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Milk Thistle's Active Components Silybin and Isosilybin: Novel Inhibitors of PXR-mediated CYP3A4 Induction.

Drug Metab Dispos. 2013 May 14;

Authors: Mooiman KD, Maas-Bakker RF, Moret EE, Beijnen JH, Schellens JH, Meijerman I


As cancer is often treated with combination therapy, unexpected pharmacological effects can occur because of drug-drug interactions. Several drugs are able to cause up or down regulation of drug transporters or cytochrome P450 (CYP) enzymes, in particular CYP3A4. Induction of CYP3A4 may result in decreased plasma levels and therapeutic efficacy of anticancer drugs. Since the Pregnane X Receptor (PXR) is one of the major transcriptional regulators of CYP3A4, PXR antagonists can possibly prevent CYP3A4 induction. Currently, a limited number of PXR antagonists is available. Some of these antagonists belong to the so-called Complementary and Alternative Medicines (CAM), such as sulphoraphane and coumestrol. Therefore, the aim was to determine the potential of selected CAM (β-carotene, Echinacea purpurea, garlic, Ginkgo biloba, ginseng, grape seed, green tea, milk thistle, saw palmetto, valerian, vitamin B6, B12 and C) to inhibit of PXR-mediated CYP3A4 induction at the transcriptional level, using a reporter gene and RT-PCR assay in LS180 colon adenocarcinoma cells. Furthermore, computational molecular docking and a LanthaScreen® TR-FRET PXR competitive binding assay were performed to explore whether the inhibiting CAM components interact with PXR. The results demonstrated that milk thistle is a strong inhibitor of PXR-mediated CYP3A4 induction. The components of milk thistle responsible for this effect were identified as silybin and isosilybin. Furthermore, computational molecular docking revealed a strong interaction between both silybin and isosilybin and PXR, which was confirmed in the TR-FRET PXR assay. In conclusion, silybin and isosilybin might be suitable candidates to design potent PXR antagonists in order to prevent drug-drug interactions via CYP3A4 in cancer patients.

PMID: 23674609 [PubMed - as supplied by publisher]