The inhibitory effects of itaconic acid in vitro and in vivo.

Finkelstein and Gold (1) administered itaconic acid and its sodium, magnesium, and calcium salts to adult cats, both acutely and chronically. They observed vomiting and diarrhea when single oral doses of 0.5 gm. per kilo or more of this compound or its salts were given. They attributed these reactions to local action in the gastrointestinal tract, since doses up to 1 gm. per kilo failed to produce signs of systemic toxicity. Oral doses of 5 gm. per kilo proved fatal after severe gastrointestinal disturbances, convulsions, and prostration. These results indicated that acute oral toxicity of itaconic acid and its salts is very low. Daily oral administration of 100 mg. per kilo of itaconic acid for 14 weeks failed to reveal toxicity, as indicated by the state of nutrition, blood picture, liver and kidney function, electrocardiogram, and histological examination of liver and kidney. Since the cat is a carnivore and since Finkelstein and Gold utilized adult rather than growing cats, it was considered important to obtain confirmatory data for another species and with growing animals. The results to be reported are based on long term feeding in which itaconic acid was mixed with the food and fed to rats from the time they were weaned until time of sacrifice after 210 days on the diet. Data are presented showing decreased rates of growth as the intake of itaconic acid was increased. It is well known that malonate competitively inhibits succinic dehydrogenase. Furthermore, Ackermann and Potter (2) have demonstrated that itaconate also competitively inhibits this enzyme. Since itaconic acid, like malonic acid, is structurally similar to succinic acid, it seemed possible that the mechanism of action could be one of competition between the analogue and the normal metabolite. Because an inhibition of succinate oxidation demonstrable in vitro might occur in vivo with a resultant increase in succinic acid excretion, as in the case of malonic acid (3), we have measured the excretion of succinic acid by the rabbit before and after oral administration of itaconic acid. The observed increase in urinary excretion of succinic acid in this experiment suggests