Inhibition of ethanol and acetate metabolism in mice by chlordimeform and related compounds

Abstract

1. Since chlordimeform or N′-(4-chloro- o-toly l)- N, N-dimethylformamidine and certain of its mammalian metabolites prolong ethanol induced sleep in mice, their effect on ethanol and acetate metabolism was examined. 2. Intraperitoneal treatment of mice with chlordimeform (50 mg/kg) and demethylchlordimeform or N′-(4-chloro- o-tolyl)- N-methylformamidine (50 mg/kg), the two most potent sleep inducers, appreciably inhibited the metabolism of ethanol to 14CO 2. Another metabolite, 4-chloro- to-formotoluidide (100 mg/kg), a very weak sleep inducer, also markedly inhibited ethanol metabolism. 3. Chlordimeform, demethylchlordimeform, and 4-chloro- o-formotoluidide inhibited the conversion of ethanol to 14CO 2 and the conversion of acetate to 14CO 2 in vitro by mouse liver preparations. 4. The potency of 4-chloro- o-formotoluidide as an inhibitor of acetate metabolism in vitro compared favorably with that of SKF-525A, a known inhibitor of microsomal mixed function oxidases. 5. At a concentration of 1 × 10 −3 M, demethylchlordimeform yielded 27.4% inhibition of yeast alcohol dehydrogenase as compared to 46.3% for thiourea, a known inhibitor of this enzyme. The other compounds gave little, if any, inhibition of yeast alcohol or aldehyde dehydrogenase. 6. Although it is not possible to explain the mechanism for ethanol sleep enhancement in mice by chlordimeform and its metabolite demethylchlordimeform, inhibition of the alcohol dehydrogenase by demethylchlordimeform may be significant in this connection. 7. The decrease in ethanol metabolism apparently was due in large part to the activity of chlordimeform, demethylchlordimeform and especially 4-chloro- o-formotoluidide as inhibitors of microsomal mixed function oxidases.