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Milk thistle's active components silybin and isosilybin: novel inhibitors of PXR-mediated CYP3A4 induction
Kim D Mooiman1, Roel F Maas-Bakker, Ed E Moret
1Division of Pharmacoepidemiology and Clinical Pharmacology, Department of Pharmaceutical Sciences, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands. K.D.Mooiman@uu.nl
Abstract:
Because cancer is often treated with combination therapy, unexpected pharmacological effects can occur because of drug-drug interactions. Several drugs are able to cause upregulation or downregulation of drug transporters or cytochrome P450 enzymes, particularly 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 are available. Some of these antagonists, such as sulphoraphane and coumestrol, belong to the so-called complementary and alternative medicines (CAM). 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, St. John's Wort, and vitamins B6, B12, and C) to inhibit PXR-mediated CYP3A4 induction at the transcriptional level, using a reporter gene assay and a real-time polymerase chain reaction assay in LS180 colon adenocarcinoma cells. Furthermore, computational molecular docking and a LanthaScreen time-resolved fluorescence resonance energy transfer (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 to prevent drug-drug interactions via CYP3A4 in cancer patients.
Insights
Milk thistle, specifically its components silybin and isosilybin, effectively inhibits PXR-mediated CYP3A4 induction. This finding suggests potential for preventing drug-drug interactions in cancer patients undergoing combination therapy.
Area of Science:
- Pharmacology
- Cancer Therapeutics
- Drug Interactions
Background:
- Cancer combination therapy can lead to drug-drug interactions due to altered drug metabolism.
- Cytochrome P450 3A4 (CYP3A4) induction by certain drugs can reduce anticancer drug efficacy.
- Pregnane X receptor (PXR) is a key regulator of CYP3A4, making PXR antagonists potential modulators.
Purpose of the Study:
- To investigate the potential of selected complementary and alternative medicines (CAM) to inhibit PXR-mediated CYP3A4 induction.
- To explore the interaction of CAM components with PXR at a molecular level.
Main Methods:
- Reporter gene assay and real-time PCR in LS180 cells to assess CYP3A4 induction.
- Computational molecular docking and TR-FRET PXR competitive binding assay to evaluate PXR interaction.
Main Results:
- Milk thistle demonstrated strong inhibition of PXR-mediated CYP3A4 induction.
- Silybin and isosilybin were identified as the active components in milk thistle.
- Molecular docking and binding assays confirmed direct interaction of silybin and isosilybin with PXR.
Conclusions:
- Silybin and isosilybin show promise as PXR antagonists.
- These compounds could be developed to prevent CYP3A4-mediated drug-drug interactions in cancer patients.
