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How Effects Of Tetradotoxin in The Puffer Fish Affect Lives of Animals.

FUGU

How Effects Of Tetradotoxin in The Puffer Fish Affect Lives of Animals.

In Japan, fugu is the general name for fish of the family Tetraodontidae, class Osteichthyes, order Tetraodontiformes. It is also widely known as the blowfish or the puffer fish, because it can swell up their bellies until they resemble a ball. It is also used more narrowly as the name of the genus Fugu of the family Tetraodontidae living only in waters surrounding Japan and the rivers flowing into the waters of Japan. Blowfish can be found in the Indian Ocean and in the South Pacific. Some can also be found in North American waters. There are nearly 100 different species of fugu worldwide, 38 of them found in Japan. Their lifespan depends on the different species. However, there are well-established methods of extinction for blowfish as a whole in Japan as Japanese consumes about 20,000 tons of blowfish per year, 6,800 tons in imports.

Puffer fish (Tetrodontidae and Diodontidae) possess paralysing toxins (tetrodotoxin and analogues) that are secreted upon stimulation (Malpezzi et al., 1997). Tetrodotoxin, a violent neurotoxin is present in puffer fish and may occur in a variety of marine animals. Outbreaks of human tetrodotoxin poisoning has been rare in other marine animals but there are cases where a 71 year old woman was admitted with hypertension and other neurological symptoms developing after ingesting in some mollusks (Yang C C et al., 1995). 16 other cases were also found to have typical symptoms of tetrodotoxication after mollusk consumption (Yang C C et al., 1995).

The puffer fish store high concentrations of tetrodotoxin in various organs. The liver, gonads, intestines, and skin of these fish contain tetrodotoxin (TTX), a powerful neurotoxin that can cause death in approximately 60% of persons who ingest it. Other animals (e.g., California newt and the eastern salamander) also possess tetrodotoxin in lethal quantities.

However, the different species of puffer fish differ widely in terms their resistance to tetrodotoxin. Lagocephalus scleratus is a lethal source of food poisoning with a high mortality; it contains tetrodotoxin, which can cause death by muscular paralysis, respiratory depression, and circulatory failure (Field J, 1995).

According to Fuchi Y et al., (1998), Arothron firmamentum were caught and examined for the anatomical distribution and the seasonal variation of toxicity and their skin showed a rather low level of toxicity and the frequency of toxic specimens was 6.1% with the maximal lethal potency of 29 mouse unit (MU)/g. Ovary showed a higher level of toxicity (frequency 80.8%) with the maximal lethal potency of 640 MU/g. On the other hand, the muscle, liver, testis and intestine were non-toxic. Ovaries collected in 6 different months (March, May, and August-November) were found to be toxic with the frequency of 50 similar to 100%. Skins were found to be toxic in August and October. It appears that this species has high toxicity in the ovary during early summer to autumn.

However in another species, Takifugu rubripes is another story. According to Lin S J et al., during November 1996 to October 1997, all specimens collected from Ilan County were non-toxic (< 10 MU/g), while the specimens collected from Taipei County during the period from January to March 1997 showed toxicity in the ovary and liver. The toxicity was as follows: ovary 105 +/- 9 (mean +/- S.E.) MU/g and liver 13 +/- 3 MU/g in January, ovary 88 +/- 12 MU/g in February, and ovary 253 +/- 55 MU/g and liver 17 +/- 6 MU/g in March. And the highest toxicity level of the ovary and liver was 624 MU/g and 119 MU/g, respectively.

Tetrodotoxin, one of the most potent molecules is known to selectively block off the voltage-sensitive sodium channels of excitable tissues and neuronal transmission in skeletal muscles. In human, paresthesias begin 10-45 minutes after ingestion, usually as tingling of the tongue and inner surface of the mouth. Other common symptoms include vomiting, lightheadedness, dizziness, feelings of doom, and weakness. An ascending paralysis develops, and death can occur within 6-24 hours, secondary to respiratory muscle paralysis. Other manifestations include salivation, muscle twitching, diaphoresis, pleuritic chest pain, dysphagia, aphonia, and convulsions. Severe poisoning is indicated by hypotension, bradycardia, depressed corneal reflexes, and fixed dilated pupils.

TTX is complex in structure by small molecule standards and contains a guanidinium moiety. The guanidinium ion is able to enter cells via the voltage sensitive Na+ channels, which are critical for cellullar signalling pathways (e.g. transmission of impulses and the mediation of many cell functions). It is likely that this imidazole ring is the part of the molecule that lodges in the channel leaving the rest of the molecule blocking its outer mouth. Their association and dissociation are independent of whether the channel is open or closed. When a neuron (nerve cell) is sending a message, tiny pores or channels in the neuron's membrane open up to let sodium ions enter the cell. Tetrodotoxin (puffer fish toxin) blocks these tiny pores, which in turn prevents any signalling in the nervous system. The result is rapid paralysis and possibly death.

Matsumura K. (Dec 1998) also describes an endogenous origin of tetrodotoxin in puffer fish. The ovulated oocytes from puffer fish Fugu niphobles were artificially fertilized and cultivated. The toxin levels of embryos increased gradually with development until the time of hatching, suggesting that the increased toxin is a product of embryos.

Respiratory arrest is the cause of death. There is no proven antidote, most likely it is because the toxin has a molecular structure unlike anything previously known to organic chemistry.





TETRADOTOXIN MOLECULE

Because of its potency -- it is 1250 times deadlier than cyanide -- the toxin is an important tool in modern neurological research. In diluted form it is also used as a painkiller for victims of neuralgia, arthritis and rheumatism.

However, the puffer fish has a mutation in the protein sequence of the sodium channel pump found on the cell membranes, this sodium channel is critical for cellullar signalling pathways (e.g. transmission of impulses and the mediation of many cell functions). This point mutation in the amino-acid sequence compared to the sequence in man makes these fish highly resistant to tetrodotoxin poisoning, as a result tetrodotoxin does not recognize the channel in puffer fish and therefore does not bind to it and block it. The puffer fish store high concentrations of tetrodotoxin in various organs. However, the species differ widely in terms their resistance to tetrodotoxin.

The Japanese has been successful in artificial cultivation of fugu. Fishermen catch fugu in spring as it is the spawning season. They will then cultivate these fish in a cage in the sea or the ocean. Artifically cultivated fugu that does not feed on plankton is not lethal. The fishermen feed fugu on fresh fish until they grow up and will be sold from late autumn to early winter. Full-scale farming such as the artificial insemination also will be carried out. They raise the fish until the price goes up and start selling fugu in the fish market only in late fall.

The puffer claims 70 to 100 lives each year, mostly in rural areas and from fish improperly cleaned at home. There are over 1,500 fugu restaurants in Tokyo, where an average of 100-200 people a year show signs of poisoning where death rate is 61%. In January 1975, the revered Mitsugoro Bando VIII, one of Japan's most gifted Kabuki actors (he had been officially designated a "living national treasure" by the government) died of paralysis and convulsions after eating fugu liver in Kyoto restaurant.

REFERENCES

Websites

http://www.american.edu/projects/mandala/TED/BLOWFISH.HTM

http://fugu.hgmp.mrc.ac.uk/fugu/pffp/toxin.html

http://vm.cfsan.fda.gov/~mow/fugu.html

Journals

Field J. Puffer Fish Poisoning. Journal of Accident & Emergency Medicine.15: (5) 334-336 Sep 1998

Fuchi Y, Hoashi K, Akaeda H, Makino Y, Noguchi T. Anatomical Distribution and Seasonal Variation of Toxicity of Puffer Fish, "Hoshifugu" Arothron firmamentum specimens collected from the Bungo Channel, Oita. Journal of The Food Hygienic Society of Japan. 39: (6) 421-425 DEC 1998

Lin SJ, Chai TJ, Jeng SS, Hwang DF.Toxicity of the puffer Takifugu rubripes cultured in northern Taiwan.Fisheries Science. 64: (5) 766-770 Oct 1998

Malpezzi ELA, deFreitas JC, Rantin FT. Occurrence of toxins, other than paralysing type, in the skin of tetraodontiformes fish. Toxicon. 35: (1) 57-65 Jan 1997

Matsui T, Taketsugu S, Kodama K, Ishii A, Yamamori K, Shimizu C. Studies on the Toxification of Puffer Fish .1. Production of Tetrodotoxin by the Intestinal Bacteria of a Puffer Fish, Takifugu niphobles. Nippon Suisan Gakkaishi. 55: (12) 2199-2203 Dec 1989

Matsumura K.A. Monoclonal-Antibody Against Tetrodotoxin That Reacts to The Active Group For the Toxicity. European Journal of Pharmacology-Environmental Toxicology and Pharmacology Section.293: (1) 41-45 May 26 1995

Matsumura, K.Tetrodotoxin concentrations in cultured puffer fish, Fugu rubripes. Journal of Agricultural and Food Chemistry. 44: (1) 1-2 Jan 1996

Matsumura K. Production of tetrodotoxin in puffer fish embryos. Environmental Toxicology and Pharmacology.6: (4) 217-219 Dec 1998

Nagashima Y, Hamada Y, Ushio H, Nishio S, Shimakura K, Shiomi K. Subcellular Distribution of Tetrodotoxin in Puffer Fish Liver. Toxicon. 37: (12) 1833-1837 Dec 1999.

Saito T, Noguchi T, Shida Y, Abe T, Hashimoto K. Screening of Tetrodotoxin and Its Derivatives in Puffer-Related Species. Nippon Suisan Gakkaishi. 57: (8) 1573-1577 Aug 1991

Sun K, Wat J, So P. Puffer Fish Poisoning. Anaesthesia and Intensive Care. 22: (3) 307-308 Jun 1994

Sun K O. Management of Puffer Fish Poisoning. British Journal of Anaesthesia. 75: (4) 500-500 Oct 1995

Yang C C, Han K C, Lin T J, Tsai W J, Deng J F. An Outbreak of Tetrodotoxin Poisoning Following Gastropod Mollusk Consumption. Human & Experimental Toxicology. 14: (5) 446-450 May 1995

Yu CF, Yu PHF. A Preliminary Study of Puffer Fishes And Their Toxins Found in Hong Kong Waters. Journal of The Food Hygienic Society of Japan 38: (6) 460-463 Dec 1997

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