Tetrodotoxin newts

California newt Tetrodotoxin Alkaloid Local anesthetic. 

FIGURE 10.2 Tetrodotoxin, a toxin from pufferfish and newts. 

Many urodeles produce irritating or even toxic secretions in their skin glands, and some are extremely toxic. The rough-skinned noNt Taricha granulosa) is the most toxic of newts from several genera. Its dorsal skin and ovarian eggs contain the very potent tetrodotoxin. Only 0.000 05 ml of newt skin is needed for a lethal peritoneal injection in mice. The skin of one newt can theoretically kill 25 000 mice. When bothered, the newt assumes a characteristic defense posture it arches, lifts its tail and releases an odor (Brodie etal., 1974). 

The level of tetrodotoxin in the skin of a particular female rough-skin newt correlates with that in her eggs. The amounts in the eggs of one clutch vaiy little, hut there is considerable variation between clutches. These findings suggest that the mother passes on the toxin to her eggs. As the amount of toxin is not correlated with egg size, it may not be transferred automatically (passively) with maternal resources to the egg. Rather, the mother may exert some control over the amount allocated to the eggs (Hanfin etal., 2003). 

Hanfin, C. T., Brodie, E. D., Ill, and Brodie, E. D., Jr. (2003). Tetrodotoxin levels in eggs of rough-skin newt, Taricha granulosa, are correlated with female toxicity. Journal of Chemical Ecology 29,1729-1739. 

Tetrodotoxin/pheromon e and toxin, T12.3.1I alkal. OH (-)-tetrodotoxin marine Bact. and Dinofl. Kodama 1996 puffers land newts and fi ogs (possibly fi-om symbiotic Bact.)... 

The highly toxic guanidinium alkaloid tetrodotoxin was first isolated from the Japanese puffer fish, Fuga rubipes. In the early 1960s, a guanidinium alkaloid was isolated from eggs of the California newt Taricha torosa and named tarichatoxin (185). It proved identical with tetrodotoxin from puffer fish (186 see Ref. 5 for a historical review). Tetrodotoxin and other guanidinium toxins, namely, chiriquitoxin and the zetekitoxins, have been shown to occur in other amphibians. 

In 1964, the structure of tetrodotoxin (XXIV) was finally elucidated by analysis of a variety of chemical. X-ray crystallographic, and spectral data (187-190). One key reaction was the facile conversion to 2-amino-6-hydroxymethyl-8-hydroxyquinazoline (XXV). Natural tetrodotoxin is levorotatory, with an [a] of -S.S (3.3, D2O). Tetrodotoxin is accompanied in certain salamanders and newts of the family Salamandridae by 4,9-anhydrotetrodotoxin, 4-epitetrodotoxin, 6-epitetrodotoxin, and 11-deoxy-tetrodotoxin, as well as trace amounts of 4,9-anhydro-4-epitetrodotoxin,... 

Nothing is known of the biosynthesis of tetrodotoxin, although the involvement of arginine and an isoprenoid has been postulated (191). Radiolabeled acetate, arginine, citrulline, or glucose were not incorporated into the tetrodotoxin of newts of the genus Taricha (210). 

More recent studies have identified the most potent toxin produced by the frog as batrachotoxin (although it is one of about a hundred toxins). This is one of the most toxic substances known—five times more potent than tetrodotoxin, the toxin found in puffer fish (see pp. 252-3)—and a dose of 200 pg would be lethal for a human. Interestingly, tetrodotoxin is also found in the Californian newt. Batrachotoxin is secreted through the skin when the animal is stressed, and so when animals hck or bite the frog they are exposed to the toxin, which causes death by stopping the heart beating. 

Chemical Abstracts Service Registry Number CAS 4368-28-9. Tetrodotoxin, a neurotoxin produced by several species of starfish, crabs, salt-water fish, octopi, newts, and salamanders, blocks sodium channels within neurons. In a terrorist scenario, tetrodotoxin could be inhaled as an aerosol or ingested in contaminated food or water. Mortality may reach 50%. 

Tetrodotoxin, a fully saturated 2-aminopolyhydroxyquinazoline, is a powerful nonprotein neurotoxin which occurs in the liver and ovaries of the Japanese puffer fish Sphoerides rubripes and S. phyreus, and in the Californian newt or salamander Taricha torosa <79AJC1805>. 

Although originally named after the tetraodontidae fish, it is now very apparent that the occurrence of tetrodotoxin is not restricted to this family. In fact it is not even the unique preserve of one phylum, as it has been identified in a series of taxonomically unrelated animals representing at least five different phyla, as noted above. The toxin has no obvious similarity to any known animal or plant natural product, so its synthesis does not merely result from the simple modification of a related (non-toxic) precursor. Whilst it was thought that tetrodotoxin only occurred in fish and newts, it was just possible that the toxin had been "invented" twice... 

Isolation of 1-Hydroxy-5,11-dideoxytetrodotoxin (see Fig. 2) and Other Tetrodotoxin Derivatives from the Newt, Taricha granular (3)... 

Fig. 2. Structures of tetrodotoxin derivatives isolated from the newt, Tancha granulosa.

Kotaki, Y. and Shimizu, Y. (1993) l-Hydroxy-5,11-dideoxytetrodotoxin, the first N-hydroxy and ring-deoxy derivative of tetrodotoxin found in the newt Taricha granulosa. J Am. Chem. Soc 115, 827-830. 

The fargefs for natural biological toxins include ion channels and receptors for transmitfers. At least four parts of fhe volfage-gafed sodium charmels are binding sifes for extremely toxic natural products. " Tetrodotoxin (Fig. 30-16), which is found in the puffer fish, certain newts, and venom of fhe blue-ringed octopus, and also the shellfish poison saxitoxin (Fig. 

Tetrodotoxin, however, has been isolated from the Californian newts Taricha torosa, Taricha rivularis, and Taricha granulosa it has formerly been called tarichatoxin but was later found to be identical with tetrodotoxin from Tetraodontidae. We now know that tetrodotoxin is a bacterial toxin (ref. 29) but we have no idea about this kind of symbiosis between bacteria and amphibia. It certainly does not act as a fungicide or bactericide (ref. 30) but it might act as a repellent against predators of the animals themselves or of their egg clusters as has been observed in Tetrodotoxin containing fish. 

Arakawa, O., Mahmud, Y., Tanu, M.B., Tsuruda, K., Okada, K., Kawatsu, K., Hamano, Y., Takatani, T., and Noguchi, T. 2003. Micro-distribution of tetrodotoxin in puffers and newts. In Proceedings of International Scientific Symposium on Marine Toxins and Marine Food Safety (D.F. Hwang and T. Noguchi, eds), pp. 57 5. National Taiwan Ocean University, Keelung. 

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