A major compound isolated from Undaria Pinnatifida downregulates CYP3A4 and MDR1 expression by antagonizes pregnane X receptor activation

Abstract

Pregnane X receptor (PXR) has been reported to regulate the expression of drug‐metabolizing enzymes, such as CYP3A4 and MDR1. A major carotenoid which isolated from brown sea algae, Undaria Pinnatifida, compound A, is a putative chemopreventive agent. In this study, we determined whether compound A may overcome inducer‐drug interaction through attenuation of rifampin‐induced CYP3A4 and MDR1 gene expression by PXR‐mediated pathways in HepG2 hepatoma cells. We found that compound A significantly attenuated rifampin‐induced CYP3A4 and MDR1 mRNA and CYP3A4 protein expression at 24 h of incubation. Mechanistically, compound A strongly attenuated the PXR‐mediated CYP3A4 promoter activity in HepG2 cells. In addition, compound A attenuated CAR‐and rPXR‐mediated CYP3A4 promoter activity in this cell line. Using the mammalian two‐hybrid assay, we found that compound A significantly decreased the interaction between PXR and SRC‐1, a PXR co‐activator. Thus, this compound A can decrease rifampin‐induced CYP3A4 and MDR1 expression through attenuation of PXR‐mediated CYP3A4 promoter activation and interaction between PXR and co‐activator. These findings could lead to potentially important new therapeutic and dietary approaches to reduce the frequency of adverse drug reactions.