Human cytochrome P450 3A-mediated two-step oxidation metabolism of dimethomorph: Implications in the mechanism-based enzyme inactivation

Dimethomorph (DMM), an effective and broad-spectrum fungicide applied in agriculture, is toxic to environments and living organisms due to the hazardous nature of its toxic residues. This study aims to investigate the human cyto-chrome P450 enzyme (CYP)-mediated oxidative metabolism of DMM by combining experimental and computational approaches. Dimethomorph was metabolized predominantly through a two-step oxidation process mediated by CYPs, and CYP3A was identified as the major contributor to DMM sequential oxidative metabolism. Meanwhile, DMM elic-ited the mechanism-based inactivation (MBI) of CYP3A in a suicide manner, and the iminium ion and epoxide reactive intermediates generated in DMM metabolism were identified as the culprits of MBI. Furthermore, three common pes-ticides, prochloraz (PCZ), difenoconazole (DFZ) and chlorothalonil (CTL), could significantly inhibit CYP3A-mediated DMM metabolism, and consequently trigger elevated exposure to DMM in vivo. Computational studies elucidated that the differentiation effects in charge distribution and the interaction pattern played crucial roles in DMM-induced MBI of CYP3A4 during sequential oxidative metabolism. Collectively, this study provided a global view of the two-step met-abolic activation process of DMM mediated by CYP3A, which was beneficial for elucidating the environmental fate and toxicological mechanism of DMM in humans from a new perspective.

Automated summary

This study investigates the oxidative metabolism of Dimethomorph (DMM) mediated by the human cytochrome P450 enzyme (CYP) and its toxicological effects. The study reveals that DMM is mainly metabolized through a two-step oxidation process mediated by CYP3A, and can cause mechanism-based inactivation (MBI) of CYP3A. Additionally, other common fungicides can inhibit the metabolism of DMM, leading to increased exposure to DMM in vivo.