sudden constriction of the muscles in the walls of the bronchioles. It is caused by the release of substances from mast cells or basophils under the influence of anaphylatoxins...

, respiratory failure, coma
Coma
In medicine, a coma is a state of unconsciousness, lasting more than 6 hours in which a person cannot be awakened, fails to respond normally to painful stimuli, light or sound, lacks a normal sleep-wake cycle and does not initiate voluntary actions. A person in a state of coma is described as...

, and hypotension
Hypotension
In physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...

. Gastroenteric symptoms are often severe and include nausea, vomiting, diarrhea, and abdominal pain. Cardiac arrhythmias may precede complete respiratory failure and cardiovascular collapse.

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
Epigastrium
The epigastrium is the upper central region of the abdomen. It is located between the costal margins and the subcostal plane....

 pain, nausea
Nausea
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...

, diarrhea
Diarrhea
Diarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...

, and/or vomiting
Vomiting
Vomiting is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose...

 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
Dyspnea
Dyspnea , shortness of breath , or air hunger, is the subjective symptom of breathlessness.It is a normal symptom of heavy exertion but becomes pathological if it occurs in unexpected situations...

, cyanosis, and hypotension
Hypotension
In physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...

. Paralysis increases and convulsions
Seizure
An epileptic seizure, occasionally referred to as a fit, is defined as a transient symptom of "abnormal excessive or synchronous neuronal activity in the brain". The outward effect can be as dramatic as a wild thrashing movement or as mild as a brief loss of awareness...

, 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.

If the patient survives 24 hours, recovery without any residual effects will usually occur over several days.

Therapy is supportive and based on symptoms, with aggressive early airway management. If ingested, 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. Alpha adrenergic agonists are recommended in addition to intravenous fluids to combat hypotension. Anticholinesterase agents have been used with mixed success. No antidote
Antidote
An antidote is a substance which can counteract a form of poisoning. The term ultimately derives from the Greek αντιδιδοναι antididonai, "given against"....

 has been developed and approved for human use; but a monoclonal antibody specific to tetrodotoxin has been developed by USAMRIID and was shown to be effective for reducing lethality in murine tests .

Geographic frequency of 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
Atlantic Ocean
The Atlantic Ocean is the second-largest of the world's oceanic divisions. With a total area of about , it covers approximately 20% of the Earth's surface and about 26% of its water surface area...

, Gulf of Mexico
Gulf of Mexico
The Gulf of Mexico is a partially landlocked ocean basin largely surrounded by the North American continent and the island of Cuba. It is bounded on the northeast, north and northwest by the Gulf Coast of the United States, on the southwest and south by Mexico, and on the southeast by Cuba. In...

, and Gulf of California
Gulf of California
The Gulf of California is a body of water that separates the Baja California Peninsula from the Mexican mainland...

. There have been no confirmed cases of tetrodotoxicity from the Atlantic pufferfish, Sphoeroides maculatus; but 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
Saxitoxin
Saxitoxin is a neurotoxin naturally produced by certain species of marine dinoflagellates and cyanobacteria Saxitoxin (STX) is a neurotoxin naturally produced by certain species of marine dinoflagellates (Alexandrium sp., Gymnodinium sp., Pyrodinium sp.) and cyanobacteria Saxitoxin (STX) is a...

, which causes paralytic shellfish poisoning
Paralytic shellfish poisoning
Paralytic shellfish poisoning is one of the four recognized syndromes of shellfish poisoning, which share some common features and are primarily associated with bivalve mollusks . These shellfish are filter feeders and, therefore, accumulate toxins produced by microscopic algae, such as...

 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.

In 2009, a major scare in the Auckland Region
Auckland Region
The Auckland Region was one of the sixteen regions of New Zealand, named for the city of Auckland, the country's largest urban area. With one third of the nation's residents, it was by far the biggest population and economy of any region of New Zealand, but the second-smallest land area.On 1...

 of New Zealand
New Zealand
New Zealand is an island country in the south-western Pacific Ocean comprising two main landmasses and numerous smaller islands. The country is situated some east of Australia across the Tasman Sea, and roughly south of the Pacific island nations of New Caledonia, Fiji, and Tonga...

 was sparked after several dogs died eating Pleurobranchaea maculata
Pleurobranchaea maculata
Pleurobranchaea maculata, or the grey side-gilled slug, is a species of sea slug, a marine opisthobranch gastropod mollusk in the family Pleurobranchidae.-Habitat:...

(grey side-gilled seaslug) on beaches. 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.

Statistical factors

From 1974 through 1983, there were 646 reported cases of pufferfish poisoning in Japan, with 179 fatalities. Statistics from the Tokyo Bureau of Social Welfare and Public Health indicate 20–44 incidents of fugu
Fugu
is the Japanese word for pufferfish and the dish prepared from it, normally species of genus Takifugu, Lagocephalus, or Sphoeroides, or porcupinefish of the genus Diodon. Fugu can be lethally poisonous due to its tetrodotoxin; therefore, it must be carefully prepared to remove toxic parts and to...

 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%. 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.

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 is thought by some believers in voodoo mythology to assist the creation of so-called zombie
Zombie
Zombie is a term used to denote an animated corpse brought back to life by mystical means such as witchcraft. The term is often figuratively applied to describe a hypnotized person bereft of consciousness and self-awareness, yet ambulant and able to respond to surrounding stimuli...

 poisons.

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. Poisoning from tetrodotoxin is of particular public health concern in Japan, where pufferfish "fugu
Fugu
is the Japanese word for pufferfish and the dish prepared from it, normally species of genus Takifugu, Lagocephalus, or Sphoeroides, or porcupinefish of the genus Diodon. Fugu can be lethally poisonous due to its tetrodotoxin; therefore, it must be carefully prepared to remove toxic parts and to...

" is a traditional delicacy. It is prepared and sold in special restaurants where trained and licensed chef
Chef
A chef is a person who cooks professionally for other people. Although over time the term has come to describe any person who cooks for a living, traditionally it refers to a highly skilled professional who is proficient in all aspects of food preparation.-Etymology:The word "chef" is borrowed ...

s carefully remove the viscera to reduce the danger of poisoning. There is potential for misidentification and mislabelling, particularly of prepared, frozen fish products.

Food analysis


The mouse bioassay developed for paralytic shellfish poisoning
Paralytic shellfish poisoning
Paralytic shellfish poisoning is one of the four recognized syndromes of shellfish poisoning, which share some common features and are primarily associated with bivalve mollusks . These shellfish are filter feeders and, therefore, accumulate toxins produced by microscopic algae, such as...

 (PSP) can be used to monitor tetrodotoxin in pufferfish and is the current method of choice. An HPLC
High-performance liquid chromatography
High-performance liquid chromatography , HPLC, is a chromatographic technique that can separate a mixture of compounds and is used in biochemistry and analytical chemistry to identify, quantify and purify the individual components of the mixture.HPLC typically utilizes different types of stationary...

 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
Trimethylsilyl
A trimethylsilyl group is a functional group in organic chemistry. This group consists of three methyl groups bonded to a silicon atom [−Si3], which is in turn bonded to the rest of a molecule...

 derivatives by gas chromatography/mass spectrometry.

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.

Regulation


In the U.S., tetrodotoxin appears on the select agent
Select agent
In United States law, Select Agents are pathogens or biological toxins which have been declared by the U.S. Department of Health and Human Services or by the U.S. Department of Agriculture to have the "potential to pose a severe threat to public health and safety"...

s list of the Department of Health and Human Services, and scientists must register with HHS to use tetrodotoxin in their research. However, investigators possessing less than 100 mg are exempt from regulation.

See also

  • Conotoxin
    Conotoxin
    A conotoxin is one of a group of neurotoxic peptides isolated from the venom of the marine cone snail, genus Conus.Conotoxins, which are peptides consisting of 10 to 30 amino acid residues, typically have one or more disulfide bonds. Conotoxins have a variety of mechanisms of actions, most of...

  • Neurotoxin
    Neurotoxin
    A neurotoxin is a toxin that acts specifically on nerve cells , usually by interacting with membrane proteins such as ion channels. Some sources are more general, and define the effect of neurotoxins as occurring at nerve tissue...

  • Saxitoxin
    Saxitoxin
    Saxitoxin is a neurotoxin naturally produced by certain species of marine dinoflagellates and cyanobacteria Saxitoxin (STX) is a neurotoxin naturally produced by certain species of marine dinoflagellates (Alexandrium sp., Gymnodinium sp., Pyrodinium sp.) and cyanobacteria Saxitoxin (STX) is a...

  • Tectin
  • Clairvius Narcisse
    Clairvius Narcisse
    Clairvius Narcisse was a Haitian man said to have been turned into a living zombie by a combination of drugs. His case was the subject of a book, The Serpent and the Rainbow.-History:...

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

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