Buratti Franca M, Testai Emanuela
Environment and Primary Prevention Department, Istituto Superiore di Sanità, Viale Regina Elena 299, I-00161 Rome, Italy.
Toxicology. 2007 Nov 20;241(1-2):33-46. doi: 10.1016/j.tox.2007.08.081. Epub 2007 Aug 6.
Dimethoate (DIM) is an organophosphorothionate (OPT) pesticide used worldwide as a systemic insecticide and acaricide. It is characterized by low-to-moderate acute mammalian toxicity; similarly to the other OPT pesticides, its mode of action is mediated by the inhibition of acetylcholinesterase (AChE), exerted by its toxic metabolite dimethoate-oxon or omethoate (OME), which is also used as a direct acting pesticide. Human hepatic DIM bioactivation to the toxic metabolite OME has been characterized by using c-DNA expressed human CYPs and human liver microsomes (HLM) also in the presence of CYP-specific chemical inhibitors, with a method based on AChE inhibition. The obtained kinetic parameters and AChE IC(50) have been compared with those previously obtained with other OPTs, indicating a lower efficiency in DIM desulfuration reaction and a lower potency in inhibiting AChE. Results showed that, similarly to the other OPTs tested so far, at low DIM concentration OME formation is mainly catalysed by CYP1A2, while the role of 3A4 is relevant at high DIM levels. Differently from the other OPTs, DIM desulfuration reaction showed an atypical kinetic profile, likely due to CYP3A4 autoactivation. The sigmoidicity degree of the activity curve increased with the level of CYP3A4 in HLM or disappeared in the presence of a CYP3A4 chemical inhibitor. This atypical kinetic behaviour can be considered one of the possible explanations for the recent findings that among patients hospitalized following OPT intoxication, DIM ingestion gave different symptoms and more severe poisoning (23.1% of fatal cases versus total) than chlorpyrifos (8% of deaths), which has a lower LD(50) value. Since DIM-poisoned patients poorly responded to pralidoxime, the possibility to use CYP3A4 inhibitors could be considered as a complementary treatment.
乐果（DIM）是一种有机磷硫代酸酯（OPT）类农药，在全球范围内用作内吸性杀虫剂和杀螨剂。其特点是对哺乳动物具有低至中度的急性毒性；与其他OPT类农药类似，其作用方式是通过抑制乙酰胆碱酯酶（AChE）来介导的，由其有毒代谢产物乐果 - 氧乐果或氧乐果（OME）发挥作用，氧乐果也用作直接作用的农药。通过使用c - DNA表达的人细胞色素P450（CYPs）和人肝微粒体（HLM），并在存在CYP特异性化学抑制剂的情况下，采用基于AChE抑制的方法，对人肝脏中乐果生物活化生成有毒代谢产物氧乐果进行了表征。已将获得的动力学参数和AChE半数抑制浓度（IC50）与先前用其他OPT类农药获得的参数进行了比较，表明乐果脱硫反应效率较低，抑制AChE的效力也较低。结果表明，与迄今为止测试的其他OPT类农药类似，在低乐果浓度下，氧乐果的形成主要由CYP1A2催化，而在高乐果水平时3A4的作用较为显著。与其他OPT类农药不同，乐果脱硫反应呈现出非典型的动力学特征，这可能是由于CYP3A4的自身激活所致。活性曲线的S形程度随HLM中CYP3A4水平的升高而增加，或在存在CYP3A4化学抑制剂时消失。这种非典型的动力学行为可被视为对最近研究结果的一种可能解释，即在OPT中毒后住院的患者中，摄入乐果与摄入毒死蜱相比，出现了不同的症状且中毒更严重（致命病例占23.1%，而毒死蜱为8%），毒死蜱的半数致死剂量（LD50）值更低。由于乐果中毒患者对解磷定反应不佳，因此可以考虑使用CYP3A4抑制剂作为辅助治疗手段。
