KAREN JANSEN
Role of PON1 in modulating the toxicity of mixtures of organophosphate pesticides
Toxicology, MS
Preceptor: Lucio Costa, PhD
We examined the role of paraoxonase (PON1) in modulating the toxicity of mixtures of organophosphate pesticides. PON1 is a serum enzyme that hydrolyzes different substrates, including the oxon forms of the organophosphorus (OP) insecticides, diazinon and chlorpyrifos. Many polymorphisms have been identified in PON1, including one that causes an amino acid substitution at Q192R, altering its catalytic efficiency, and others that affect PON1 levels. Mice were exposed sequentially to chlorpyrifos oxon (CPO) or diazinonoxon (DZO) and malaoxon (MO), active metabolites of the widely used insecticides chlorpyrifos, diazinon, and malathion. CPO and DZO inhibit carboxylesterase (CaE) and are metabolized by PON1. The R192 allozyme has a higher catalytic efficiency for detoxifying CPO but both alloforms have equal catalytic efficiency for detoxifying DZO. MO is metabolized by CaE, and is not a PON1 substrate. When wild-type mice were exposed dermally to either CPO (0.75 mg/kg) or DZO (0.5mg/kg) and then, after 4 hours, to different doses of MO (0-100 mg/kg), the toxicity of the latter (assessed by measuring inhibition of brain acetylcholinesterase activity) was increased, compared to mice that received only MO. This potentiation was due to inhibition of CaE by CPO and DZO. A much greater potentiation was observed in PON1 knockout mice, which are unable to detoxify CPO or DZO. Further, in humanized hPON1Q192 transgenic mice, the potentiation of MO toxicity after exposure to CPO was more pronounced than in hPON1R192 mice, because of the decreased ability of the Q192 alloform to detoxify CPO. The potentiation of MO toxicity by DZO was similar in the two transgenic mice, as both are equally effective at hydrolyzing DZO. These results indicate that PON1 status can greatly influence the outcome of the interaction between CPO or DZO and MO, and demonstrate that PON1 status can affect the toxicity of a compound that is not a PON1 substrate, in this case by protecting against CaE inhibition.
