Chapter 70 - Paraoxonase (PON1), detoxification of nerve agents, and modulation of their toxicity

Abstract

Paraoxonase (PON1) is a serum and liver enzyme that can hydrolyze in vitro several 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 in animals, including transgenic mice, have shown that PON1 modulates the in vivo acute toxicity of certain OPs, such as 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, though 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 being devoid of immunogenicity. Such PON1s would be excellent candidates for prophylactic and therapeutic applications in the case of OP nerve agent poisoning. A parallel strategy would be that of identifying and studying agents which would increase levels of endogenous PON1.