Biological Activity and Metabolism of Phosphoramidate Insecticides

Abstract

The mode of action of phosphoramidothioates was examined with reference to their anti-AChE activity. N-Isopropylphosphoramidothioate, isofenphos, was the most toxic to the adzuki bean weevil among N-alkyl substituted compounds. LD50 values for the insects were not correlated with the in vitro anti-AChE activity of these oxons. It was demonstrated that phosphoramidothioates and these oxons became potent inhibitors of AChE by the incubation with the rat liver microsomal NADPH system and the chemical treatment with peracid. The inhibition of AChE activity was reduced by the addition of SKF 525-A to the microsomal system. The stereospecificity of isofenphos and its oxon on biological activity was obvious. The (+)-isomers of both the compounds were more toxic to insects than the (-)-isomers. Chiral isomers and racemate of isofenphos-oxon were activated with the microsomal NADPH system and the I50 values became 1.47×10-7M, and 6.19×10-5M for the (+)- and (-)-oxon, respectively. The data suggested that the (+)-isomer was easily bioactivated and the I50 values of chiral isomers after the bioactivation were sufficient to explain their insecticidal activity. 14C-Isofenphos metabolism was different between animals and plants. In mammals and insects, isofenphos was rapidly transformed into the water soluble metabolites, and in plant isofenphos and isofenphos-oxon were very persistent. Isofenphos was metabolized by (1) oxidative desulfuration, (2) desphenylation, (3) desN-alkylation and (4) N-desalkylation, and the formation of water soluble metabolites through isofenphos-oxon was proposed to be the main metabolic pathway. In all experiments, the conversion to water soluble metabolites was dominant in the cleavage of P-O-C (aryl) bond and only desphenyl compounds were found in plants. The effect of chirality was seemingly small in the metabolism of isofenphos based on the examination in the rat liver microsomal system and in the housefly. The amount of isofenphos-oxon metabolized from the (-)-isofenphos was always larger than that from the (+)-isomer, but quantitative differences of other metabolites between both the chiral isofenphos was obscure.