Tetrodotoxin frogs

Currently we know very little about naturally occurring tetrodotoxin analogs or precursors. Chiriquitoxin, isolated along with tetrodotoxin from the Costa Rican frog Atelopus chiriquiensis (21,22), is known to possess the same basic skeleton as tetrodotoxin but differs by an uncharacterized substituent at C-6, as shown in the structure below. It also was shown, based on isolation experiments, that... 

The puffer fish is probably the best known neurotoxic fish. Several related species of fish, as well as other marine life, such as some frogs, starfish, octopus, and others, contain tetrodotoxin. Many people consider this fish a delicacy despite the occasional death from poor preparation. Tetrodotoxin is heat stable but water soluble, so careful preparation is necessary to limit neurological effects. Symptoms of poisoning include a rapid onset of numbness in the lips and mouth, which then extends to the fingers and toes, followed by general weakness, dizziness, and respiratory failure, leading to death. The mechanism of action is similar to that of saxitoxin and affects sodium channel permeability. 

Fish Puffer fish (fugu) blowfish, toadfish. . . some frogs, starfish, ocopus Tetrodotoxin Nervous system numbness, paralysis, respiratory failure, death Decreased sodium channel permeability... 

Reeves JJ, Jones CA, Sheehan MJ, Vardey CJ, Whelan CJ (1997) Adenosine A3 receptors promote degranulation of rat mast cells both in vitro and in vivo. Inflamm Res 46(5) 180-184 Ribeiro JA, Walker J (1975) The effects of adenosine triphosphate and adenosine diphosphate on transmission at the rat and frog neuromuscular junctions. Br J Pharmacol 54(2) 213-218 Ribeiro JA, Sebastiao AM (1984) Enhancement of tetrodotoxin-induced axonal blockade by adenosine, adenosine analogues, dibutyryl cyclic AMP and methylxanthines in the frog sciatic nerve. Br J Pharmacol 83(2) 485—492... 

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. 

Batrachotoxin (459), the steroidal alkaloid from the poison arrow frog Phyllo-bates aurotaenia, continues to engage the attention of chemists and pharmacologists. This substance exerts novel, selective effects on electrogenic membranes. In many cases this activity can be explained in terms of an irreversible increase in permeability to sodium ions. The subsequent reactions promoted by (459) can be blocked reversibly by tetrodotoxin. ... 

Tetrodotoxin, saxitoxin, ciguatoxin, and batrachotoxin are sodium-channel toxins found in various fish, frogs, or diflageliates. 

Several studies employing oocytes of the clawed frog, Xenopus laevis, for the in vitro translation of sodium channel encoding mRNAs (53-55) suggest that this experimental system may be particularly useful toward this end. The biophysical properties of sodium channels expressed in oocytes following injection of rat brain mRNA were similar to those of sodium channels in their native membrane environment, and were specifically inhibited by the sodium channel blockers tetrodotoxin and saxitoxin (i5.). Sodium channels encoded by mRNAs from rat skeletal muscle and eel electroplax have also been expressed in Xenopus oocytes (56-57). To date the expression of insect sodium channels in the Xenopus oocyte has not been reported, but the utility of this system for the translation and expression of insect acetylcholine receptor mRNA has recently been demonstrated (58). Successful application of this methodology to the expression of insect mRNAs encoding functional sodium channels offers a novel method to test some of the hypotheses for the molecular basis of the kdr mechanism. 

Most toxic of the steroidal alkaloids present in the skin of dart-poison frogs, Phyllobates. Used as an arrow poison in western Colombia. Opens Na+ channels and depolarizes nerve fibres irreversible depolarization leading to paralysis ventricular fibrillation, cardiac and respiratory failure and death. Effect abolished by tetrodotoxin. Only toxic via damaged skin or digestive tract. Mice lethal at 2-3 pg/kg SC and 0.1 pg/kg IV. 

It may be mentioned here that veratridine is also reported to partially block Na" channels in jellyfish neurones which, however, are tetrodotoxin-insensitive and show other unusual pharmacological features (Spafford et al. 1996). In neuroblastoma ceUs veratridine-induced block of Ca + channels was observed at concentrations which stimulate Na" channels (Romey and Lazdunski 1982). Such suppression of Ca + current, however, at relatively large concentrations of veratridine, is also seen in frog muscle fibers (Ndndsi et al. 1994). Even the block of voltage-gated K channels in T lymphocytes and neuroblastoma cells has been reported (Verheugen et al. 

LSnnendonker U (1989) Use-dependent block of sodium channels in frog myelinated nerve by tetrodotoxin and saxitoxin at negative holding potentials. Biochim Biophys Acta 985 153-160... 

Kao, C.Y. and Walker, S.E., Active groups of saxitoxin and tetrodotoxin as deduced from actions of saxitoxin analogues on frog muscle and squid axon, J. Physiol, 323, 619, 1982. 

Daly, J.W., Gusovsky, F., Myers, C.W., Yotsu-Yamashita, M., and Yasumoto, T. 1994. First occurrence of tetrodotoxin in a dendrobatid frog Colostethus inguinalis, with further reports for the bufonid genus Atelopus. Toxicon 32, 279-285. 

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