PON1 and Organophosphate Toxicity

Abstract

Early studies on different human populations showed that the hydrolytic activity of serum paraoxonase (PON1) was polymorphically distributed, raising the hypothesis that individuals with low PON1 activity may be at higher risk from toxic effects due to exposure to organophosphorus (OP) insecticides. Evidence that this may be the case has been obtained from a number of animal studies. First, animal species with low serum PON1 activity (e.g. birds) are especially sensitive to OP toxicity. Among mammals, the rabbits, which have a high serum PON1 activity, are more resistant to OP toxicity than rats. Second, injection of purified PON1 into rats and mice protects them against the acute toxic effects of various OPs. Third, PON1 knockout mice are more sensitive than wild type animals to the toxicity of the oxygen analogs of OPs, such as chlorpyrifos oxon and diazoxon, and resistance can be restored by injecting purified PON1. Surprisingly, PON1 null mice do not show an increased sensitivity to the toxicity of paraoxon, the substrate after which PON1 was named. In vitro studies on catalytic efficiency of PON1, assayed at physiological conditions, indicated that PON1 may be relevant for the detoxication, and hence influence the toxicity, of some OPs (e.g. chlorpyrifos oxon, diazoxon), but not of paraoxon. The increased sensitivity of young animals, and possibly children, to the toxicity of OPs, may be explained in some cases (e.g. chlorpyrifos oxon) by low PON1 activity.