Original Article

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

Authors: Qiang Qu, Jian Qu, Lu Han, Min Zhan, Lan-xiang Wu, Yi-wen Zhang, Wei Zhang, Hong-hao Zhou
DOI: 10.1038/aps.2013.202


Qiang QU1, 2, Jian QU1, Lu HAN2, Min ZHAN1, Lan-xiang WU3, Yi-wen ZHANG1, Wei ZHANG1, Hong-hao ZHOU1, *
1Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Xiangya Hospital, Central South University, Changsha 410078, China; 2Xiangya Hospital, Central South University, Changsha 410008, China; 3Institute of Life Sciences, Chongqing Medical University, Chongqing 400016, China

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.

Keywords: CYP2D6; drug interaction; herbal medicine; coptisine; bilobalide; schizandrin; luteolin; puerarin

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.
* To whom correspondence should be addressed.
E-mail honghaozhou2012@gmail.com
Received 2013-10-03 Accepted 2013-11-11

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