Interaction between paraoxon and tri- o-tolyl phosphate in rats

Abstract

Pretreatment of rats with tri- o-tolyl phosphate (TOTP) inhibited the binding of low concentrations of O,O-diethyl O-p-nitrophenyl phosphate (paraoxon) by their livers and plasma in vitro. TOTP pretreatment did not inhibit the enzymatic hydrolysis of paraoxon by the same tissues. TOTP was, therefore, used as a tool for evaluating the importance of tissue-binding as a mechanism for paraoxon detoxication in vivo. Sixteen hours after rats were given 125 mg/kg of TOTP, intraperitoneally, the capacities of their livers and plasma to bind paraoxon in vitro were completely abolished, and they were about twice as susceptible to acute poisoning by paraoxon administered intraperitoneally, orally, or subcutaneously. Oral administration of TOTP (250 mg/kg) reduced the paraoxon binding capacities of rat liver and plasma by 75% and slightly increased susceptibility to the acute intraperitoneal (but not oral) toxicity of paraoxon. The results of this investigation suggest that binding of paraoxon by relatively nonvital tissue constituents is an important protective mechanism against paraoxon poisoning, and that interference with this mechanism potentiates paraoxon's anticholinesterase action and toxicity.