Tetrodotoxin: From Poison to Powerful Tool

TETRODOTOXIN: FROM POISON TO POWERFUL TOOL* J. E. BLANKENSHIPÎ Introduction The history of tetrodotoxin (TTX) is a revealing lesson in the means by which modern biomedical researchers bring their skills to bear on the solution of a serious health hazard. More than this, an account of the study of tetrodotoxin illustrates how application of the scientific method transformed this compound from a menacing poison to a very powerful analytical tool, providing unique insights into biophysical and neurophysiological phenomena. Kao [1] earlier provided a detailed review of the history and actions of TTX, and more recently Fuhrman [2], Dettbarn [3], Gage [4] and Evans [5] have reviewed aspects of the mechanisms of action of this remarkable compound. My discussion, in addition to presenting a brief synopsis of the general history of tetrodotoxin as a marine poison, will concentrate on the use ofTTX as a modern research tool in unraveling three major problems: (a) the nature of the sodium channel in excitable membranes, (b)the development of the quantal theory of synaptic transmission, and (c)the evolution of excitatory-current channels in vertebrate muscle. Historical Background SOURCE AND SYMPTOMS The effects of tetrodotoxin were discussed even in ancient literature. As long ago as 2700 b.c., the Chinese warned of eating certain types of puffer fish around the China coast, and in approximately 2500 b.c. an Egyptian pharaoh died following ingestion of raw puffer fish. From that time to the present, countless people have been killed by ingesting raw puffer fish by-products. Today, about 50-100 people per year are lost in *Part of this review was presented at the symposium on Man, Medicine, and the Marine Environment, sponsored by the Marine Biomedical Institute, Galveston, Tex., January 17-18, 1974. tMarine Biomedical Institute and Department of Physiology and Biophysics, University of Texas Medical Branch, Galveston, Texas 77550. This work has been supported in part by NIH grant NSl 1255, and the author by NIH award NS70613. The assistance of Mrs. R. Schmidt and Mrs. P. Williamson with the manuscript is gratefully acknowledged. Perspectives in Biology and Medicine · Summer 1976 I 509 Japan, where the best public-health records are available [1, 6]. Even such a famous person as the British explorer Cook in 1774 ate raw puffer fish containing toxin and almost died on board his ship. A physician present described the classic symptoms of the poison. The first effect is normally numbness of the lips, gums, and tongue. This is followed by a lowering of the blood pressure, usually some wobbliness in the gait, and then, very rapidly, respiratory arrest and death. The onset of the symptoms is remarkably swift. An excellent modern account of the clinical symptoms may be found in the report of an Australian boy who barely survived ingestion of puffer fish [7]. The upper part of figure 1 illustrates one of many species of puffer fish of the suborder Gymnodontes which inhabit the Japanese Sea and contain TTX. In fish the toxin is most highly concentrated in the reproductive organs, particularly the ovary. The animal in the lower part of the figure is one of a group of newts of the genus Taricha, found on the west coast of the United States. It is interesting that, in the Taricha salamanders, the same compound is found in glands ofthe skin and not in other organs. For many years, the newt toxin was called tarichatoxin. In the recent past, it has been established that tarichatoxin and the toxin isolated from the Tetrodon fish, tetrodotoxin, are chemically the same compound [8]. Recently, Noguchi and Hashimoto [9] reported the isolation of TTX from a Pacific goby, and Kim and coworkers [10] have identified TTX in the skin of three populations of Central American frogs of the genus Atelopus. Although several hypotheses have emerged to explain the occurrence of this unique compound in four widely different animals, it appears most reasonable to accept the explanation that "the ability to synthesize tetrodotoxin was a coincidental genetic development in certain fishes and amphibians either because it has survival value or because it is a metabolic end product that happens to be toxic" [10, p. 152]. toxicity Tetrodotoxin is easily absorbed in the...