"Antagonism of the human nuclear hormone receptor SXR, a novel mechanism of action for the chemopreventative agent, Sulforaphane"
Sulforaphane, a natural product found in cruciferous vegetables, has been demonstrated to have chemopreventative properties both in vitro and in vivo. Most studies have focused on the ability Sulforaphane to upregulate phase II enzymes through the NRF2/Keap1 antioxidant response element pathway. This project aims to clarify another putative mechanism of action, the effects of SFN as an in vitro inhibitor of ligand binding to the human steroid and xenobiotic receptor (hSXR). This receptor is instrumental in controlling the regulation of many genes including CYP3A4, a key drug-metabolizing enzyme. This project will use molecular approaches to probe the kinetics of the SFN/hSXR antagonism, and to determine if any specific residues appear to be instrumental in the interaction. Simultaneously in vivo mouse studies using humanized PXR mice and a human feeding study are being undertaken to probe these effects in vivo.