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Chlorpyrifos, parathion, and their oxons bind to and desensitize a nicotinic acetylcholine receptor: relevance to their toxicities.
Toxicol Appl Pharmacol. 1997 Oct; 146(2):227-36.TA

Abstract

The nicotinic acetylcholine receptor (nAChR) of the electric organ of the electric ray. Torpedo sp., the richest source of nAChR, with similar structure and pharmacology to the mammalian skeletal muscle nAChR, carries several binding sites for different ligands. Incubation of Torpedo membrane-bound nAChRs with the agonist carbamylcholine (Carb) stimulated the binding of [3H]thienyl-cyclohexylpiperidine ([3H]TCP), which binds to the receptor's noncompetitive antagonist binding site in its ionic channel, with high affinity (Kd of 196 nM). The agonist-stimulated binding of [3H]TCP (i.e., binding to activated nAChRs) was inhibited in a concentration-dependent manner by four organophosphate (OP) anticholinesterases, chlorpyrifos oxon (CPO), chlorpyrifos (CPS), parathion (PS), and paraoxon (PO) with IC50 (concentration that inhibits 50% of the effect) values of 5, 150, 200, and 300 microM, respectively. The binding of CPO was totally reversible. The OPs had no effect on equilibrium binding of [alpha-125I]bungarotoxin ([alpha-125I]BGT) to the receptor's acetylcholine (ACh)-binding site, but preincubation of the membranes with the OPs increased this site's affinity for Carb. In absence of agonist, 100 microM of the OPs increased the binding of [3H]TCP by two- to fivefold with the following order of decreasing potency: PS > CPO > CPS > PO. The data suggest that in addition to inhibition of acetylcholinesterase, these OPs bind to a site on the nAChR that is different from the sites that bind ACh or TCP and that this binding induces nAChR desensitization. The relevance of this direct action of OPs on nAChRs on their acute toxicities is discussed.

Authors+Show Affiliations

School of Medicine, University of Maryland at Baltimore, 655 West Baltimore Street, Baltimore, Maryland, 21201, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

9344890

Citation

Katz, E J., et al. "Chlorpyrifos, Parathion, and Their Oxons Bind to and Desensitize a Nicotinic Acetylcholine Receptor: Relevance to Their Toxicities." Toxicology and Applied Pharmacology, vol. 146, no. 2, 1997, pp. 227-36.
Katz EJ, Cortes VI, Eldefrawi ME, et al. Chlorpyrifos, parathion, and their oxons bind to and desensitize a nicotinic acetylcholine receptor: relevance to their toxicities. Toxicol Appl Pharmacol. 1997;146(2):227-36.
Katz, E. J., Cortes, V. I., Eldefrawi, M. E., & Eldefrawi, A. T. (1997). Chlorpyrifos, parathion, and their oxons bind to and desensitize a nicotinic acetylcholine receptor: relevance to their toxicities. Toxicology and Applied Pharmacology, 146(2), 227-36.
Katz EJ, et al. Chlorpyrifos, Parathion, and Their Oxons Bind to and Desensitize a Nicotinic Acetylcholine Receptor: Relevance to Their Toxicities. Toxicol Appl Pharmacol. 1997;146(2):227-36. PubMed PMID: 9344890.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Chlorpyrifos, parathion, and their oxons bind to and desensitize a nicotinic acetylcholine receptor: relevance to their toxicities. AU - Katz,E J, AU - Cortes,V I, AU - Eldefrawi,M E, AU - Eldefrawi,A T, PY - 1997/11/5/pubmed PY - 1997/11/5/medline PY - 1997/11/5/entrez SP - 227 EP - 36 JF - Toxicology and applied pharmacology JO - Toxicol Appl Pharmacol VL - 146 IS - 2 N2 - The nicotinic acetylcholine receptor (nAChR) of the electric organ of the electric ray. Torpedo sp., the richest source of nAChR, with similar structure and pharmacology to the mammalian skeletal muscle nAChR, carries several binding sites for different ligands. Incubation of Torpedo membrane-bound nAChRs with the agonist carbamylcholine (Carb) stimulated the binding of [3H]thienyl-cyclohexylpiperidine ([3H]TCP), which binds to the receptor's noncompetitive antagonist binding site in its ionic channel, with high affinity (Kd of 196 nM). The agonist-stimulated binding of [3H]TCP (i.e., binding to activated nAChRs) was inhibited in a concentration-dependent manner by four organophosphate (OP) anticholinesterases, chlorpyrifos oxon (CPO), chlorpyrifos (CPS), parathion (PS), and paraoxon (PO) with IC50 (concentration that inhibits 50% of the effect) values of 5, 150, 200, and 300 microM, respectively. The binding of CPO was totally reversible. The OPs had no effect on equilibrium binding of [alpha-125I]bungarotoxin ([alpha-125I]BGT) to the receptor's acetylcholine (ACh)-binding site, but preincubation of the membranes with the OPs increased this site's affinity for Carb. In absence of agonist, 100 microM of the OPs increased the binding of [3H]TCP by two- to fivefold with the following order of decreasing potency: PS > CPO > CPS > PO. The data suggest that in addition to inhibition of acetylcholinesterase, these OPs bind to a site on the nAChR that is different from the sites that bind ACh or TCP and that this binding induces nAChR desensitization. The relevance of this direct action of OPs on nAChRs on their acute toxicities is discussed. SN - 0041-008X UR - https://www.unboundmedicine.com/medline/citation/9344890/Chlorpyrifos_parathion_and_their_oxons_bind_to_and_desensitize_a_nicotinic_acetylcholine_receptor:_relevance_to_their_toxicities_ DB - PRIME DP - Unbound Medicine ER -