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Metabolism-Coupled Cell-Independent Acetylcholinesterase Activity Assay for Evaluation of the Effects of Chlorination on Diazinon Toxicity
Chemical Research in Toxicology ( IF 3.7 ) Pub Date : 2021-08-10 , DOI: 10.1021/acs.chemrestox.1c00155 Taku Matsushita 1 , Yuji Kikkawa 2 , Kei Omori 2 , Yoshihiko Matsui 1 , Nobutaka Shirasaki 1
Chemical Research in Toxicology ( IF 3.7 ) Pub Date : 2021-08-10 , DOI: 10.1021/acs.chemrestox.1c00155 Taku Matsushita 1 , Yuji Kikkawa 2 , Kei Omori 2 , Yoshihiko Matsui 1 , Nobutaka Shirasaki 1
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Drinking water quality guideline values for toxic compounds are determined based on their acceptable daily intake. The toxicological end point for determining the acceptable daily intake of most organophosphorus insecticides is inhibition of acetylcholinesterase (AChE). Although insecticides ingested with drinking water are partly metabolized by the liver before transport to the rest of the body, no current cell-independent AChE activity assay takes the effects of metabolism into account. Here, we incorporated metabolism into a cell-independent AChE activity assay and then evaluated the change in anti-AChE activity during chlorination of a solution containing the organophosphorus insecticide diazinon. The anti-AChE activities of solutions of diazinon or diazinon-oxon, the major transformation product of diazinon during chlorination, were dramatically changed by metabolism: the activity of diazinon solution was markedly increased, whereas that of diazinon-oxon solution was slightly decreased, clearly indicating the importance of incorporating metabolism into assays examining toxicity after oral ingestion. Upon chlorination, diazinon was completely transformed, in part to diazinon-oxon. Although diazinon solution without metabolism did not show anti-AChE activity before chlorination, it did after chlorination. In contrast, with metabolism, diazinon solution did show anti-AChE activity before chlorination, but chlorination gradually decreased this activity over time. The observed anti-AChE activities were attributable solely to diazinon and diazinon-oxon having been contained in the samples before metabolism, clearly suggesting that the presence not only of diazinon but also of diazinon-oxon should be monitored in drinking water. Further examination using a combination of tandem mass spectrometry and in silico site-of-metabolism analyses revealed the structure of a single metabolite that was responsible for the observed anti-AChE activity after metabolism. However, because this compound is produced via metabolism in the human body after oral ingestion of diazinon, its presence in drinking water need not be monitored and regulated.
中文翻译：
代谢偶联的细胞非依赖性乙酰胆碱酯酶活性测定，用于评估氯化对二嗪农毒性的影响
有毒化合物的饮用水质量准则值是根据其可接受的每日摄入量确定的。确定大多数有机磷杀虫剂每日可接受摄入量的毒理学终点是乙酰胆碱酯酶 (AChE) 的抑制作用。尽管与饮用水一起摄入的杀虫剂在运输到身体其他部位之前会被肝脏部分代谢，但目前没有细胞独立的 AChE 活性测定将代谢的影响考虑在内。在这里，我们将代谢纳入不依赖细胞的 AChE 活性测定，然后评估了在含有有机磷杀虫剂二嗪农的溶液氯化过程中抗 AChE 活性的变化。二嗪农或二嗪酮-oxon溶液的抗AChE活性，二嗪农在氯化过程中的主要转化产物，代谢显着改变：二嗪农溶液的活性显着增加，而二嗪酮-氧磷溶液的活性略有下降，清楚地表明将代谢纳入口服摄入后毒性测定的重要性。氯化后，二嗪农完全转化，部分转化为二嗪农-氧磷。尽管没有代谢的二嗪农溶液在氯化前没有表现出抗乙酰胆碱酯酶活性，但在氯化后却表现出抗AChE活性。相比之下，随着代谢，二嗪农溶液在氯化前确实显示出抗 AChE 活性，但随着时间的推移，氯化逐渐降低了这种活性。观察到的抗乙酰胆碱酯酶活性仅归因于代谢前样品中含有二嗪农和二嗪农氧磷，清楚地表明，不仅应监测饮用水中二嗪农的存在，还应监测二嗪农-氧磷的存在。使用串联质谱和计算机代谢位点分析相结合的进一步检查揭示了单一代谢物的结构，该代谢物负责观察到的代谢后的抗乙酰胆碱酯酶活性。然而，由于该化合物是在口服摄入二嗪农后通过人体代谢产生的，因此无需监测和调节其在饮用水中的存在。
更新日期：2021-09-20
中文翻译：
代谢偶联的细胞非依赖性乙酰胆碱酯酶活性测定，用于评估氯化对二嗪农毒性的影响
有毒化合物的饮用水质量准则值是根据其可接受的每日摄入量确定的。确定大多数有机磷杀虫剂每日可接受摄入量的毒理学终点是乙酰胆碱酯酶 (AChE) 的抑制作用。尽管与饮用水一起摄入的杀虫剂在运输到身体其他部位之前会被肝脏部分代谢，但目前没有细胞独立的 AChE 活性测定将代谢的影响考虑在内。在这里，我们将代谢纳入不依赖细胞的 AChE 活性测定，然后评估了在含有有机磷杀虫剂二嗪农的溶液氯化过程中抗 AChE 活性的变化。二嗪农或二嗪酮-oxon溶液的抗AChE活性，二嗪农在氯化过程中的主要转化产物，代谢显着改变：二嗪农溶液的活性显着增加，而二嗪酮-氧磷溶液的活性略有下降，清楚地表明将代谢纳入口服摄入后毒性测定的重要性。氯化后，二嗪农完全转化，部分转化为二嗪农-氧磷。尽管没有代谢的二嗪农溶液在氯化前没有表现出抗乙酰胆碱酯酶活性，但在氯化后却表现出抗AChE活性。相比之下，随着代谢，二嗪农溶液在氯化前确实显示出抗 AChE 活性，但随着时间的推移，氯化逐渐降低了这种活性。观察到的抗乙酰胆碱酯酶活性仅归因于代谢前样品中含有二嗪农和二嗪农氧磷，清楚地表明，不仅应监测饮用水中二嗪农的存在，还应监测二嗪农-氧磷的存在。使用串联质谱和计算机代谢位点分析相结合的进一步检查揭示了单一代谢物的结构，该代谢物负责观察到的代谢后的抗乙酰胆碱酯酶活性。然而，由于该化合物是在口服摄入二嗪农后通过人体代谢产生的，因此无需监测和调节其在饮用水中的存在。
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