ToxSci Advance Access originally published online on May 12, 2004
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Toxicological Sciences 80, 239-248 (2004)
Toxicological Sciences vol. 80 no. 2 © Society of Toxicology 2004; all rights reserved.
Comparison of Chlorpyrifos-Oxon and Paraoxon Acetylcholinesterase Inhibition Dynamics: Potential Role of a Peripheral Binding Site
* Battelle, Pacific Northwest Division, Richland, Washington 99352, and University of Medicine and Dentistry New Jersey, Newark, New Jersey
Received March 2, 2004; accepted April 26, 2004
The primary mechanism of action for organophosphorus (OP) insecticides, like chlorpyrifos and parathion, is to inhibit acetylcholinesterase (AChE) by their oxygenated metabolites (oxons), due to the phosphorylation of the serine hydroxyl group located in the active site of the molecule. The rate of phosphorylation is described by the bimolecular inhibitory rate constant (ki), which has been used for quantification of OP inhibitory capacity. It has been proposed that a peripheral binding site exists on the AChE molecule, which, when occupied, reduces the capacity of additional oxon molecules to phosphorylate the active site. The aim of this study was to evaluate the interaction of chlorpyrifos oxon (CPO) and paraoxon (PO) with rat brain AChE to assess the dynamics of AChE inhibition and the potential role of a peripheral binding site. The ki values for AChE inhibition determined at oxon concentrations of 1–100 nM were 0.206 ± 0.018 and 0.0216 nM–1h–1 for CPO and PO, respectively. The spontaneous reactivation rates of the inhibited AChE for CPO and PO were 0.084–0.087 (two determinations) and 0.091 ± 0.023 h–1, respectively. In contrast, the ki values estimated at a low oxon concentration (1 pM) were 
1,000- and 10,000-fold higher than those determined at high CPO and PO concentrations, respectively. At low concentrations, the ki estimates were approximately similar for both CPO and PO (150–180 [two determinations] and 300 ± 180 nM–1h–1, respectively). This implies that, at low concentrations, both oxons exhibited similar inhibitory potency in contrast to the marked difference exhibited at higher concentrations. These results support the potential importance of a secondary peripheral binding site associated with AChE kinetics, particularly at low, environmentally relevant concentrations.
Key Words: acetylcholinesterase; organophosphate insecticide; chloropyrifos oxon; paraoxon.
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