Biological Activity and Metabolism of Hercules AC-528 Components in Rats and Cockroaches12

Abstract

Technical Hercules AC-528 (Delnav) was separated by partition chromatography into eight different fractions. The major Components were the cis and trans isomers of 2,3-p-dioxanedithiol S,S-bis(O,O-diethyl phosphorodithioate). The structure, toxicity to house flies and rats, ant cholinesterase activity and stability to alkaline hydrolysis were studied for these eight Hercules AC-528 components. Radioactive Hercules AC-528 was prepared and the metabolism in rats and cockroaches studied for the cis and trans isomers, 2-p-dioxenethiol S-(O,O-diethyl phosphorodithioate) and bis(diethoxyphosphinothioyl) disulfide. In a wide variety of in vivo and in vitro biological systems the cis and trans isomers were the most stable of the radioactive components; the single exception was a study on hydrolysis by human plasma where the dioxene derivative was the most stable. In a sub-acute feeding study with rats, Hercules AC-528 was found to accumulate to a small degree in fat. However, the residues disappeared rapidly when feeding of Hercules AC-528 was discontinued. Other factors in investigating Hercules AC-528 included: cholinesterase depression and recovery in rats following administration of a sub-lethal dose; the effect of sub-acute feeding on rat plasma, red blood corpuscle and brain cholinesterase activity; metabolism of the components of Hercules AC-528 by Periplaneta americana (L.) and rat liver slices; the formation of more polar, non-hydrolyzed metabolites from the radioactive components by rats and cockroaches; and the nature of the hydrolysis products formed from the components in human plasma and following oral administration to rats.