Student Research: Emma-Jane Poulton

, Environmental Toxicology (Tox), 2010
Faculty Advisor: David L. Eaton

The Characterization of Sulforaphane as a Novel Antagonist to the Human Pregnane and Xenobiotic Receptor (PXR)


Abstract

Much scientific attention has been focused on Sulforaphane, a naturally occurring isothiocyanate with chemopreventative properties. Investigations brought to light a novel mechanism of action, inhibition of the Pregnane and Xenobiotic Receptor (PXR) and subsequent down-regulation of the CYP3A4 gene. PXR is a ligand-activated nuclear transcription factor, a master regulator of xenobiotic dispositions, with diverse targets including the important metabolizing enzyme, cytochrome P450 3A4 (CYP3A4). CYP3A4 contributes to the biotransformation of over 50% of all pharmaceuticals, so changes in its levels can lead to dangerous drug-drug interactions. SFN acts as an antagonist to PXR in vitro, preventing the up-regulation of CYP3A4 both basally and by xenobiotic inducers. In vivo models in humanized mice did not find a similar antagonism of cyp3a11 levels. A clinical trial conducted at the University of Washington found that 7 daily doses of 400 mMol SFN delivered in a broccoli sprout extract, could not prevent CYP3A4 up-regulation caused by rifampicin, but effects were seen on basal CYP3A4 levels. SFN remains a useful in vitro PXR antagonist but is unlikely to full fill the therapeutic need for such an antagonist in vivo.