Inhibition with simultaneous spontaneous reactivation and aging of acetylcholinesterase by organophosphorus compounds: Demeton-S-methyl as a model.

Autor: Estévez J; Unidad de Toxicología y Seguridad Química, Instituto de Bioingeniería, Universidad Miguel Hernández, 03202, Elche, Alicante, Spain; Department of Medicine (Division of Medical Genetics) and Genome Sciences, University of Washington, 1959 NE Pacific Street, Seattle, WA, 98195, USA. Electronic address: jorge.estevez@umh.es., Pizarro L; Unidad de Toxicología y Seguridad Química, Instituto de Bioingeniería, Universidad Miguel Hernández, 03202, Elche, Alicante, Spain., Marsillach J; Department Environmental and Occupational Health Sciences, University of Washington, 4225 Roosevelt Way NE, Suite 100, Seattle, WA, 98105, USA., Furlong C; Department of Medicine (Division of Medical Genetics) and Genome Sciences, University of Washington, 1959 NE Pacific Street, Seattle, WA, 98195, USA., Sogorb MA; Unidad de Toxicología y Seguridad Química, Instituto de Bioingeniería, Universidad Miguel Hernández, 03202, Elche, Alicante, Spain., Richter R; Department of Medicine (Division of Medical Genetics) and Genome Sciences, University of Washington, 1959 NE Pacific Street, Seattle, WA, 98195, USA., Vilanova E; Unidad de Toxicología y Seguridad Química, Instituto de Bioingeniería, Universidad Miguel Hernández, 03202, Elche, Alicante, Spain.
Jazyk: angličtina
Zdroj: Chemico-biological interactions [Chem Biol Interact] 2024 Jan 05; Vol. 387, pp. 110789. Date of Electronic Publication: 2023 Nov 04.
DOI: 10.1016/j.cbi.2023.110789
Abstrakt: The kinetic analysis of esterase inhibition by acylating compounds (organophosphorus, carbamates and sulfonylfluorides) sometimes cannot yield consistent results by fitting simple inhibition kinetic models to experimental data of complex systems. In this work kinetic data were obtained for demeton-S-methyl (DSM) with human acetylcholinesterase in two kinds of experiments: (a) time progressive inhibition with a range of concentrations, (b) progressive spontaneous reactivation starting with pre-inhibited enzyme. DSM is an organophosphorus compound used as pesticide and considered a model for studying the dermal exposure of nerve agents such as VX gas. A kinetic model equation was deduced with four different molecular phenomena occurring simultaneously: (1) inhibition; (2) spontaneous reactivation; (3) aging; and (4) ongoing inhibition (inhibition during the substrate reaction). A 3D fit of the model was applied to analyze the inhibition experimental data. The best-fitting model is compatible with a sensitive enzymatic entity. The second-order rate constant of inhibition (ki = 0.0422 μM -1  min -1 ), the spontaneous reactivation constant (ks = 0.0202 min -1 ) and the aging constant (kg = 0.0043 min -1 ) were simultaneously estimated. As an example for testing the model and approach, it was tested also in the presence of 5 % ethanol (conditions as previously used in the literature), the best fitting model is compatible with two apparent sensitive enzymatic entities (17 % and 83 %) and only one spontaneously reactivates and ages. The corresponding second-order rate constants of inhibition (ki = 0.0354 and 0.0119 μM -1  min -1 ) and the spontaneous reactivation and aging constants for the less sensitive component (kr = 0.0203 min -1 and kg = 0.0088 min -1 ) were estimated. The results were also consistent with a significant ongoing inhibition. These parameters were similar to those deduced in spontaneous reactivation experiments of the pre-inhibited samples with DSM in the absence or presence of ethanol. The two apparent components fit was interpreted by an equilibrium between ethanol-free and ethanol-bound enzyme. The consistency of results in inhibition and in spontaneous reactivation experiments was considered an internal validation of the methodology and the conclusions.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jorge Estevez reports equipment, drugs, or supplies and travel were provided by Government of Spain Ministry of Education and Vocational Training.
(Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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