Human Biotransformation Pathway of Temephos Using an In Silico Approach

Abstract

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.

In silico study of the admet properties of potential inhibitors of new Delhi methalo-ß-lactamase-1 (NDM-1)

“…The compounds used (Figure 1) are a compilation of possible inhibitors of the NDM-1 enzyme, which have shown action against the pharmacological target alone or in combinations with some antibiotics such as meropenem, generating a synergistic antibacterial action (Shen et al, 2013). The SMILES codes (simplified online molecular data entry system), see Table 1, were obtained through the MedChem Designer 5.5. software, these codes are a chemical notation that allows the representation of chemical structures for use in computational analysis (Reyes et al, 2020); for this, five rules are followed that detail the representation of atoms, relationships, simple chains, chain trees and ring structure (Cardenas et al, 2019). All in-silico predictions of ADMET properties were carried out with the same SMILES code, both for the molecules under study, and for the carbapenems Meropenem and Imipenem, which are the reference compounds to make possible comparisons of the calculated properties.…”

Tracing the degradation pathway of temephos pesticide achieved with photocatalytic ZnO nanostructured films

“…Unfortunately, Tem-SO is more toxic than Tem as it causes DNA damage, and both cancer and reproductive hazards increase. 33 Thus, it is imperative to investigate if ZnO photocatalysts can also destroy the degradation subproducts of Tem. In the present work, we produced two different types of ZnO nanostructured films and evaluated their efficacy to destroy not only Tem but also Tem subproducts.…”