The delayed neurotoxic effect of some organophosphorus compounds. Identification of the phosphorylation site as an esterase
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Abstract:
1. Organophosphorus compounds that produce a delayed neurotoxic effect in hens phosphorylate a specific site in the brain soon after administration. 2. Phosphorylation of the specific site by di-isopropyl [(32)P]phosphorofluoridate in vitro is blocked by the prior addition of phenyl phenylacetate. 3. 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. 4. This enzyme is only slightly inhibited in vitro by concentrations of tetraethyl pyrophosphate and paraoxon (diethyl 4-nitrophenyl phosphate) up to 64mum and is completely inhibited by 6mum-di-isopropyl phosphorofluoridate and 128mum-mipafox. 5. It is also inhibited in vivo by effective doses of neurotoxic organophosphorus compounds but not by high doses of non-neurotoxic analogues. 6. It is deduced that the active site of this enzyme is the phosphorylation site associated with the genesis of delayed neurotoxicity.
Insights
Organophosphorus compounds cause delayed neurotoxicity by phosphorylating a specific brain site. A novel enzyme
Area of Science:
- Neuroscience
- Biochemistry
- Toxicology
Background:
- Organophosphorus compounds are known to cause delayed neurotoxicity in hens.
- This neurotoxicity is linked to the phosphorylation of a specific site in the brain.
Purpose of the Study:
- To identify and characterize the enzyme responsible for phosphorylating the neurotoxic site.
- To investigate the enzyme's inhibition by various organophosphorus compounds.
Main Methods:
- In vitro studies using hen brain extracts and radiolabeled di-isopropyl phosphorofluoridate.
- Enzyme activity assays and inhibition studies with different organophosphorus compounds (e.g., tetraethyl pyrophosphate, paraoxon, mipafox).
Main Results:
- A novel enzyme in hen brain hydrolyzes phenyl phenylacetate.
- This enzyme is specifically inhibited by neurotoxic organophosphorus compounds and di-isopropyl phosphorofluoridate, but not by non-neurotoxic analogues.
- The enzyme's active site is implicated in the phosphorylation event leading to delayed neurotoxicity.
Conclusions:
- The identified enzyme is the target phosphorylation site responsible for organophosphorus-induced delayed neurotoxicity.
- Understanding this enzyme's mechanism can aid in developing strategies to mitigate neurotoxic effects.