Abstract
The interaction in vivo of four O-alkyl O-2,5-dichlorophenyl phosphoramidates with neural neuropathy target esterase (NTE) and acetylcholinesterase (AChE) and their ability to cause delayed polyneuropathy in hens has been examined. Previous studies in vitro (Vilanova, Johnson & Vicedo, Pestic. Biochem. Physiol., 28 (1987) 224) had led to the prediction that these compounds would not be neuropathic but, rather, would be prophylactic agents against organophosphorus-induced delayed polyneuropathy. In vivo the effects of these esters on the enzymes differ in 2 respects from effects in vitro: 1. (i) Relative sensitivity of the enzymes was different: thus >50% of brain NTE remained 24 h after an oral dose of 15 mg/kg of the n-hexyl ester while only 10–30% of AChE remained although NTE was the more sensitive enzyme in vitro; 2. (ii) In no case could the inhibited NTE or AChE in autopsy samples from birds dosed with any of the 4 esters be reactivated by treatment with potassium fluoride in vitro: the inhibited enzymes produced by incubation of tissue with the esters in vitro had been reactivatable. Prophylaxis, with therapy in some cases, was required to prevent acute anticholinesterase poisoning when doses were sufficient to cause high inhibition of neural NTE. Inhibition in brain was typically 5–10% more than in spinal cord and 10–15% more than in sciatic nerve. Unambiguous signs of polyneuropathy (Grade 3 or more on an 8-point scale) were not seen in birds observed up to 3 weeks after doses which caused less than 70% inhibition of NTE in brain and spinal cord or less than 60% inhibition in sciatic nerve of pair-dosed birds assayed 24 h after dosing. Doses of 300, 10, 100 and 65 mg/kg, respectively, of the methyl, ethyl, n-butyl and n-hexyl esters caused >70% inhibition of NTE in all 3 neural tissues and neuropathy in the majority of observed birds. Analysis of consolidated dose/response data from 36 assayed and 51 observed birds showed that effects of Grade 3 or more were produced in about 90% of birds when inhibition of NTE was >90% in brain, >85% in spinal cord or >75% in sciatic nerve. We propose that after administration of each of these chiral phosphoramidates there is selective destruction of the isomer which is most active against NTE in vitro; the inhibited NTE and AChE formed from the surviving isomer is unreactivatable (presumably aged) and the formation of aged inhibited NTE initiates delayed polyneuropathy as has been demonstrated for many organophosphates. Selective disposal of 1 isomer in a racemic mixture may confuse attempts to extrapolate from in vitro effects to in vivo responses: studies with resolved isomers are desirable.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have