Author:
Čadež Tena,Kolić Dora,Šinko Goran,Kovarik Zrinka
Abstract
AbstractToxicity 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.
Funder
Hrvatska Zaklada za Znanost
Publisher
Springer Science and Business Media LLC
Reference54 articles.
1. Kwong, T. C. Organophosphate pesticides: Biochemistry and clinical toxicology. Ther. Drug Monit. 24, 144–149 (2002).
2. Goh, K. T., Yew, F. S., Ong, K. H. & Tan, I. K. Acute organophosphorus food poisoning caused by contaminated green leafy vegetables. Arch. Environ. Health 45, 180–184 (1990).
3. Wu, M., Deng, J., Tsai, W., Wong, S. & Li, H. Food poisoning due to methamidophos- contaminated vegetables. Clin. Toxicol. 39, 333–336 (2001).
4. Bolognesi, C. & Merlo, F. D. Pesticides: Human Health Effects. In Encyclopedia of Environmental Health 438–453 (Elsevier, 2011). https://doi.org/10.1016/b978-0-444-52272-6.00592-4.
5. Lushchak, V. I., Matviishyn, T. M., Husak, V. V., Storey, J. M. & Storey, K. B. Pesticide toxicity: A mechanistic approach. Excli J. 17, 1101–1136 (2018).
Cited by
28 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献