Screening of Medicinal Plants for Possible Herb-Drug Interactions Through Modulating Nuclear Receptors, Drug-Metabolizing Enzymes and Transporters

Ethnopharmacological relevance: The last three decades have witnessed a surge in popularity and consumption of herbal products. An unintended consequence of such popularity is that chronic consumption of these products can often modulate the functions of various proteins involved in drug disposition and may, in turn, impose risks for herb-drug interactions (HDIs), leading to serious adverse health outcomes. Identifying plants that may give rise to clinically relevant HDIs is essential, and proactive dissemination of such research outcomes is necessary for researchers, clinicians, and average consumers. Aim of the study: The main objective of this study was to evaluate the HDI potential of plants commonly used as ingredients in many herbal products, including BDS. Materials and methods: The dried material of 123 plants selected from the NCNPR repository was extracted with 95% ethanol. The extracts were screened for agonistic effects on nuclear receptors (PXR and AhR) by reporter gene assays in PXR-transfected HepG2 and AhR-reporter cells. For cytochrome P450 enzyme (CYP) inhibition studies, CYP450 baculosomes were incubated with enzyme-specific probe substrates by varying concentrations of extracts. The inhibitory effect on the efflux transporter P-glycoprotein (P-gp) was investigated via rhodamine (Rh-123) uptake assay in P-gp overexpressing MDR1-MDCK cells. Results: Out of 123 plants, 16 increased transcriptional activity of human PXR up to 4 to 7-fold at 60 mu g/mL, while 18 plants were able to increase AhR activity up to 10 to 40-fold at 30 mu g/mL. Thirteen plants inhibited the activity of CYP3A4, while 10 plants inhibited CYP1A2 activity with IC50 values in the range of 1.3-10 mu g/mL. Eighteen plants (at 50 mu g/mL) increased intracellular accumulation of Rh-123 (>150%) in MDR1-MDCK cells. Additionally, other plants tested in this study were able to activate PXR, AhR, or both to lesser extents, and several inhibited the catalytic activity of CYPs at higher concentrations (IC50 >10 mu g/mL). Conclusions: The results indicate that prolonged or excessive consumption of herbal preparations rich in such plants (presented in Figs. 1a, 2a, 3a, 4a, and 5a) may pose a risk for CYP- and P-gp-mediated HDIs, leading to unwanted side effects due to the altered pharmacokinetics of concomitantly ingested medications.