Quasi-Irreversible Inhibition of CYP2D6 by Berberine
Ha Gyeong Kim,
Han Sol Lee,
Jang Su Jeon,
Young Jae Choi,
Yeon Jung Choi,
So-Yeol Yoo,
Eun-yeong Kim,
Kiho Lee,
InWha Park,
MinKyun Na,
Han-Jin Park,
Seung-Woo Cho,
Jong-Hoon Kim,
Jae-Young Lee,
Sang Kyum Kim
Affiliations
Ha Gyeong Kim
College of Pharmacy, Chungnam National University, Daejeon 34134, Korea
Han Sol Lee
College of Pharmacy, Chungnam National University, Daejeon 34134, Korea
Jang Su Jeon
College of Pharmacy, Chungnam National University, Daejeon 34134, Korea
Young Jae Choi
College of Pharmacy, Chungnam National University, Daejeon 34134, Korea
Yeon Jung Choi
College of Pharmacy, Chungnam National University, Daejeon 34134, Korea
So-Yeol Yoo
College of Pharmacy, Chungnam National University, Daejeon 34134, Korea
Eun-yeong Kim
College of Pharmacy, Korea University, Sejong 30019, Korea
Kiho Lee
College of Pharmacy, Korea University, Sejong 30019, Korea
InWha Park
College of Pharmacy, Chungnam National University, Daejeon 34134, Korea
MinKyun Na
College of Pharmacy, Chungnam National University, Daejeon 34134, Korea
Han-Jin Park
Predictive Model Research Center, Korea Institute of Toxicology, Daejeon 34114, Korea
Seung-Woo Cho
Department of Biotechnology, Yonsei University, Seoul 03722, Korea
Jong-Hoon Kim
Laboratory of Stem Cells and Tissue Regeneration, Department of Biotechnology, College of Life Sciences and Biotechnology, Science Campus, Korea University, Seoul 02841, Korea
Jae-Young Lee
College of Pharmacy, Chungnam National University, Daejeon 34134, Korea
Sang Kyum Kim
College of Pharmacy, Chungnam National University, Daejeon 34134, Korea
In our previous study, Hwang-Ryun-Hae-Dok-Tang, which contains berberine (BBR) as a main active ingredient, inhibited cytochrome P450 (CYP) 2D6 in a quasi-irreversible manner. However, no information is available on the detailed mechanism of BBR-induced CYP2D6 inhibition. Thus, the present study aimed to characterize the inhibition mode and kinetics of BBR and its analogues against CYP2D6 using pooled human liver microsomes (HLM). BBR exhibited selective quasi-irreversible inhibition of CYP2D6 with inactivation rate constant (kinact) of 0.025 min−1, inhibition constant (KI) of 4.29 µM, and kinact/KI of 5.83 mL/min/µmol. In pooled HLM, BBR was metabolized to thalifendine (TFD), demethyleneberberine (DMB), M1 (proposed as demethylene-TFD), and to a lesser extent berberrubine (BRB), showing moderate metabolic stability with a half-life of 35.4 min and a microsomal intrinsic clearance of 7.82 µL/min/mg protein. However, unlike BBR, those metabolites (i.e., TFD, DMB, and BRB) were neither selective nor potent inhibitors of CYP2D6, based on comparison of half-maximal inhibitory concentration (IC50). Notably, TFD, but not DMB, exhibited metabolism-dependent CYP2D6 inhibition as in the case of BBR, which suggests that methylenedioxybenzene moiety of BBR may play a critical role in the quasi-irreversible inhibition. Moreover, the metabolic clearance of nebivolol (β-blocker; CYP2D6 substrate) was reduced in the presence of BBR. The present results warrant further evaluation of BBR–drug interactions in clinical situations.