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

作　　者：Qiang QU Jian QU Lu HAN Min ZHAN Lan-xiang WU Yi-wen ZHANG Wei ZHANG Hong-hao ZHOU 

机构地区：[1]Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Xiangya Hospital, Central South University, Changsha 410078, China [2]Xiangya Hospital, Central South University, Changsha 410008, China [3]Institute of Life Sciences, Chongqing Medical University, Chongqing 400016, China

出　　处：《Acta Pharmacologica Sinica》2014年第5期685-696,共12页中国药理学报（英文版）

基　　金：This work was supported by the State Scholarship Fund from China Scholarship Council （No 201206370103）, the National Natural Science Foundation of China （No 81273595, 81072706, and 84402511）, the Scientific Foundation of Hunan （No 11K073 and 10JJ4020）, the ＂863＂ Project （No 2012AA02A518）, NCET- 10-0843 and the Research Innovation Foundation of Graduate Student in Hunan province, China （CX2011B056）. We are grateful to Dr Curtis D KLAASSEN and Helen RENAUD who provided language help.

摘　　要：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.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.

关 键 词：CYP2D6 drug interaction herbal medicine COPTISINE BILOBALIDE schizandrin LUTEOLIN PUERARIN 

分 类 号：TQ464.9[化学工程—制药化工] Q559.9[生物学—生物化学]