Integrated Analysis of Hepatic Responses to Deoxynivalenol in Mice: Changes in Cytochrome P450 and Carboxylesterase Expression, Activity, and Transcriptomic Profiles.

BACKGROUND: Deoxynivalenol (DON) is among the most prevalent mycotoxins and exerts adverse effects on the liver. However, a systematic evaluation of its effects on hepatic cytochrome P450 enzymes (Cyp450) and carboxylesterases (Ces) in mice is lacking. METHODS: Using combined in vivo and in vitro models, we investigated the impact of DON on these key enzymes. C57BL/6 mice and AML12 cells were exposed to DON. Histological and ultrastructural changes were assessed by hematoxylin and eosin staining and transmission electron microscopy. The expression and activity of target enzymes were evaluated using reverse transcription quantitative polymerase chain reaction (RT-qPCR), Western blotting, and enzymatic activity assays. Transcriptomic sequencing (RNA-seq) was further performed to identify differentially expressed genes (DEGs) and enriched pathways. RESULTS: DON exposure induced histopathological alterations in mouse liver. In vivo, it significantly enhanced the activity of multiple Cyp450 enzymes, including Cyp1a2, Cyp2b10, Cyp2c29, Cyp2c50, and Cyp3a11 (all P<0.05). Consistent upregulation at both mRNA and protein levels was observed for most of these Cyp450 isoforms in both AML12 cells and mouse liver. Regarding Ces, DON elevated the transcriptional levels, while their protein expression and enzymatic activity showed no significant changes. Transcriptomic sequencing further revealed 1,014 DEGs, predominantly enriched in xenobiotic and drug metabolism pathways such as drug metabolism-cytochrome P450 and carboxylic ester hydrolase activity. CONCLUSION: DON exposure upregulates multiple Cyp450 isoforms at transcriptional, translational, and functional levels. These findings provide a scientific basis for understanding the mechanisms of DON-induced alterations in drug-metabolizing enzymes and highlight potential risks for drug-mycotoxin interactions in clinical and public health contexts.