Studies on the toxicity of dimethoate analogs and their hydrolysis by sheep liver amidase

Abstract

Various O,O-dialkyl, N-alkyl and N,N-dialkyl analogs of dimethoate [ O,O-dimethyl S-( N-methylcarbamoylmethyl) phosphorodithioate] were synthesized and their toxicity to mice and houseflies was determined. Of the N-alkyl analogs tested, the N-methyl analog of the diethyl ester was the most toxic to mice and houseflies. In the N,N-dialkyl series, N,N-dimethyl was the most toxic to mice, while the N,N-dimethyl, -diethyl, and di- n-propyl were equally toxic to houseflies. The relative rate of hydrolysis of these compounds by a purified sheep liver amidase was also examined. Substrate specificity with dimethoate showed that structural changes in the O,O-dialkyl portion of the phosphorodithioate as well as modifications in the branching indicate a critical size is required for hydrolysis. No direct correlation was found between their toxicity and the rate of hydrolysis by the enzyme. Three amide-containing organophosphorus insecticides, dimethoxon, Bidrin, and Azodrin, were not hydrolyzed by this amidase but they inhibited the enzyme. This finding explains in part the reason for the high mammalian toxicity as well as the inability to find substantial quantities of the corresponding carboxylic acid derivatives in vivo.