Enantioselective Distribution, Degradation, and Metabolite Formation of Myclobutanil and Transcriptional Responses of Metabolic-Related Genes in Rats

Myclobutanil (MT), a chiral fungicide, can be metabolized enantioselectively in organisms. In this work, the associated absorption, distribution, metabolism and transcriptional responses of MT in rats were determined following a single-dose (10 mg·kg^–1 body weight) exposure to <i>rac</i>-, (+)- or (−)-MT. The enantiomer fractions (EFs) were less than 0.5 with time in the liver, kidney, heart, lung, and testis, suggesting preferential enrichment of (−)-MT in these tissues. Furthermore, there was conversion of (+)-form to (−)-form in the liver and kidney after 6 h exposure to enantiopure (+)-MT. Enrichment and degradation of the two enantiomers differed between <i>rac</i>-MT and MT-enantiomers groups, suggesting that MT bioaccumulation is enantiomer-specific. Interestingly, the degradation half-life of MT in the liver with <i>rac</i>-MT treatment was shorter than that with both MT-enantiomer treatments. One reason may be that the gene expression levels of cytochrome P450 1a2 (<i>cyp1a2</i>) and <i>cyp3a2</i> genes in livers treated with <i>rac</i>-MT were the highest among the three exposure groups. In addition, a positive correlation between the expression of <i>cyp2e1</i> and <i>cyp3a2</i> genes and <i>rac</i>-MT concentration was found in livers exposed to <i>rac</i>-MT. Simultaneously, five chiral metabolites were detected, and the enantiomers of three metabolites, RH-9090, RH-9089, and M2, were separated. The detected enantiomers of (+)-MT metabolites were in complete contrast with those of (−)-MT metabolites. According to the results, a metabolic pathway of MT in male rats was proposed, which included the following five metabolites: RH-9089, RH-9090, RH-9090 Sulfate, M1, and M2. The possible metabolic enzymes were marked in the pathway. The findings of this study provide more specific insights into the enantioselective metabolic mechanism of chiral triazole fungicides