TY - JOUR
T1 - Comparison of chlorpyrifos-oxon and paraoxon acetylcholinesterase inhibition dynamics
T2 - Potential role of a peripheral binding site
AU - Kousba, A. A.
AU - Sultatos, L. G.
AU - Poet, T. S.
AU - Timchalk, Charles
N1 - Funding Information: Although the research described in this report has been partially funded by the U.S. Environmental Protection Agency’s (EPA) STAR program through grant R828608, it has not been subject to any EPA review, does not necessarily reflect the views of the EPA, and no public endorsement should be inferred. This study was also partially supported by grant 1 R01 OH03629-01A2 from the Centers for Disease Control and Prevention (CDC). The contents are solely the responsibility of the authors and do not necessarily represent the official views of the CDC.
PY - 2004/8
Y1 - 2004/8
N2 - 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.
AB - 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.
KW - Acetylcholinesterase
KW - Chloropyrifos oxon
KW - Organophosphate insecticide
KW - Paraoxon
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U2 - 10.1093/toxsci/kfh163
DO - 10.1093/toxsci/kfh163
M3 - Article
C2 - 15141101
SN - 1096-6080
VL - 80
SP - 239
EP - 248
JO - Toxicological Sciences
JF - Toxicological Sciences
IS - 2
ER -