Departamento de Toxicologı́a, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (Cinvestav-IPN), Av. IPN 2508, Col. Zacatenco, G. A. Madero, Mexico City 07360, Mexico.
Chem Res Toxicol. 2020 Nov 16;33(11):2765-2774. doi: 10.1021/acs.chemrestox.0c00105. Epub 2020 Oct 28.
Temephos is an organophosphorothioate (OPT) larvicide used for controlling vectors of diseases such as dengue, chikungunya, and Zika. OPTs require a metabolic activation mediated by cytochrome P540 (CYP) to cause toxic effects, such as acetylcholinesterase (AChE) activity inhibition. There is no information about temephos biotransformation in humans, and it is considered to have low toxicity in mammals. Recent studies have reported that temephos-oxidized derivatives cause AChE inhibition. The aim of this study was to propose the human biotransformation pathway of temephos using tools. The metabolic pathway was proposed using the MetaUltra program of MultiCase software as well as the Way2Drug and Xenosite web servers. The results show the following three essential reactions of phase I metabolism: (1) -oxidation, (2) oxidative desulfurization, and (3) dephosphorylation, as well as the formation of 19 possible intermediary metabolites. Temephos dephosphorylation is the most likely reaction, and it enables phase II metabolism for glucuronidation to be excreted. However, the CYP-dependent metabolism showed that temephos oxon can be formed, which could lead to toxic effects in mammals. CYP2B6, 2C9, and 2C19 are the main isoforms involved in temephos metabolism, and CYP3A4 and 2D6 have minor contributions. According to computational predictions, the highest probability of temephos metabolism is dephosphorylation and phase II reactions that do not produce cholinergic toxic effects; nonetheless, the participation of CYPs is highly possible if the primary reaction is depleted.
涕灭威是一种有机磷硫代酯（OPT）杀虫剂，用于控制登革热、基孔肯雅热和寨卡病毒等疾病的病媒。OPTs 需要细胞色素 P540（CYP）介导的代谢激活才能产生毒性作用，如乙酰胆碱酯酶（AChE）活性抑制。目前尚无关于涕灭威在人体内生物转化的信息，并且它被认为在哺乳动物中毒性较低。最近的研究报告称，涕灭威氧化衍生物会导致 AChE 抑制。本研究旨在使用工具提出涕灭威的人体生物转化途径。代谢途径使用 MultiCase 软件的 MetaUltra 程序以及 Way2Drug 和 Xenosite 网络服务器进行了提出。结果表明，一期代谢有三个必不可少的反应：（1）-氧化，（2）氧化脱硫和（3）去磷酸化，以及 19 种可能的中间代谢物的形成。涕灭威去磷酸化是最有可能的反应，它使相 II 代谢能够通过葡萄糖醛酸化排泄。然而，CYP 依赖性代谢表明，涕灭威氧肟酸可以形成，这可能导致哺乳动物产生毒性作用。CYP2B6、2C9 和 2C19 是参与涕灭威代谢的主要同工酶，CYP3A4 和 2D6 的贡献较小。根据计算预测，涕灭威代谢的最高概率是去磷酸化和不产生胆碱能毒性作用的相 II 反应；然而，如果主要反应耗尽，CYP 的参与是极有可能的。
