Cannabinoid CB1 receptor as a target for chlorpyrifos oxon and other organophosphorus pesticides

• Published in: Toxicology letters Vol. 135; no. 1; pp. 89 - 93
• Main Authors: Quistad, Gary B., Nomura, Daniel K., Sparks, Susan E., Segall, Yoffi, Casida, John E.
• Format: Journal Article
• Language: English
• Published: Shannon Elsevier Ireland Ltd 05.09.2002; Amsterdam Elsevier Science
• Subjects: Animals; Binding, Competitive; Biological and medical sciences; Brain - drug effects; Brain - metabolism; Cannabinoid receptor; Cannabinoid Receptor Modulators; CB1 receptor; Chlorpyrifos - analogs & derivatives; Chlorpyrifos - metabolism; Chlorpyrifos - toxicity; Chlorpyrifos oxon; Defoliants, Chemical - metabolism; Insecticides; Insecticides - metabolism; Insecticides - toxicity; Male; Medical sciences; Mice; Naphthalenes - metabolism; Naphthalenes - toxicity; Organophosphonates; Organophosphorus Compounds - metabolism; Organophosphorus Compounds - toxicity; Organophosphorus pesticides; Pesticides, fertilizers and other agrochemicals toxicology; Receptors, Cannabinoid; Receptors, Drug - antagonists & inhibitors; Receptors, Drug - metabolism; Toxicology; Tribufos; Insecticides; Chlorpyrifos oxon; Organophosphorus pesticides; CB1 receptor; Tribufos; Cannabinoid receptor; Chlorpyrifos; CB1 cannabinoid receptor; Insecticide; Metabolite; Toxicity; Rodentia; Pesticides; Defoliant; In vitro; Herbicide; In vivo; Vertebrata; Mammalia; Mouse; Animal; Organophosphorus compounds; Mechanism of action
• ISSN: 0378-4274; 1879-3169
• DOI: 10.1016/S0378-4274(02)00251-5

Binding of the endocannabinoid anandamide or of Δ 9-tetrahydrocannabinol to the agonist site of the cannabinoid receptor (CB1) is commonly assayed with [ 3H]CP 55,940. Potent long-chain alkylfluorophosphonate inhibitors of agonist binding suggest an additional, important and closely-coupled nucleophilic site, possibly undergoing phosphorylation. We find that the CB1 receptor is also sensitive to inhibition in vitro and in vivo by several organophosphorus pesticides and analogs. Binding of [ 3H]CP 55,940 to mouse brain CB1 receptor in vitro is inhibited 50% by chlorpyrifos oxon at 14 nM, chlorpyrifos methyl oxon at 64 nM and paraoxon, diazoxon and dichlorvos at 1200–4200 nM. Some 15 other organophosphorus pesticides and analogs are less active in vitro. The plant defoliant tribufos inhibits CB1 in vivo, without cholinergic poisoning signs, by 50% at 50 mg/kg intraperitoneally with a recovery half-time of 3–4 days, indicating covalent derivatization. [ 3H-ethyl]Chlorpyrifos oxon may be suitable for radiolabeling and characterization of this proposed nucleophilic site.