The delayed neurotoxic effect of some organophosphorus compounds. Identification of the phosphorylation site as an esteràse

1969 ◽  
Vol 115 (5) ◽  
pp. 865.b1-865.b1
Keyword(s):  
Organophosphorus Compounds ◽  
Phosphorylation Site ◽  
Neurotoxic Effect

scholarly journals The delayed neurotoxic effect of some organophosphorus compounds. Identification of the phosphorylation site as an esterase

1969 ◽  
Vol 114 (4) ◽  
pp. 711-717 ◽  
Author(s):  
M K Johnson
Keyword(s):  
Organophosphorus Compounds ◽  
Phosphorylation Site ◽  
Total Activity ◽  
Specific Site ◽  
Neurotoxic Effect ◽  
Nitrophenyl Phosphate ◽  
Effective Doses ◽  
High Doses

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 [32P]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 64μm and is completely inhibited by 6μm-di-isopropyl phosphorofluoridate and 128μm-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.

scholarly journals A phosphorylation site in brain and the delayed neurotoxic effect of some organophosphorus compounds

1969 ◽  
Vol 111 (4) ◽  
pp. 487-495 ◽  
Author(s):  
M K Johnson
Keyword(s):  
Organophosphorus Compounds ◽  
Specific Binding ◽  
Phosphorylation Site ◽  
Test System ◽  
Binding Activity ◽  
Specific Component ◽  
Esterase Inhibitors ◽  
Brain And Spinal Cord

1. It is proposed 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. 2. A test system in vitro was devised that removes many di-isopropyl phosphorofluoridate-binding sites and indicates that the specific component may be a protein present in brain at a concentration comparable with that of the cholinesterases. 3. The site was found to be present and capable of binding di-isopropyl phosphorofluoridate in vitro in brain samples taken from either normal hens or those dosed with organophosphorus esterase inhibitors that are not neurotoxic. 4. Very little of the specific binding activity was found in brain samples from hens pre-dosed with a variety of neurotoxic organophosphorus compounds. 5. A solubilized preparation of the active brain component was obtained, suitable for further purification and study.

FEATURES OF ORGANOPHOSPHATES IMMOBILIZATION VIA STREPTAVIDIN-BIOTIN SYSTEM FOR EXPERIMENTS ON SELECTION OF APTAMERS

2020 ◽  
pp. 12-20
Author(s):  
D. A. Belinskaya ◽  
Yu. V. Chelusnova ◽  
V. V. Abzianidze ◽  
N. V. Goncharov
Keyword(s):  
Polyethylene Glycol ◽  
Organophosphorus Compounds ◽  
Binding Energies ◽  
Rna Aptamers ◽  
Main Method ◽  
Modeling Methods ◽  
Molecular Dynamics Methods ◽  
Systematic Evolution ◽  
Exponential Enrichment ◽  
Selection Of

Poisoning with organophosphorus compounds occupy one of the leading places in exotoxicosis. At the first stage, the detoxification of organophosphates can be provided with the help of DNA or RNA aptamers that bind the poison in the bloodstream. Currently, the main method of searching for aptamers is the experimental method of systematic evolution of ligands by exponential enrichment (SELEX). In the process of aptamer selection, the target molecule must be immobilized via the streptavidin-biotin complex. Since the poison molecule is small in size, to increase its availability for binding to aptamer, it is necessary to use a spacer between organophosphorus compounds and biotin. The aim of this work was to optimize the selection of aptamers for organophosphorus compounds by increasing the availability of a poison molecule immobilized via the streptavidin-biotin complex on the example of paraoxon. For this purpose, three spacers between organophosphorus compounds and biotin were tested using molecular modeling methods: three links of polyethylene glycol (3-PEG), four links of polyethylene glycol (4-PEG) and aminohexyl. The conformation of the biotinylated paraoxon complex with streptavidin and the interaction of paraoxon with the binding fragment of the aptamer were modeled using molecular docking and molecular dynamics methods. The ability of biotinylated paraoxon to bind to the aptamer has been evaluated by analyzing the surface area of the paraoxon available to the solvent, as well as by calculating the free binding energies. It has been shown that only in the case of aminohexyl immobilized paraoxon can contact the aptamer. At the final stage, the synthesis of paraoxon bound to biotin via aminohexyl was carried out.

RISK FACTORS FOR THE DEVELOPMENT OF INITIAL MANIFESTATIONS OF ATHEROGENIC CARDIOVASCULAR DISEASES IN PERSONNEL OF CHEMICALLY HAZARDOUS FACILITIES

2017 ◽  
pp. 2-7 ◽  
Author(s):  
V. A. Gorichny ◽  
D. Yu. Serdukov ◽  
A. V. Yazenok ◽  
A. V. Nosov ◽  
G. G. Zagorodnikov ◽  
...  
Keyword(s):  
Risk Factors ◽  
Statistical Analysis ◽  
Cardiovascular Diseases ◽  
Organophosphorus Compounds ◽  
Atherogenic Dyslipidemia ◽  
Chemical Weapons ◽  
Analysis Methods ◽  
High Incidence ◽  
And Control ◽  
Statistical Analysis Methods

An outpatient examination of 530 employees engaged in work with chemical weapons related to organophosphorus compounds at chemically hazardous facilities was carried out. Risk factors for the development of cardiovascular diseases of atherogenic etiology among personnel of the facilities were studied in relation to the type of work performed using statistical analysis methods. When assessing the lipidogram, a high incidence of atherogenic dyslipidemia in a group of personnel involved in the storage of chemical weapons was found out in comparison with a group of people engaged in the destruction and control of chemical weapons (73.1 vs 61.2 vs 59.6%, p

Review about structure and evaluation of reactivators of Acetylcholinesterase inhibited with neurotoxic organophosphorus compounds

2020 ◽  
Vol 27 ◽  
Author(s):  
José Daniel Figueroa-Villar ◽  
Elaine C. Petronilho ◽  
Kamil Kuca ◽  
Tanos C. C. Franca
Keyword(s):  
Organophosphorus Compounds ◽  
Chemical Warfare Agents ◽  
Nerve Impulse ◽  
Limited Capacity ◽  
New Agents ◽  
Long Time ◽  
Warfare Agents ◽  
Comprehensive Search ◽  
Pharmacology And Toxicology ◽  
The Many

Background: Neurotoxic chemical warfare agents can be classified as some of the most dangerous chemicals for humanity. The most effective of those agents are the organophosphates (OPs) capable of restricting the enzyme acetylcholinesterase (AChE), which in turn controls the nerve impulse transmission. When AChE is inhibited by OPs, its reactivation can be usually performed through cationic oximes. However, until today it has not been developed one universal defense agent, with complete effective reactivation activity for AChE inhibited by any of the many types of existing neurotoxic OPs. For this reason, before treating people intoxicated by an OP, it is necessary to determine the neurotoxic compound that was used for contamination, in order to select the most effective oxime. Unfortunately, this task usually requires a relative long time, raising the possibility of death. Cationic oximes also display a limited capacity of permeating the blood-brain barrier (BBB). This fact compromises their capacity of reactivating AChE inside the nervous system. Methods: We performed a comprehensive search on the data about OPs available on the scientific literature today in order to cover all the main drawbacks still faced in the research for the development of effective antidotes against those compounds. Results: Therefore, this review about neurotoxic OPs and the reactivation of AChE, provides insights for the new agents’ development. The most expected defense agent is a molecule without toxicity and effective to reactivate AChE inhibited by all neurotoxic OPs. Conclusion: To develop these new agents it is necessary the application of diverse scientific areas of research, especially theoretical procedures as computational science (computer simulation, docking and dynamics); organic synthesis; spectroscopic methodologies; biology, biochemical and biophysical information; medicinal chemistry, pharmacology and toxicology.

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