Organophosphorus and other inhibitors of brain ‘neurotoxic esterase’ and the development of delayed neurotoxicity in hens
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TLDR
It is concluded that the nature of the group substituted at the enzyme active site determines the toxic response and the delayed neurotoxic effects of some organophosphorus compounds.Abstract:
1. The delayed neurotoxic effects of some organophosphorus compounds are associated with phosphorylation of the active site of a nervous-tissue enzyme capable of hydrolysing phenyl phenylacetate. 2. Neurotoxic organophosphorus compounds and some carbamates and sulphonyl fluorides progressively inhibit the enzyme, attaching a substituent covalently at the active site. 3. Prolonged inhibition of the enzyme by phenyl N-benzyl-N-methylcarbamate or phenylmethane-sulphonyl fluoride does not lead to neurotoxic effects. 4. Prior inhibition of the enzyme by carbamates or sulphonyl fluorides in vivo prevents the neurotoxic effects of several organophosphorus compounds. 5. After dosage of hens with protective compounds, protection lasts until about 70% of the enzyme site again becomes available for phosphorylation. 6. Reaction of all the inhibitors at the active site of the enzyme leads to the same inhibitory effect with respect to hydrolysis of phenyl phenylacetate but does not in all cases lead to delayed neurotoxicity. It is concluded that the nature of the group substituted at the enzyme active site determines the toxic response.read more
Citations
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Organophosphorus ester-induced delayed neurotoxicity.
TL;DR: Study of the relationship between the chemical structure of organophosphorus esters and their neurotoxic potencies suggests that two hydrophobic areas may be present in the vicinity of the active site of the neurotoxicity protein.
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Pharmacology and toxicology of cholinesterase inhibitors: uses and misuses of a common mechanism of action.
TL;DR: Reports indicate that a number of cholinesterase inhibitors have additional sites of action that may have pharmacologic or toxicologic relevance, and studies of interactive toxicity of binary mixtures of common organophosphorus insecticides indicate that non-cholinesTERase targets may be important in cumulative toxicity.
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The delayed neuropathy caused by some organophosphorus esters: mechanism and challenge.
TL;DR: The aim of the Toxicology Unit is to establish the basic concepts necessary for explaining at a molecular level the mechanisms of toxicity and of chemical and physical injury.
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Organophosphorus esters causing delayed neurotoxic effects: mechanism of action and structure activity studies.
TL;DR: In this article, the mechanism by which some phosphinates protect hens against neurotoxic compounds is explained, and the effects of compounds on NE activity of hen brain in vitro and in vivo are assessed.
References
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Journal ArticleDOI
The delayed neurotoxic effect of some organophosphorus compounds. Identification of the phosphorylation site as an esterase.
TL;DR: A small proportion of the total activity of hen brain hydrolysing phenyl phenylacetate in vitro was shown to be due to an enzyme different from two others previously described, and it was deduced that the active site is the phosphorylation site associated with the genesis of delayed neurotoxicity.
Journal ArticleDOI
A phosphorylation site in brain and the delayed neurotoxic effect of some organophosphorus compounds.
TL;DR: A test system in vitro indicates that part of a neurotoxic dose of di-isopropyl phosphorofluoridate will be covalently bound in vivo to a specific component in the brain and spinal cord as the initial biochemical event in the genesis of the lesion.
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Sulfonyl fluorides as inhibitors of esterases. 3. identification of serine as the site of sulfonylation in phenylmethanesulfonyl alpha-chymotrypsin.
Journal ArticleDOI
Protection by some carbamates against the delayed neurotoxic effects of di-isopropyl phosphorofluoridate.
M. K. Johnson,R. Lauwerys +1 more
TL;DR: The effect produced by di-isopropyl phosphorofluoridate (DFP) is studied because it is a potent neurotoxic compound and does not need to be metabolized to produce the active agent.