Inhibitory effects of phytochemicals on metabolic capabilities of.CYP2D6＊1 and CYP2D6＊10 using cell-based models in vitro

Aim： Herbal products have been widely used, and the safety of herb-drug interactions has aroused intensive concerns. This study aimed to investigate the effects of phytochemicals on the catalytic activities of human CYP2D6＊1 and CYP2D6＊10 in vitro. Methods： HepG2 cells were stably transfected with CYP2D6＊1 and CYP2D6＊10 expression vectors. The metabolic kinetics of the enzymes was studied using HPLC and fluorimetry. Results： HepG2-CYP2D6＊1 and HepG2-CYP2D6＊10 cell lines were successfully constructed. Among the 63 phytochemicals screened 6 compounds, including coptisine sulfate, bilobalide, schizandrin B, iuteolin, schizandrin A and puerarin, at 100 pmol/L inhibited CYP2D6＊1- and CYP2D6＊10-mediated O-demethylation of a coumarin compound AMMC by more than 50%. Furthermore, the inhibition by these compounds was dose-dependent. Eadie-Hofstee plots demonstrated that these compounds competitively inhibited CYP2D6＊1 and CYP2D6＊10. However, their K1 values for CYP2D6＊I and CYP2D6＊IO were very close, suggesting that genotype- dependent herb-drug inhibition was similar between the two variants. Conclusion： Six phytochemicals inhibit CYP2D6＊1 and CYP2D6＊lO-mediated catalytic activities in a dose-dependent manner in vitro. Thus herbal products containing these phytochemicals may inhibit the in vivo metabolism of co-administered drugs whose primary route of elimination is CYP2D6.