Karen L. Jansen
Project title: Role of Paraoxonase (PON1) in Modulating Toxicity of Mixtures of Organophosphorus Compounds
Completed in: 2008
Most environmental and occupational exposures involve complex mixtures. The toxicities associated with such exposures are modified by differences in activity of detoxication enzymes. To address the role of paraoxonase (PON1) in modulating toxicity associated with sequential exposures to organophosphorous (OP) compounds, we used a transgenic mouse model that included the following genotypes: PON1-/-, hPON1R192, hPON1Q192, and PON1+/+. We demonstrate here that chlorpyrifos oxon (CPO), diazoxon (DZO), and paraoxon (PO) are potent inhibitors of carboxylesterase (CaE). We hypothesized that prior exposure to these OPs would increase sensitivity to malaoxon (MO), a CaE substrate, and the degree of effect would vary among PON1 genotypes if the OP was a physiologically significant PON1 substrase. CPO and DZO are detoxified by PON1. For CPO hydrolysis, hPON1R192 has a higher catalytic efficiency than hPON1Q192. For DZO hydrolysis, the two alloforms have equal catalytic efficiencies. For PO hydrolysis, the catalytic efficiency of PON1 is too low to be physiologically relevant. When wild-type mice were exposed dermally to CPO, DZO, or PO follwed 4-f later by different doses of MO, MO toxicity was increased compared to mice receiving MO alone. This potentiation was due presumably to CaE inhiibition. Potentiation of MO toxicity by CPO and DZO was greater in PON1-/- mice, which have greatly reduced capacity to detoxify CPO or DZO. Potentiation by CPO was more pronounced in hPON1Q192 mice than in hPON1R192 mice due to the decreased efficiency of hPON1Q192 for detoxifying CPO. Potentiation by DZO was similar in hPON1Q192 and hPON1R192 mice, which are equally effective at hydrolyzing DZO. Potentiation by PO was equivalent among all four genotypes. These results indicate that PON1 status can have a major influence on detoxication of OP compounds or metabolism of drugs by CaE.