628 



3. DEHYDROACETATE 



weights, or tissue cytology, with the possible exception of an increase in 

 liver fat at the highest dose level. Monkeys maintained on oral doses of 50- 

 100 mg/kg/day for a year likewise showed no evidence of a toxic effect. 

 Even the maximum tolerated dose of 200 mg/kg/day, producing some toxic 

 effects in the monkeys, produced no pathological changes in the tissues. One 

 must conclude that dehydroacetate is a relatively nontoxic substance. Hu- 

 man subjects can tolerate 14-17 mg/kg/day for 26-48 days (approximately 

 1.2 g/day or a total of 30-60 g), maintaining a plasma level of 15-25 mg% 

 (around 1 mM), and experience only occasional anorexia and nausea. Hu- 

 man subjects are more sensitive to dehydroacetate than are experimental 

 animals on a dosage basis, but the plasma concentrations are approximately 

 the same, indicating that man either metabolizes or excretes dehydroacetate 

 less readily (see accompanying tabulation). 



Urinary Excretion of Succinate 



If dehydroacetate is able to inhibit succinate oxidase in the whole animal, 

 one would expect to find an accumulation of succinate in the body and an 

 increased excretion. This was indeed found, providing the best evidence 

 that such enzyme inhibition actually occurs in vivo. Rats given 600 mg/kg 

 of dehydroacetic acid orally show an increase in urinary succinate during 

 the first day from a control level of 3.2 mg/day to 24.8 mg/day (Seevers et 

 al., 1950). Dogs given 200 mg/kg orally for 3 days produce a maximal ex- 

 cretion of succinate on the second day (more than 175 mg/day compared to 

 a control of 28 mg/day), and the rise is maintained after cessation of 

 administration, being around 90 mg/day 4 days after the last dose. One 

 would also expect other acids to accumulate if the cycle is depressed and 

 the appearance of ketonemia, but this is not mentioned. 



Antidotes 



Seevers et al. (1950) attempted to combat the toxic effects of dehydroace- 

 tate in dogs by the administration of glucose, ammonium lactate, calcium 



