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, luteolin, schizandrin A and puerarin, at 100 μmol/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 Ki values for CYP2D6(*)1 and CYP2D6(*)10 were very close, suggesting that genotype-dependent herb-drug inhibition was similar between the two variants.
Conclusion: Six phytochemicals inhibit CYP2D6(*)1 and CYP2D6(*)10-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.