Paraoxonase (PON1) and Detoxication of Nerve Agents

Paraoxonase (PON1) is a serum and liver enzyme that can hydrolyze in vitro a number of organophosphorus (OP) compounds, including the active metabolites of specific OP insecticides, and certain OP nerve agents such as sarin and soman. PON1 presents several genetic polymorphisms that influence its ability to hydrolyze OPs as well as its level of expression. Studies using animals, including transgenic mice, have shown that PON1 modulates the in vivo acute toxicity of certain OPs, particularly chlorpyrifos oxon and diazoxon. In contrast, because of its low catalytic efficiency toward paraoxon, PON1 does not influence the acute toxicity of this OP in vivo. The catalytic efficiency of PON1 toward nerve agents is similarly low, although some studies have shown that administration of exogenous PON1 can protect against the toxicity of soman and sarin. For use as catalytic bioscavengers, recombinant engineered PON1s need to be developed with an enhanced catalytic efficiency toward nerve agents. Such PON1s would be excellent candidates for prophylactic and therapeutic applications in case of OP poisoning. A parallel strategy would be that of identifying and studying agents that would increase levels of endogenous PON1.