Crossroads in the evaluation of paraoxonase 1 for protection against nerve agent and organophosphate toxicity

Human paraoxonase 1 (PON1), a 45 kDa arylesterase associated with circulating high density lipoproteins (HDL), has been described as an anti-atherogenic element in cardiovascular disorders. The efficacy of PON1 as a catalytic bioscavenger against OP and CWNA toxicity has been on debate for the last few decades. Hydrolysis of various organophosphates (OPs) and chemical warfare nerve agents (CWNAs) by PON1 has been demonstrated in both in vitro and in vivo experiments. Recently, we established the protective efficacy of human and rabbit serum purified PON1 as well as human recombinant PON1 expressed in Trichoplusia ni larvae against nerve agent toxicity in guinea pigs. Exogenous administration of purified PON1 was effective in protecting against 1.2 X LCt50 of sarin and soman administered endotracheally with microinstillation technology. However, the short half-life of exogenously administered PON1, probably due to poor association with circulating HDL, warrant alternative approaches for successful utility of PON1 in the treatment of OP/CWNA toxicity. In this mini review, we address the pros and cons of current PON1 prophylaxis and propose potential solutions for successful development of PON1 as an effective catalytic bioscavenger.

► Paraoxonase 1 prophylaxis against nerve agent toxicity.
► In vitro and in vivo efficacy of paraoxonase 1 against organophosphates/nerve agents.
► Half-life and pharmacokinetics of paraoxonase 1.
► Endogenous induction of paraoxonase 1.
► Combination therapy against nerve agent toxicity.