Triphenyl phosphite neurotoxicity in the hen: inhibition of neurotoxic esterase and of prophylaxis by phenylmethylsulfonyl fluoride.
The neuropathic syndrome resulting in the cat and the rat from single or multiple doses of the phosphorous acid ester tiphenyl phosphite (TPP) has been reported to differ from the syndrome caused by numerous phosphoric acid esters, which is known as organophosphorous compound-induced delayed neurotoxicity (OPIDN). Since the hen is used to test compounds for OPIDN, we chose to study the neurotoxicity of single subcutaneous doses of TPP using this animal model. TPP (1000 mg/kg) produced progressive ataxia and paralysis which began to develop 5-10 days after dosing. Similar signs were observed when subcutaneous doses of the OPIDN-causing agents tri-o-cresyl phosphate (TOCP) or diisopropyl phosphorofluoridate (DFP) were administered. The minimum neurotoxic dose of TPP was 500 mg/kg. Prior administration of phenylmethylsulfonyl fluoride (PMSF) prevented the development of a neuropathy induced by DFP, but did not fully protect the hens from TPP or TOCP. PMSF slowed, but did not prevent, the neuropathy caused by TOCP. PMSF reduced the neurotoxicity of 500 mg/kg TPP, but increased the neurotoxicity of 1000 mg/kg TPP. TPP was found to be a very potent inhibitor of neurotoxic esterase (NTE), the putative target site for OPIDN, in vitro, with a ki of about 2.1 x 10(5) M-1 min-1. Equimolar doses of either TPP (1000 mg/kg) and TOCP (1187 mg/kg) caused over 80% inhibition of neurotoxic esterase (NTE) in brain and sciatic nerve. This high level of NTE inhibition persisted for several weeks. This prolonged inhibition probably accounts for the inability of PMSF to block the neurotoxicity of TOCP.(ABSTRACT TRUNCATED AT 250 WORDS)
Carrington
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CD
Department of Pharmacology, Duke University Medical Center, Durham, North Carolina 27710.
Abou-Donia
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MB
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002265:Carboxylic Ester Hydrolases / Q000037:antagonists & inhibitors*; D002645:Chickens; D004347:Drug Interactions; D005260:Female; D007531:Isoflurophate / Q000633:toxicity; D009498:Neurotoxins / Q000633:toxicity*; D009943:Organophosphorus Compounds / Q000633:toxicity*; D010664:Phenylmethylsulfonyl Fluoride / Q000627:therapeutic use*; D017905:Phosphites; D010968:Plasticizers / Q000633:toxicity; D013450:Sulfones / Q000627:therapeutic use*; D014317:Tritolyl Phosphates / Q000633:toxicity
D009498:Neurotoxins; D009943:Organophosphorus Compounds; D017905:Phosphites; D010968:Plasticizers; D013450:Sulfones; D014317:Tritolyl Phosphates; D007531:Isoflurophate; D010664:Phenylmethylsulfonyl Fluoride; C013318:triphenyl phosphite; D002265:Carboxylic Ester Hydrolases; C021859:neurotoxic esterase; C025541:tri-o-cresyl phosphate