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Letters in Drug Design & Discovery

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ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

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Research Article

Oxidative Biotransformation of Organophosphotioate Pesticides and Acetylcholinesterase Enzymatic Inhibition

Author(s): Isabela Aparecida Militani, Daiana Teixeira Mancini*, Alexandre Alves de Castro and Teodorico Castro Ramalho*

Volume 21, Issue 10, 2024

Published on: 03 May, 2023

Page: [1847 - 1857] Pages: 11

DOI: 10.2174/1570180820666230503095544

Price: $65

Abstract

Introduction: Pesticides have lethal properties, capable of controlling or eliminating a living organism; they block the organisms' vital metabolic processes. They cause serious problems for human health, as they are highly toxic. The most used pesticides that are considered toxic are known as organophosphothioates (OP/P=S) in their commercialized form and organophosphates (OP/P=O) in their active form. These compounds have been the subject of studies on their metabolism and toxicology. According to research, these pesticides' toxicity is increased when oxidative metabolic desulfurization reactions occur, with the P=S bond being transformed into a P=O bond. This toxicity is due to the ability of OP/P=O species to inhibit the human acetylcholinesterase enzyme (HssAChE).

Methods: To study the oxidative biotransformation of OP/P=S pesticides and the inhibition of the HssAChE enzyme by OP/P=S and OP/P=O using the molecular docking technique and QM/MM calculations.

Results: The theoretical results showed that parathion is the compound with the greatest capacity to transform its P=S bonds into P=O bonds, thus forming the active paraoxon metabolite in the oxidative biotransformation process. In the HssAChE inhibition by OP/P=S and OP/P=O, our results showed that of all the compounds investigated, those with the highest inhibitory activities are parathion, paraoxon, malathion, diazoxon, chlorpyrifos and omethoate.

Conclusion: This study was essential due to the lack of information in the literature about the oxidative biotransformation process of OP/P=S pesticides and the ability of these compounds to inhibit HssAChE. With this study, it was possible to observe that, in the oxidative biotransformation, chlorpyrifos and parathion have greater capacities to transform into their active metabolites and in the inhibition of the HssAChE enzyme, it was possible to observe that not all OF/P=O are the ones with the highest abilities to inhibit the HssAChE enzyme.

« Previous Next »
[1]
Nascimento, L.; Melnyk, A. The chemistry of pesticides in the environment and health. Academic Mangaio Magazine, 2016, 1(1), 2525-2801.
[2]
Bello-Ramírez, A.M.; Carreón-Garabito, B.Y.; Nava-Ocampo, A.A. A theoretical approach to the mechanism of biological oxidation of organophosphorus pesticides. Toxicology, 2000, 149(2-3), 63-68.
[http://dx.doi.org/10.1016/S0300-483X(00)00222-5] [PMID: 10967403]
[3]
Dikshit, P.C. Textbook of Forensic Medicine and Toxicology, 2nd ed; Pee Pee Publishers: New Delhi, 2007.
[4]
Araújo, C.R.M.; Santos, V.L. dos A.; Gonsalves, A.A. Acetylcholinesterase- AChE: An enzyme of pharmacological interest. Virtual J. Chem., 2016, 8(6), 1818-1834.
[http://dx.doi.org/10.21577/1984-6835.20160122]
[5]
Ecobichon, D.J. Toxic effects of pesticides. In: Casarett and Doull’s Toxicology: The Basic Science of Poisons; Klaassen, C.D., Ed.; New York City, United States: McGraw-Hill, 2001; pp. 763-810.
[6]
Taylor, P. Anticholinesterase agents. In: Goodman & Gillman’s The Pharmacological Basis of Therapeutics; Hardman, J.G.; Limbird, L.E.; Gilman, A.G., Eds.; New York City, United States: McGraw-Hill, 2001; pp. 175-192.
[7]
Cocker, J.; Mason, H.J.; Garfitt, S.J.; Jones, K. Biological monitoring of exposure to organophosphate pesticides. Toxicol. Lett., 2002, 134(1-3), 97-103.
[http://dx.doi.org/10.1016/S0378-4274(02)00168-6] [PMID: 12191866]
[8]
Costa, L.G. Current issues in organophosphate toxicology. Clin. Chim. Acta, 2006, 366(1-2), 1-13.
[http://dx.doi.org/10.1016/j.cca.2005.10.008] [PMID: 16337171]
[9]
Buratti, F.M.; Testai, E. Evidences for CYP3A4 autoactivation in the desulfuration of dimethoate by the human liver. Toxicology, 2007, 241(1-2), 33-46.
[http://dx.doi.org/10.1016/j.tox.2007.08.081] [PMID: 17897769]
[10]
Bibi, Z. Role of cytochrome P450 in drug interactions. Nutr. Metab. (Lond.), 2008, 5(1), 27.
[http://dx.doi.org/10.1186/1743-7075-5-27] [PMID: 18928560]
[11]
Guengerich, F.P. Characterization of human cytochrome P450 enzymes. FASEB J., 1992, 6(2), 745-748.
[http://dx.doi.org/10.1096/fasebj.6.2.1537465] [PMID: 1537465]
[12]
Lemos, A. J. G.; Trindade, E. J. Interferences in the pharmacological effect mediated by cytochrome P450 biotransformations. Revista Científica do ITPAC 2014.
[13]
Santiago, L.M. Metabolism in the cytochrome P450 system and its importance in general practice. Rev. Port. Med. Geral Fam., 2003, 19, 121-129.
[14]
Hernandez, J.; Robledo, N.R.; Velasco, L.; Quintero, R.; Pickard, M.A.; Vazquez-Duhalt, R. Chloroperoxidase-mediated oxidation of organophosphorus pesticides. Pestic. Biochem. Physiol., 1998, 61(2), 87-94.
[http://dx.doi.org/10.1006/pest.1998.2351]
[15]
Albuquerque, E.X.; Pereira, E.F.R.; Aracava, Y.; Fawcett, W.P.; Oliveira, M.; Randall, W.R.; Hamilton, T.A.; Kan, R.K.; Romano, J.A., Jr; Adler, M. Effective countermeasure against poisoning by organophosphorus insecticides and nerve agents. Proc. Natl. Acad. Sci. USA, 2006, 103(35), 13220-13225.
[http://dx.doi.org/10.1073/pnas.0605370103] [PMID: 16914529]
[16]
Giacoppo, J.O.S.; Lima, W.E.A.; Kamil, K.; França, T.C.C.; da Cunha, E.F.F.; Ramalho, T.C. Guerra química: Perspectivas no estudo de reativadores da enzima acetilcolinesterase inibida por organofosforados. Revista Virtual de Química, 2014, 6(3), 653-670.
[17]
Patočka, J.; Cabal, J.; Kuča, K.; Jun, D. Oxime reactivation of acetylcholinesterase inhibited by toxic phosphorus esters: in vitro kinetics and thermodynamics. J. Appl. Biomed., 2005, 3(2), 91-99.
[http://dx.doi.org/10.32725/jab.2005.011]
[18]
Hörnberg, A.; Tunemalm, A.K.; Ekström, F. Crystal structures of acetylcholinesterase in complex with organophosphorus compounds suggest that the acyl pocket modulates the aging reaction by precluding the formation of the trigonal bipyramidal transition state. Biochemistry, 2007, 46(16), 4815-4825.
[http://dx.doi.org/10.1021/bi0621361] [PMID: 17402711]
[19]
Soreq, H.; Ben-Aziz, R.; Prody, C.A.; Seidman, S.; Gnatt, A.; Neville, L.; Lieman-Hurwitz, J.; Lev-Lehman, E.; Ginzberg, D.; Lipidot-Lifson, Y. Molecular cloning and construction of the coding region for human acetylcholinesterase reveals a G + C-rich attenuating structure. Proc. Natl. Acad. Sci. USA, 1990, 87(24), 9688-9692.
[http://dx.doi.org/10.1073/pnas.87.24.9688] [PMID: 2263619]
[20]
Dvir, H.; Silman, I.; Harel, M.; Rosenberry, T.L.; Sussman, J.L. Acetylcholinesterase: From 3D structure to function. Chem. Biol. Interact., 2010, 187(1-3), 10-22.
[http://dx.doi.org/10.1016/j.cbi.2010.01.042] [PMID: 20138030]
[21]
Soreq, H.; Seidman, S. Acetylcholinesterase — new roles for an old actor. Nat. Rev. Neurosci., 2001, 2(4), 294-302.
[http://dx.doi.org/10.1038/35067589] [PMID: 11283752]
[22]
Santos, V.M.R.; Donnici, C.L.; DaCosta, J.B.N.; Caixeiro, J.M.R. Pentavalent organophosphate compounds: History, synthetic methods of preparation, and applications as insecticides and antitumor agents. Quim. Nova, 2007, 30(1), 159-170.
[http://dx.doi.org/10.1590/S0100-40422007000100028]
[23]
Frisch, M.J.; Trucks, G.W.; Schlegel, H.B.; Scuseria, G.E.; Robb, M.A.; Cheeseman, J.R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G.A. Gaussian 09; Gaussian Inc., 2004.
[24]
da Cunha, E.F.F.; Ramalho, T.C.; Reynolds, R.C. Binding Mode Analysis of 2,4-diamino-5-methyl-5-deaza-6-substituted Pteridines with Mycobacterium tuberculosis and Human Dihydrofolate Reductases. J. Biomol. Struct. Dyn., 2008, 25(4), 377-385.
[http://dx.doi.org/10.1080/07391102.2008.10507186] [PMID: 18092832]
[25]
de Castro, A.A.; Soares, F.V.; Pereira, A.F.; Silva, T.C.; Silva, D.R.; Mancini, D.T.; Caetano, M.S.; da Cunha, E.F.F.; Ramalho, T.C. Asymmetric biodegradation of the nerve agents Sarin and VX by human dUTPase: Chemometrics, molecular docking and hybrid QM/MM calculations. J. Biomol. Struct. Dyn., 2019, 37(8), 2154-2164.
[http://dx.doi.org/10.1080/07391102.2018.1478751] [PMID: 30044197]
[26]
Thomsen, R.; Christensen, M.H. MolDock: A new technique for high-accuracy molecular docking. J. Med. Chem., 2006, 49(11), 3315-3321.
[http://dx.doi.org/10.1021/jm051197e] [PMID: 16722650]
[27]
Berman, H.M.; Westbrook, J.; Feng, Z.; Gilliland, G.; Bhat, T.N.; Weissig, H.; Shindyalov, I.N.; Bourne, P.E. The protein data bank. Nucleic Acids Res., 2000, 28(1), 235-242.
[http://dx.doi.org/10.1093/nar/28.1.235] [PMID: 10592235]
[28]
Lynch, T.; Price, A. The effect of cytochrome P450 metabolism on drug response, interactions, and adverse effects. Am. Fam. Physician, 2007, 76(3), 391-396.
[PMID: 17708140]
[29]
Wilkinson, G.R. Drug metabolism and variability among patients in drug response. N. Engl. J. Med., 2005, 352(21), 2211-2221.
[http://dx.doi.org/10.1056/NEJMra032424] [PMID: 15917386]
[30]
Kohls, V.N. CYP2C9 polymorphism: study of the relationship between the use of pesticides and the development of diseases in farmers in Espírito Santo. Dissertation (Master in Biotechnology) - Postgraduate in Biotechnology; Federal University of Espirito Santo: Vitória 2023. Available From: https://sappg.ufes.br/tese_drupal/tese_14366_Disserta%E7%E3o_Victor%20Nogueira%20da%20Gama%20Kohls.pdf (Accessed on March 8, 2023).
[31]
da Cunha, E.F.F.; Barbosa, E.F.; Oliveira, A.A.; Ramalho, T.C. Molecular modeling of Mycobacterium tuberculosis DNA gyrase and its molecular docking study with gatifloxacin inhibitors. J. Biomol. Struct. Dyn., 2010, 27(5), 619-625.
[http://dx.doi.org/10.1080/07391102.2010.10508576] [PMID: 20085379]
[32]
da Cunha, E.F.F.; Mancini, D.T.; Ramalho, T.C. Molecular modeling of the Toxoplasma gondii adenosine kinase inhibitors. Med. Chem. Res., 2012, 21(5), 590-600.
[http://dx.doi.org/10.1007/s00044-011-9554-z]
[33]
Ramalho, T.C.; Caetano, M.S.; da Cunha, E.F.F.; Souza, T.C.S.; Rocha, M.V.J. Construction and assessment of reaction models of class I EPSP synthase: Molecular docking and density functional theoretical calculations. J. Biomol. Struct. Dyn., 2009, 27(2), 195-207.
[http://dx.doi.org/10.1080/07391102.2009.10507309] [PMID: 19583445]
[34]
Mancini, D.T. Computational Studies of Potential Inhibitors of the Enzyme Nucleoside Hydrolase from Brucella Suis. Dissertation (Master in Agrochemistry) - Graduate in Agrochemistry; Universidade Federal de Lavras: Lavras, 2011. Available From: http://repositorio.ufla.br/jspui/bitstream/1/1912/1/DISSERTA%C3%87%C3%83O_Estudos%20computacionais%20de%20potenciais%20inibidores%20da%20enzima%20nucleos%C3%ADdeo%20hidrolase%20de%20Brucella%20suis.pdf(Accessed on May 20, 2022).
[35]
Accelrys Software. Discovery Studio Modeling Environment. 2012. Available From: https://discover.3ds.com/discovery-studio-visualizer-download
[36]
Frisch, M.J.; Trucks, G.W.; Schlegel, H.B.; Scuseria, G.E.; Robb, M.A.; Cheeseman, J.R.; Zakrzewski, V.G.; Montgomery, J.A.; Stratmann, R.E.; Burant, J.C.; Dapprich, S.; Millam, J.M.; Daniels, A.D.; Kudin, K.N.; Strain, M.C.; Farkas, O.; Tomasi, J.; Barone, V.; Cossi, M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo, C.; Clifford, S.; Ochterski, J.; Petersson, G.A.; Ayala, P.Y.; Cui, Q.; Morokuma, K.; Salvador, P.; Dannenberg, J.J.; Malick, D.K.; Rabuck, A.D.; Raghavachari, K.; Foresman, J.B.; Cioslowski, J.; Ortiz, J.V.; Baboul, A.G.; Stefanov, B.B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Gomperts, R.; Martin, R.L.; Fox, D.J.; Keith, T.; Al-Laham, M.A.; Peng, C.Y.; Nanayakkara, A.; Challacombe, M.; Gill, P.M.W.; Johnson, B.; Chen, W.; Wong, M.W.; Andres, J.L.; Gonzalez, C.; Head-Gordon, M.; Replogle, E.S.; Pople, J.A. Gaussian, Inc., Pittsburgh, PA , 1998.
[37]
Besler, B.H.; Merz, K.M.; Kollman, P.A. Atomic charges derived from semiempirical methods. J. Comput. Chem., 1990, 11(4), 431-439.
[http://dx.doi.org/10.1002/jcc.540110404]
[38]
Singh, U.C.; Kollman, P.A. An approach to computing electrostatic charges for molecules. J. Comput. Chem., 1984, 5(2), 129-145.
[http://dx.doi.org/10.1002/jcc.540050204]
[39]
Gustin, D.J.; Mattei, P.; Kast, P.; Wiest, O.; Lee, L.; Cleland, W.W.; Hilvert, D. Heavy atom isotope effects reveal a highly polarized transition state for chorismate mutase. J. Am. Chem. Soc., 1999, 121(8), 1756-1757.
[http://dx.doi.org/10.1021/ja9841759]
[40]
Guimarães, A.P. Docking and molecular dynamics studies of potential bacillus anthracis nucleoside hydrolase inhibitors. Dissertation (Master in Agrochemistry) – Graduate in Agrochemistry; Universidade Federal de Lavras: Lavras, 2022. Available From: http://repositorio.ufla.br/jspui/bitstream/1/1866/1/DISSERTA%C3%87%C3%83O_Estudos%20por%20ancoramento%20e%20din%C3%A2mica%20molecular%20de%20potenciais%20inibidores%20da%20Nucleos%C3%ADdeo%20Hidrolase%20de%20Bacillus%20anthracis.pdf (Accessed on: April 14, 2022).
[41]
Warren, D.K.; Guth, R.M.; Coopersmith, C.M.; Merz, L.R.; Zack, J.E.; Fraser, V.J. Epidemiology of methicillin- resistant Sthaphylococcus aureus colonization in a surgical intensive care unit. Infect. Control Hosp. Epidemiol., 2006, 27(10), 1032-1040.
[http://dx.doi.org/10.1086/507919] [PMID: 17006825]
[42]
Deshpande, L.S.; Carter, D.S.; Phillips, K.F.; Blair, R.E.; DeLorenzo, R.J. Development of status epilepticus, sustained calcium elevations and neuronal injury in a rat survival model of lethal paraoxon intoxication. Neurotoxicology, 2014, 44, 17-26.
[http://dx.doi.org/10.1016/j.neuro.2014.04.006] [PMID: 24785379]
[43]
Deshpande, L.S.; Phillips, K.; Huang, B.; DeLorenzo, R.J. Chronic behavioral and cognitive deficits in a rat survival model of paraoxon toxicity. Neurotoxicology, 2014, 44, 352-357.
[http://dx.doi.org/10.1016/j.neuro.2014.08.008] [PMID: 25172410]
[44]
The National Center for Biotechnology Information advances science and health by providing access to biomedical and genomic information. Available From: https://www.ncbi.nlm.nih.gov/
[45]
Borman, S. Much to do about enzyme mechanism. Chem. Eng. News, 2004, 82(8), 35-39.
[http://dx.doi.org/10.1021/cen-v082n008.p035]
[46]
Lima, L. S. Activation energy. Elementary Science Magazine, 2015, 3(2), 035.
[47]
Organophosphorus pesticides. 2022. Available From: http://www.inchem.org/documents/pims/chemical/pimg001.htm#PartTitle:1.%20%20NAME(Accessed on August 13, 2022).
[48]
Moreira, E.L.T.; Sales, L.A.; Bautista, A.R.P.L. Assessment of acute toxicity (LD50): Proposal for harmonization of protocols adopted in Brazil. Pesticides. Journal of Ecotoxicology and the Environment, 1993, 3(3)

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