Phosphorothionates, weak anticholinesterases, are bioactivated by P450 to potent oxon metabolites by desulfuration. P450-mediated detoxication, dearylation, can also occur, and is more effective against chlorpyrifos than parathion. The oxons can persistently inhibit serine esterases, including nervous system acetylcholinesterase (the target enzyme), and protective �-esterases such as carboxylesterases. Chlorpyrifos-oxon (CPO) is a more potent inhibitor of serine esterases than is paraoxon (PO). The oxons can be hydrolyzed by paraoxonase (PON) which is more efficient with CPO than PO. Despite greater potency of CPO as an anticholinesterase, chlorpyrifos is 10 - 20 fold less acutely toxic than parathion because of greater detoxication of chlorpyrifos. However, using a sensitive indirect assay for CPO hydrolysis with human serum, overall level of PON activity as monitored at high oxon concentrations does not influence the amount of CPO that is hydrolyzed at low more toxicologically relevant concentrations, presumably because PON is not saturated. (Support: NIH ES00190, ES04394, ES15107)

Comparison of esterase sensitivity, metabolic efficiency, and toxicity levels of two organophosphorus insecticides, parathion, and chlorpyrifos

242nd National Meeting (2011)

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