Assessment of four organophosphorus pesticides as inhibitors of human acetylcholinesterase and butyrylcholinesterase

Abstract Toxicity of organophosphorus compounds (OPs) remains a major public health concern due to their widespread use as pesticides and the existence of nerve agents. Their common mechanism of action involves inhibition of enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) which...

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Autores principales:	Tena Čadež, Dora Kolić, Goran Šinko, Zrinka Kovarik
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/84c80dcf48b74102bea7fa36b69f14b0
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spelling	oai:doaj.org-article:84c80dcf48b74102bea7fa36b69f14b02021-11-08T10:54:15ZAssessment of four organophosphorus pesticides as inhibitors of human acetylcholinesterase and butyrylcholinesterase10.1038/s41598-021-00953-92045-2322https://doaj.org/article/84c80dcf48b74102bea7fa36b69f14b02021-11-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-00953-9https://doaj.org/toc/2045-2322Abstract Toxicity of organophosphorus compounds (OPs) remains a major public health concern due to their widespread use as pesticides and the existence of nerve agents. Their common mechanism of action involves inhibition of enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) which are crucial for neurotransmission. Both chronic and acute poisoning by OPs can leave long-lasting health effects even when the patients are treated with standard medical therapy. Therefore, an increasing urgency exists to find more effective oxime reactivators for compounds which are resistant to reactivation, especially phosphoramidates. Here, we investigated in silico and in vitro interactions and kinetics of inhibition for human cholinesterases with four organophosphate pesticides—ethoprophos, fenamiphos, methamidophos and phosalone. Overall, ethoprophos and fenamiphos displayed higher potency as inhibitors for tested cholinesterases. Our results show that methamidophos-inhibited hAChE was more susceptible to reactivation than hAChE inhibited by fenamiphos by selected oximes. Molecular modelling enabled an evaluation of interactions important for specificity and selectivity of both inhibition and reactivation of cholinesterases. Two newly developed reactivators—bispyridinium triazole oxime 14A and zwitterionic oxime RS194B possess remarkable potential for further development of antidotes directed against pesticides and related phosphoramidate exposures, such as nerve agents tabun or Novichoks.Tena ČadežDora KolićGoran ŠinkoZrinka KovarikNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Tena Čadež Dora Kolić Goran Šinko Zrinka Kovarik Assessment of four organophosphorus pesticides as inhibitors of human acetylcholinesterase and butyrylcholinesterase
description	Abstract Toxicity of organophosphorus compounds (OPs) remains a major public health concern due to their widespread use as pesticides and the existence of nerve agents. Their common mechanism of action involves inhibition of enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) which are crucial for neurotransmission. Both chronic and acute poisoning by OPs can leave long-lasting health effects even when the patients are treated with standard medical therapy. Therefore, an increasing urgency exists to find more effective oxime reactivators for compounds which are resistant to reactivation, especially phosphoramidates. Here, we investigated in silico and in vitro interactions and kinetics of inhibition for human cholinesterases with four organophosphate pesticides—ethoprophos, fenamiphos, methamidophos and phosalone. Overall, ethoprophos and fenamiphos displayed higher potency as inhibitors for tested cholinesterases. Our results show that methamidophos-inhibited hAChE was more susceptible to reactivation than hAChE inhibited by fenamiphos by selected oximes. Molecular modelling enabled an evaluation of interactions important for specificity and selectivity of both inhibition and reactivation of cholinesterases. Two newly developed reactivators—bispyridinium triazole oxime 14A and zwitterionic oxime RS194B possess remarkable potential for further development of antidotes directed against pesticides and related phosphoramidate exposures, such as nerve agents tabun or Novichoks.
format	article
author	Tena Čadež Dora Kolić Goran Šinko Zrinka Kovarik
author_facet	Tena Čadež Dora Kolić Goran Šinko Zrinka Kovarik
author_sort	Tena Čadež
title	Assessment of four organophosphorus pesticides as inhibitors of human acetylcholinesterase and butyrylcholinesterase
title_short	Assessment of four organophosphorus pesticides as inhibitors of human acetylcholinesterase and butyrylcholinesterase
title_full	Assessment of four organophosphorus pesticides as inhibitors of human acetylcholinesterase and butyrylcholinesterase
title_fullStr	Assessment of four organophosphorus pesticides as inhibitors of human acetylcholinesterase and butyrylcholinesterase
title_full_unstemmed	Assessment of four organophosphorus pesticides as inhibitors of human acetylcholinesterase and butyrylcholinesterase
title_sort	assessment of four organophosphorus pesticides as inhibitors of human acetylcholinesterase and butyrylcholinesterase
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/84c80dcf48b74102bea7fa36b69f14b0
work_keys_str_mv	AT tenacadez assessmentoffourorganophosphoruspesticidesasinhibitorsofhumanacetylcholinesteraseandbutyrylcholinesterase AT dorakolic assessmentoffourorganophosphoruspesticidesasinhibitorsofhumanacetylcholinesteraseandbutyrylcholinesterase AT goransinko assessmentoffourorganophosphoruspesticidesasinhibitorsofhumanacetylcholinesteraseandbutyrylcholinesterase AT zrinkakovarik assessmentoffourorganophosphoruspesticidesasinhibitorsofhumanacetylcholinesteraseandbutyrylcholinesterase
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Assessment of four organophosphorus pesticides as inhibitors of human acetylcholinesterase and butyrylcholinesterase

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