Historical review on chemical and medical studies of globefish toxin before World War II

• Published in: Yakushigaku zasshi Vol. 29; no. 3; p. 428
• Main Author: Suehiro, M
• Format: Journal Article
• Language: Japanese
• Published: Japan 1994
• Subjects: Animals; Fish Products - history; Fishes, Poisonous; History, 19th Century; History, 20th Century; Humans; Japan; Poisoning - history; Japan
• ISSN: 0285-2314

"Fugu," a species of globefish has eaten by Japanese people for a long time, so globefish poisoning in Japan has been prevalent. Figures are shown in the Annual Food Poisoning Report collected and issued by health service authorities of Japanese Government since 1879. These reports prompted Dr. Yoshizumi Tahara, National Institute of Hygienic Sciences to conduct a chemical investigation of the toxic substance of globefish in 1884. However, the analysis was very difficult and his report of investigation was delayed. Before publication of the report of Dr. Tahara, pharmacological and toxicological studies of globefish poisoning were reported by three research groups from the Facultly of Medicine, University of Tokyo in 1889. These reports concluded that globefish poison has curare-like activity and its distribution was limited to specific organs such as the ovaries and the liver. Dr. Tahara successfully isolated the poison from aqueaous extract of ovaries of globefish by precipitation with lead acetate in the presence of ammonia. He presented the results at the monthly meeting of the Pharmaceutical Society of Japan in July 1894. He continued the studies and established an improved method for extraction and purification suitable for large-scale production. Finally, he confirmed that globefish contains only one toxic substance and named it Tetrodotoxin (TTX) in 1909. He elucidated the chemical nature of TTX as follows: 1) TTX is an amorphous hygroscopic powder and its character is neither alkaloid nor protein. 2) The possibility of TTX being a protamine was excluded by chemical analysis. Before the discovery ot TTX, according to folklore, globefish was regarded as medicine for leprosy because flesh of globefish contaminated with a sublethal dose of toxic substance alleviated the neuralgia of patients affected with leprosy. The clinical effect of TTX prepared by Tahara's method to suppress severe neuralgia due to leprosy and to reduce muscle spasms due to tetanus were reported by dermatologists in 1911. TTX was also given to patients with rheumatoid arthritis due to its analgesic effect. Thus, injectable TTX was manufactured and distributed by Sankyo Co., Ltd. from 1913. In terms of purity, the TTX preparation manufactured by Tahara's method seemed to be much more crude than the crystalline TTX obtained by Professor Tsuda and Dr. Kawamura in 1952. According to their report, the LD50 of the preparation for clinical use manufactured by Tahara's method was 4-5 mg/kg mouse compared to 4-6 microg/kg mouse of crystalline TTX.