Studies on the mechanism of action of thiourea and related compounds; inhibition of oxidative enzymes and oxidations catalyzed by copper.

The recent discovery of the rodenticidal properties of a-naphthylthiourea (ANTU) by Richter (1) has aroused interest in the mechanism by which this compound produces its acute toxic effects in animals. Factors associated with the toxicity of ANTU such as (a) the high toxicity to Norway rats, (b) the lower toxicity to most other species, (c) the development of tolerance after administration of sublethal doses, and (d) the severe pleural effusion and pulmonary edema produced by lethal doses are individually important to other toxic compounds. Information concerning the reactions undergone by ANTU may be of value in future studies on the mechanism of action and the factors which influence its toxicity to animals. The biochemical changes which result in animals acutely poisoned by ANTU have been studied previously in this laboratory (2, 3) and it was found that marked hyperglycemia and depletion of liver glycogen occur in dogs and rats poisoned by this compound. Several investigations on the effects of other thiourea derivatives on enzyme systems have been carried out in the hope of understanding their thyroid-inhibiting action. Enzymes included in these various studies were cytochrome oxidase (4, 5), succinic dehydrogenase (6), and tyrosinase (6,7). The effect of monosubstituted derivatives of thiourea on oxidations catalyzed by copper (6) has also been studied. However, various investigators have obtained different results with the thiourea derivatives on these catalytic reactions. It was not possible, therefore, to predict the action of ANTU on these systems. The present study was, therefore, undertaken to ascertain whether ANTU inhibits cytochrome oxidase and succinic dehydrogenase in vitro or in vivo after lethal doses of ANTU are given to rats. The effect of this rodenticide on tyrosinase and on oxidations catalyzed by inorganic copper was also measured. Since other thiourea derivatives which differ considerably in their toxicity to rats were available, it was of interest to com-