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


CONCLUSIONS
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.
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.
Qiang
Q
Qu
Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Xiangya Hospital, Central South University, Changsha 410078, China.
Jian
J
Qu
Xiangya Hospital, Central South University, Changsha 410008, China.
Lu
L
Han
Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Xiangya Hospital, Central South University, Changsha 410078, China.
Min
M
Zhan
Institute of Life Sciences, Chongqing Medical University, Chongqing 400016, China.
Lan-xiang
LX
Wu
Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Xiangya Hospital, Central South University, Changsha 410078, China.
Yi-wen
YW
Zhang
Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Xiangya Hospital, Central South University, Changsha 410078, China.
Wei
W
Zhang
Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Xiangya Hospital, Central South University, Changsha 410078, China.
Hong-hao
HH
Zhou
D001599:Berberine / Q000031:analogs & derivatives / Q000494:pharmacology; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D003374:Coumarins / Q000494:pharmacology; D034242:Cyclooctanes / Q000494:pharmacology; D003517:Cyclopentanes / Q000494:pharmacology; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D065690:Cytochrome P-450 CYP2D6 Inhibitors / Q000494:pharmacology*; D005663:Furans / Q000494:pharmacology; D046934:Ginkgolides / Q000494:pharmacology; D056945:Hep G2 Cells; D006801:Humans; D007529:Isoflavones / Q000494:pharmacology; D007700:Kinetics; D017705:Lignans / Q000494:pharmacology; D047311:Luteolin / Q000494:pharmacology; D064209:Phytochemicals / Q000494:pharmacology*; D011083:Polycyclic Compounds / Q000494:pharmacology
D003374:Coumarins; D034242:Cyclooctanes; D003517:Cyclopentanes; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D005663:Furans; D046934:Ginkgolides; D007529:Isoflavones; D017705:Lignans; D064209:Phytochemicals; D011083:Polycyclic Compounds; C015499:schizandrin B; C034384:coptisine; D001599:Berberine; C034734:schizandrin A; C030123:coumarin; D019389:Cytochrome P-450 CYP2D6; D047311:Luteolin; C073710:bilobalide; C033607:puerarin