Because the PXR-CYP3A4 pathway is e

Because the PXR-CYP3A4 pathway is extremely important in drug efficacy, it is very important to find an agent that may reduce the effect of inducer-drug interaction. PXR antagonists may be useful for the study of the molecular basis of receptor function. Although many PXR agonists have been reported, comparatively few PXR compounds antagonizing the PXR-CYP3A4 pathway have been identified [43–47].

In this study, the effects of sesamin on the PXR-CYP3A4 pathway and the underlying mechanisms were characterized. Sesamin potently attenuated CYP3A4 induction in a dose-dependent manner by blocking the activation of nuclear receptors, especially PXR through CYP3A4 reporter assay. The PXR inducer-mediated inhibition of CYP3A4 was further evidenced by the ability of sesamin to attenuate the effects of rifampin, paclitaxel, and SR12813 in the CYP3A4 reporter assay. Further mechanistic studies showed that sesamin inhibited PXR by interrupting the binding of steroid receptor coactivator-1 (SRC-1) and hepatocyte nuclear factor 4α (HNF4α). Our results may lead to the development of important new therapeutic and dietary approaches to reduce the frequency of undesirable drug interactions. Here, we established sesamin as a novel and natural potent inhibitor of PXR and proved that it can be a useful tool for modulating DMEs expression. Modification of CYP3A4 by consumption of sesamin could have important implications for drug safety.