Prophylaxis against and promotion of organophosphate-induced delayed neuropathy by phenyl di-n-pentylphosphinate.
Phenyl di-n-pentylphosphinate (PPP) is a potent inhibitor of neuropathy target esterase (NTE) with negligible effect on acetylcholinesterase: I50S at 37 degrees C for 20 min and pH 8, respectively are 0.2 microM and > 2mM. PPP is not neuropathic. This is compatible with the fact that inhibited NTE is autopsy material from hens dosed with PPP can always be reactivated in vitro, presumably because no 'aging' reaction has occurred. PPP (10 mg/kg s.c.) given to hens up to 4 days before severely neuropathic doses (1.7 mg/kg) of diisopropylphosphorofluoridate (DFP) prevented neuropathic but not cholinergic effects of DFP. Hens given PPP 3 days after a sub-neuropathic dose of DFP (0.4 mg/kg) developed severe clinical neuropathy (clinical scores of 7 and 5 compared with DFP-plus-solvent scores 0,1,3). These prophylactic and promoting effects are similar to those exerted by phenylmethanesulphonyl fluoride (PMSF) at doses which inhibit NTE. In 3 out of 4 birds a pre-dose with PMSF (15 mg/kg) prevented the promoting effect of 120 mg/kg PMSF given after DFP.
Johnson
M K
MK
MRC Toxicology Unit, University of Leicester, UK.
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D J
DJ
D000818:Animals; D001921:Brain / Q000201:enzymology; D002265:Carboxylic Ester Hydrolases / Q000037:antagonists & inhibitors; D002645:Chickens; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D009422:Nervous System Diseases / Q000139:chemically induced* / Q000201:enzymology / Q000517:prevention & control*; D009943:Organophosphorus Compounds / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity*; D010664:Phenylmethylsulfonyl Fluoride / Q000633:toxicity; D013116:Spinal Cord / Q000201:enzymology
D009943:Organophosphorus Compounds; C057114:phenyl di-n-pentylphosphinate; D010664:Phenylmethylsulfonyl Fluoride; D002265:Carboxylic Ester Hydrolases; C021859:neurotoxic esterase