Tetrodotoxin
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| Tetrodotoxin | |
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| Formula | C11H17N3O8 |
| LD50 | 8.0 - 10.0 µg/kg |
| Molecular mass | 319.28 u |
Tetrodotoxin (anhydrotetrodotoxin 4-epitetrodotoxin, tetrodonic acid, TTX) is a potent neurotoxin, which blocks the nerve function in nerves by binding to the pore of voltage-gated sodium channel in nerve cell membranes. The binding site of this toxin is located at the pore opening the voltage-gated Na+ channel. Its name derives from Tetraodontidae, the scientific family name of the puffer fishes, some species of which carry the toxin. Although tetrodotoxin was discovered in these fish and found in several other animals, it is actually thought to be a product of bacteria such as Pseudoalteromonas tetraodonis, certain Pseudomonas and Vibrio species, as well as some others.
Fish poisoning by consumption of members of the order Tetraodontiformes is one of the most violent intoxications from marine species. The gonads, liver, intestines, and skin of pufferfish can contain levels of tetrodotoxin sufficient to produce rapid and violent death. The flesh of many pufferfish may not usually be dangerously toxic.
Tetrodotoxin has also been isolated from widely differing animal species, including the California newt, parrotfish, frogs of the genus Atelopus, the blue-ringed octopus, starfish, angelfish, and xanthid crabs.
Common causes of tetrodotoxin poisoning include the eating of the puffer fish known as fugu, which is a popular but rare delicacy in Japan and often contains significant amounts of toxin in its liver and other viscera. Cone snail stings represent another common source, which most often affect divers. Blue-ringed octopus, which inhabit tidepools, also sometimes contain the toxin, and people have died from their bites. Lethal dose is about .01 mg/kg, less than ricin but more than botulism toxin.
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Biochemistry
Tetrodotoxin binds to what is now known as site 1 of the 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.
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.
Tetrodotoxin has been synthesized by Kishi et al at Harvard University in 1972.
Tetrodotoxin Poisoning
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.
The toxin was first isolated in 1909.
Symptoms and diagnosis
The diagnosis of pufferfish poisoning is based on the observed symptomology and recent dietary history.
The effects of tetrodotoxin poisoning include shortness of breath, numbness, tingling, lightheadedness, paralysis and irregular heartbeat. Symptoms typically onset quickly, minor ones instantaneously. Death is the usual outcome. Although the toxin unbinds from channels as its concentration around nerves diminishes, its molecules are exceptionally potent and unbind only very slowly. Treatment usually consists of respiratory assistance. Nothing equivalent to an antivenin has been developed--presumably because the toxin acts quickly and binds with an affinity that isn't easily overcome.
Course of disease 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.
Areas where tetrodotoxin poisoning is most common
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 poisoning from the Atlantic pufferfish, Spheroides maculatus. However, in one study, extracts from fish of this species were highly toxic in mice. 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 when an individual swallowed a California newt.
Relative frequency of disease
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.
Target populations
All humans are susceptible to tetrodotoxin poisoning. This toxicosis may be avoided by not consuming pufferfish or other animal species containing tetrodotoxin. Most other animal species known to contain tetrodotoxin are not usually consumed by humans. Poisoning from tetrodotoxin is of major 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. Importation of pufferfish into the United States is not generally permitted, although special exceptions may be granted. There is potential for misidentification and/or 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. These chromatographic methods have not yet been validated.
See also
External links
da:Tetradotoxin de:Tetrodotoxin ja:テトロドトキシン nl:Tetrodotoxine