Nuclear Receptors Mediated Induction Of Drug Metabolizing Enzymes By Traditional Chinese Medicines

Herb-drug combination use is very popular in our country. However, herb-drug interactions and adverse effects have not been well examined. More attention should be paid to elder patients because polypharmacy is common in this population. A retrospective analysis of combination use and the potential herb-drug interactions among 1186 elder patients was conducted. Our results indicated that combination use was very popular in these elder patients, accounting for 42% of the total subjects. Statistical analysis showed that medical conditions, number of disease and age were three important factors influencing the prevalence of combination use. In addition, this elderly cohort had the risk of herb-drug interactions and 3 herbal medicines (ginkgo biloba, Danshen, Chinese Angelica) and anticoagulant were the prevalent herb-drug interacting pairs.Induction of CYP3A4 mediated by pregnane X receptor (PXR) represents an important mechanism for herb-drug metabolic interactions. This work attempted to evaluate the inducible potential of CYP3A4 by Traditional Chinese Medicines (TCMs) and their constituents. First, we established a cell-based reporter gene assay and then 29 TCMs were examined. The results showed that most of the TCMs tested, including ginkgo biloba, Danshen, Chinese Angelica and Schisandra chinensis could induce CYP3A4 through PXR pathway.We further examined trans-activation activities of the constituents from ginkgo biloba. Danshen, Chinese Angelica and Schisandra chinensis on CYP3A4 reporter. Tanshinone IIA and cryptotanshinone from Danshen, ligustilide from Chinese Angelica, schisandrin A, schisandrin B. schisandrol A and schisantherin A from Schisandra chinensis, ginkgolide A from ginkgo biloba, trans-resveratrol, berberine hydrochloride were identified as PXR agonists. Constitutive androstane receptor (CAR) and glucocorticoid receptor (GR) were also involved in tanshinones mediated CYP3A4 induction.We tried a docking approach to study the ligand-receptor interactions between herb constituents and PXR ligand binding domain. Based on our docking model, schisantherin A was found to interact with polar residue Ser247 and other 12 hydrophobic residues lining in the ligand binding pocket of PXR.Taken together, PXR can be served as a useful tool to study CYP3A4 induction mediated by TCMs.