Deoxynivalenol binds and impairs nuclear receptor pregnane X receptor function perturbing modulatory control over xenobiotic metabolism and disposition machinery.

Mycotoxins are prominent environmental pollutants that pose serious health risks. Deoxynivalenol (DON), a trichothecene mycotoxin, is a widespread food contaminant known to cause metabolic and hepatotoxic effects in humans and animals. Although DON-induced inflammatory responses and ribotoxic stress are well characterized, its impact on xenobiotic metabolism and disposition machinery remains unclear. The pregnane X receptor (PXR) is a ligand-activated nuclear receptor that functions as the "master regulator" of detoxification and disposition machinery, including several enzymes and drug transporters. In this study, we investigated the molecular mechanism of DON-induced impairment of PXR. It is revealed that DON selectively induces nuclear translocation of PXR and its heterodimeric partner, retinoid X receptor, implying intermolecular interactions. The DON-PXR interaction appears to impair PXR transcription function, reflected in reduced transcriptional induction of key xenobiotic-metabolizing enzymes. Surprisingly, DON-induced cellular toxicity appeared to occur through generation of alternate translational isoforms of PXR. Additionally, DON disrupted receptor-chromatin interactions exhibited by PXR during mitosis. This apparently led to loss of regulatory control of PXR over the xenobiotic metabolism and disposition, thereby increasing the retention of toxicants. The findings provide the first evidence that DON acts via functional impairment of PXR, revealing a novel mechanism by which environmental mycotoxins can perturb nuclear receptor function and cellular homeostasis. SIGNIFICANT STATEMENT: The study reveals a previously unrecognized molecular mechanism by which deoxynivalenol impairs hepatic detoxification by disrupting pregnane X receptor function and chromatin interactions. Deoxynivalenol interferes as a pregnane X receptor antagonist by reducing transcription function and aberrant isoform generation, highlighting a novel pathway by which mycotoxins may influence nuclear receptor-mediated hepatic homeostasis.