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Comparison of chlorpyrifos-oxon and paraoxon acetylcholinesterase inhibition dynamics: potential role of a peripheral binding site.
Toxicol Sci. 2004 Aug; 80(2):239-48.TS

Abstract

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 (k(i)), 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 k(i) values for AChE inhibition determined at oxon concentrations of 1-100 nM were 0.206 +/- 0.018 and 0.0216 nM(-1)h(-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 k(i) values estimated at a low oxon concentration (1 pM) were approximately 1,000- and 10,000-fold higher than those determined at high CPO and PO concentrations, respectively. At low concentrations, the k(i) estimates were approximately similar for both CPO and PO (150-180 [two determinations] and 300 +/- 180 nM(-1)h(-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.

Authors+Show Affiliations

Battelle, Pacific Northwest Division, Richland, Washington 99352, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

15141101

Citation

Kousba, A A., et al. "Comparison of Chlorpyrifos-oxon and Paraoxon Acetylcholinesterase Inhibition Dynamics: Potential Role of a Peripheral Binding Site." Toxicological Sciences : an Official Journal of the Society of Toxicology, vol. 80, no. 2, 2004, pp. 239-48.
Kousba AA, Sultatos LG, Poet TS, et al. Comparison of chlorpyrifos-oxon and paraoxon acetylcholinesterase inhibition dynamics: potential role of a peripheral binding site. Toxicol Sci. 2004;80(2):239-48.
Kousba, A. A., Sultatos, L. G., Poet, T. S., & Timchalk, C. (2004). Comparison of chlorpyrifos-oxon and paraoxon acetylcholinesterase inhibition dynamics: potential role of a peripheral binding site. Toxicological Sciences : an Official Journal of the Society of Toxicology, 80(2), 239-48.
Kousba AA, et al. Comparison of Chlorpyrifos-oxon and Paraoxon Acetylcholinesterase Inhibition Dynamics: Potential Role of a Peripheral Binding Site. Toxicol Sci. 2004;80(2):239-48. PubMed PMID: 15141101.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Comparison of chlorpyrifos-oxon and paraoxon acetylcholinesterase inhibition dynamics: potential role of a peripheral binding site. AU - Kousba,A A, AU - Sultatos,L G, AU - Poet,T S, AU - Timchalk,C, Y1 - 2004/05/12/ PY - 2004/5/14/pubmed PY - 2005/1/6/medline PY - 2004/5/14/entrez SP - 239 EP - 48 JF - Toxicological sciences : an official journal of the Society of Toxicology JO - Toxicol Sci VL - 80 IS - 2 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 (k(i)), 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 k(i) values for AChE inhibition determined at oxon concentrations of 1-100 nM were 0.206 +/- 0.018 and 0.0216 nM(-1)h(-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 k(i) values estimated at a low oxon concentration (1 pM) were approximately 1,000- and 10,000-fold higher than those determined at high CPO and PO concentrations, respectively. At low concentrations, the k(i) estimates were approximately similar for both CPO and PO (150-180 [two determinations] and 300 +/- 180 nM(-1)h(-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. SN - 1096-6080 UR - https://www.unboundmedicine.com/medline/citation/15141101/Comparison_of_chlorpyrifos_oxon_and_paraoxon_acetylcholinesterase_inhibition_dynamics:_potential_role_of_a_peripheral_binding_site_ DB - PRIME DP - Unbound Medicine ER -