Neuropathy target esterase: rates of turnover in vivo following covalent inhibition with phenyl di-n-pentylphosphinate.
Phenyl di-n-pentylphosphinate is a reasonably stable easily synthesized inhibitor of neuropathy target esterase (NTE) with low anticholinesterase activity. Like phenylmethylsulphonyl fluoride it protects hens against neuropathic effects of compounds such as diisopropylphosphorofluoridate. At intervals up to 15 days after dosing hens (10 mg/kg s.c. to inhibit 90% NTE) assays were made of catalytically active and of phosphinylated NTE in autopsy tissue. The sum of these components was always within the range of catalytic activity in undosed controls. However, the half-life of reappearance of active NTE was 2.07 days +/- 0.13 (SD, n = 6) for brain and 3.62 days +/- 0.23 (SD, n = 6) for spinal cord--shorter than after dosing with phenylmethylsulphonyl fluoride. It is proposed that: (1) The physiological turnover mechanism cannot distinguish between catalytically active and di-n-pentylphosphinylated NTE although initiation of organophosphate-induced delayed polyneuropathy might involve recognition of aged di-alkyl-phosphorylated NTE as "foreign". (2) The short half-lives indicate a slow spontaneous dephosphinylation of inhibited NTE occurs in vivo as well as de novo synthesis. The difference in half-lives for brain and spinal cord NTE may be due to different rates of synthesis de novo or (more likely) to different rates of spontaneous reactivation of the inhibited NTE in the two tissues.
Meredith
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MRC Toxicology Unit, Carshalton, Surrey, England.
Johnson
M K
MK
D000818:Animals; D001921:Brain / Q000201:enzymology*; D002265:Carboxylic Ester Hydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002645:Chickens; D004793:Enzyme Reactivators; D005260:Female; D007700:Kinetics; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D010658:Phenylglyoxal / Q000031:analogs & derivatives / Q000494:pharmacology; D013116:Spinal Cord / Q000201:enzymology*
D004793:Enzyme Reactivators; D009943:Organophosphorus Compounds; C057114:phenyl di-n-pentylphosphinate; C057115:isonitrosoacetophenone; D002265:Carboxylic Ester Hydrolases; C021859:neurotoxic esterase; D010658:Phenylglyoxal