Serum paraoxonase and its influence on paraoxon and chlorpyrifos-oxon toxicity in rats

Paraoxon and chlorpyrifos-oxon, the active metabolites of the organophosphorus insecticides parathion and chlorpyrifos, respectively, are hydrolyzed by an "A"-esterase, paraoxonase, which is present in the sera of several mammalian species. In this study, we investigated whether levels of serum paraoxonase activity in laboratory animals can influence the in vivo toxicity of paraoxon and chlorpyrifos-oxon. Paraoxonase was found to be 7-fold higher in rabbit serum than in rat serum. The dose of paraoxon required to produce similar signs of toxicity and similar degrees of cholinesterase inhibition in rats and rabbits (0.5 and 2.0 mg/kg, respectively) differed by 4-fold. Paraoxonase was then purified from rabbit serum and 8.35 units was injected in the tail veins of rats, increasing the peak hydrolytic activity of rat serum by 9-fold toward paraoxon and by 50-fold toward chlorpyrifos-oxon. The increase in serum paraoxonase/chlorpyrifos-oxonase activity was long-lasting, with a 2- and 10-fold increase, respectively, still present after 24 hr. Thirty minutes following enzyme injection, rats were challenged with an acute dose of paraoxon or chlorpyrifos-oxon given by the intravenous, intraperitoneal, dermal, or oral route. Cholinesterase activities were measured in plasma, red blood cells, brain, and diaphragm after 4 hr. Rats pretreated with paraoxonase exhibited less inhibition of cholinesterase than vehicle-treated controls following identical doses of paraoxon, particularly when the organophosphate was given iv or dermally. A very high degree of protection, particularly toward brain and diaphragm cholinesterase, was provided by paraoxonase pretreatment in animals challenged with chlorpyrifos-oxon by all routes. These results indicate that levels of serum paraoxonase activity can affect the toxicity of paraoxon and chlorpyrifos-oxon.