The modulation of abcb4 and cyp3a65 gene expression and multidrug/multixenobiotic resistance (MDR/MXR) functional activity in the model teleost, Danio rerio (zebrafish)

The multidrug/multixenobiotic resistance (MDR/MXR) mechanism is a cellular response involving the induction and coordinated action of the ATP-binding cassette (ABC) transporter, P-glycoprotein (P-gp), and the phase I metabolizing enzyme, cytochrome P450 3A (CYP3A), which confers protection against potentially cytotoxic exposures of various drugs and environmental contaminants. In mammals, ligand-mediated pregnane X receptor (PXR) transcriptional activity regulates the induction of P-gp and CYP3A but this mechanism is not well characterized in fish species. In this study, zebrafish treated with the Pxr (PXR) agonist PCN co-modulated P-gp (Abcb4) and CYP3A (Cyp3a65) mRNA expression and this co-modulation was associated with increased hepatic MDR/MXR functional activity in vivo. Consistent with a mammalian-like MDR/MXR mechanism regulated by PXR, zebrafish co-treated with PCN and the mammalian PXR antagonist, ketoconazole (KTC) attenuated the PCN-mediated modulation of hepatic abcb4 and cyp3a mRNA levels, as well as attenuated the PCN-mediated modulation of MDR/MXR functional activity. These results suggest abcb4 may be involved with the MDR/MXR response in the adult zebrafish liver, and that Pxr (PXR) may regulate this dynamic process. Finally, the lack of Cyp3c1 mRNA modulation by PCN suggests that Cyp3c1 and Cyp3a65 may be regulated by separate transcriptional pathways.