Prediction and Characterization of CYP3A4-mediated Metabolisms of Azole Fungicides: an Application of the Fused-grid Template* system

Abstract

Human CYP3A4 is involved in metabolisms of diverse hydrophobic chemicals. Using the data of therapeutic azole fungicides known to interact with CYP3A4, applicability of CYP3A4 Template system was first confirmed to reconstitute faithfully the interaction on Template. More than twenty numbers of pesticide azoles were then applied to the Template system. All the azole stereo-isomers applied, except for talarozole, interacted through nitrogen atoms of triazole or imidazole parts and sat stably for inhibitions through fulfilling three-essential interactions. For their CYP3A4-mediated oxidations, clear distinctions were suggested among the enantiomers and diastereomers of azole pesticides on Templates. Thus, the stereoisomers would have their-own regio- and stereo-selective profiles of the metabolisms. A combined metabolic profile of each azole obtained with CYP3A4 Template system, however, resembled with the reported profile of the in vivo metabolism in rats. These results suggest the major roles of CYP3A forms on the metabolisms of most of azole pesticides in both rats and humans. Free triazole is a metabolite of azole fungicides having a methylene-spacer between triazole and the rest of the main structures in experimental animals and humans. During the simulation experiments, a placement for the oxidation of a methylene spacer between the triazole and main carbon-skeleton was found to be available throughout the azole fungicides tested on Template. The occurrence of this reaction to lead to triazole-release is thus discussed in relation to the possible involvement of CYP3A forms.