title: The R-(+)isomer of O-n-hexyl S-methyl phosphorothioamidate causes delayed neuropathy in hens after generation of a form of inhibited neuropathy target esterase (NTE) which can be reactivated ex vivo.
abstract: To initiate delayed neuropathy (DN) in adult hens organophosphates and phosphonates must inhibit most neural NTE and the inhibited NTE must undergo an 'aging' reaction. Phosphinates and those chiral isomers of phosphonates which produce non-aging NTE do not cause DN but act as prophylactic agents. Some racemic phosphoramidates cause DN although the inhibited NTE in autopsy samples can be reactivated in vitro (Johnson, Read and Vilanova, 1991, Arch. Toxicol., 65, 618-624). We now report that pure R(+)isomer of O-n-hexyl S-methyl phosphorothioamidate (5-20 mg/kg per os) caused slight acute effects but typical DN associated with high inhibition of NTE in brain, spinal cord and sciatic nerve (maximum by 6-24 h): the inhibited NTE was easily reactivated by KF (presumed not aged). For each dose the average residual NTE activity in the three tissues 24 h after dosing and the clinical ataxia severity on peak days 15-17 (score out of 4) was: 5 mg/kg: 13, 14, 27% (2,2,2,1); 10 mg/kg: 10, 14, 12%, (4,3,2); 15 mg/kg: 10,11,17%, (3,3,4); 20 mg/kg: 6, 10, 8% (3,3,3,2). The ability of this isomer and of other racemic phosphoramidates to initiate DN by covalent reaction at the active site of NTE (inhibition) without subsequent aging suggests that the chemistry (? charge distribution) in the region of the phosphorus atom determines that disturbance in the molecular environment of NTE which initiates DN.
authors.affiliation: MRC Toxicology Unit, University of Leicester, UK.
authors.forename: M K
authors.initials: MK
authors.lastname: Johnson
authors.forename: J M
authors.initials: JM
authors.lastname: Safi
mesh_terms: D000818:Animals; D001259:Ataxia / Q000139:chemically induced / Q000201:enzymology; D002265:Carboxylic Ester Hydrolases / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism; D002645:Chickens; D002800:Cholinesterase Inhibitors / Q000494:pharmacology / Q000633:toxicity; D004793:Enzyme Reactivators / Q000494:pharmacology*; D005260:Female; D005459:Fluorides; D009422:Nervous System Diseases / Q000139:chemically induced* / Q000201:enzymology*; D009946:Organothiophosphorus Compounds / Q000633:toxicity*; D011188:Potassium / Q000494:pharmacology; D017680:Potassium Compounds; D013237:Stereoisomerism
chemical_list: D002800:Cholinesterase Inhibitors; D004793:Enzyme Reactivators; D009946:Organothiophosphorus Compounds; D017680:Potassium Compounds; C082480:O-n-hexyl-S-methylphosphorothioamidate; C033320:potassium fluoride; D002265:Carboxylic Ester Hydrolases; C021859:neurotoxic esterase; D005459:Fluorides; D011188:Potassium