Human Biotransformation Pathway of Temephos Using an In Silico Approach

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 in silico 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) S-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.