Phosphoacetylcholinesterase: Toxicity of phosphorus oxychloride to mammalsand insects that can be attributed to selective phosphorylation of acetylcholinesterase by phosphorodichloridic acid

Citation
Gb. Quistad et al., Phosphoacetylcholinesterase: Toxicity of phosphorus oxychloride to mammalsand insects that can be attributed to selective phosphorylation of acetylcholinesterase by phosphorodichloridic acid, CHEM RES T, 13(7), 2000, pp. 652-657
Citations number
20
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Pharmacology & Toxicology
Journal title
CHEMICAL RESEARCH IN TOXICOLOGY
ISSN journal
0893-228X → ACNP
Volume
13
Issue
7
Year of publication
2000
Pages
652 - 657
Database
ISI
SICI code
0893-228X(200007)13:7<652:PTOPOT>2.0.ZU;2-L
Abstract
Phosphorus oxychloride (POCl3) is an intermediate in the synthesis of many organophosphorus insecticides and chemical warfare nerve gases that are tox ic to insects and mammals by inhibition of acetylcholinesterase (AChE) acti vity. It was therefore surprising to observe that POCl3 which is hydrolytic ally unstable, also itself gives poisoning signs in ip-treated mice and fum igant-exposed houseflies similar to those produced by the organophosphorus eater insecticides and chemical warfare agents. In mice, POCl3 inhibits ser um butyrylcholinesterase (BuChE) at a sublethal dose and muscle but not bra in AChE at a lethal dose. In houseflies, POCl3-induced brain AChE inhibitio n is correlated with poisoning and the probable cause thereof. POCl3 in vit ro is selective for AChE (IC50 = 12-36 mu M) compared with several other se rine hydrolases (BuChE, carboxylesterase, elastase, alpha-chymotrypsin, and thrombin) (IC50 = 88-2000 mu M). With electric eel AChE, methylcarbamoylat ion of the active site with eserine reversibly protects against subsequent irreversible inhibition by POCl3. Most importantly, POCl3-induced electric eel AChE inhibition prevents postlabeling with [H-3]diisopropyl phosphorofl uoridate; i.e., both compounds phosphorylate at Ser-200 in the catalytic tr iad. Pyridine-2-aldoxime methiodide does not reactivate POCl3-inhibited ACh E, consistent with an anionic phosphoserine residue at the esteratic site. The actual phosphorylating agent is formed within seconds from POCl3 in wat er, has a half-life of similar to 2 min, and is identified as phosphorodich loridic acid [HOP(O)Cl-2] by P-31 NMR and derivatization with dimethylamine to HOP(O)(NMe2)(2). POCl3 on reaction with water and HOP(O)Cl-2 have the s ame potency for inhibition of AChE from either electric eel or housefly hea d as well as the same toxicity for mice. In summary, the acute toxicity of POCl3 is attributable to hydrolytic activation to HOP(O)Cl-2 that phosphory lates AChE at the active site to form enzymatically inactive [O-phosphoseri ne]AChE.