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Enzyme kinetic and molecular docking studies for the inhibitions of miltirone on major human cytochrome P450 isozymes.

ARTICLE INFO

Keywords:

Salvia miltiorrhiza

Miltirone

Cytochrome P450

Probe substrates

Molecular docking

ABSTRACT

Previous studies have shown that major tanshinones isolated from Danshen (Salvia miltiorrhiza) inhibited human and rat CYP450 enzymes-mediated metabolism of model probe substrates, with potential in causing herb--drug interactions. Miltirone, another abietane type-diterpene quinone isolated from Danshen, has been reported for its anti-oxidative, anxiolytic and anti-cancer effects. The aim of this study was to study the effect of miltirone on the metabolism of model probe substrates of CYP1A2, 2C9, 2D6 and 3A4 in pooled human liver microsomes. Miltirone showed moderate inhibition on CYP1A2 (I[C.sub.50] = 1.73 [micro].M) and CYP2C9 (I[C.sub.50] = 8.61 [micro]M), and weak inhibition on CYP2D6 (I[C.sub.50] = 30.20 [micro]M) and CYP3A4 (I[C.sub.50] = 33.88 [micro]M). Enzyme kinetic studies showed that miltirone competitively inhibited CYP2C9 ([K.sub.i] = 1.48 [micro]M), and displayed mixed type inhibitions on CYPIA2, CYP2D6 and CYP3A4 with K, values of 3.17 [micro]M, 24.25 [micro]M and 35.09 [micro]M, respectively. Molecular docking study further confirmed the ligand-binding conformations of miltirone in the active sites of these human CYP450 isoforms, and provided some information on structure--activity relationships for the CYPs inhibition by tanshinones. Taken together, CYPs inhibitions of miltirone were weaker than dihydrotanshi none, but stronger than cryptotanshinone, tanshinone land tanshinone IIA.

[C] 2012 Elsevier GmbH, All rights reserved.

Introduction

Tanshinones are the major lipid-soluble components in Danshen (Salvia miltiorrhiza) ethanolic extract that is officially approved and widely used in China (Comission 2010; Zhou et al. 2012a). These tanshinones, such as tanshinone I, tanshinone IIA, cryptotanshinone and dihydrotanshinone, have shown their potential pharmacological effects on cardiovascular disease (Lam et al. 2008a,b), ischemia reperfusion injury (Adams et al. 2006), anti-cancer (Lee et al. 2010; Dong et al. 2011), and anti-hepatic fibrosis (Wang et al. 2007). Miltirone is one of these abietane type-diterpene quinones isolated from Danshen, structurally similar to tanshinone IIA and cryptotanshinone on rings A, B and C (Fig. 1). Miltirone has been reported for its strong anti-oxidative effect (Weng and Gordon 1992), anxiolytic effect (Chang et al. 1991), positive modulation on GABA(A) receptor (MostaIlino et al. 2004; Colombo et al. 2006), and anti-proliferative activities in multidrug-resistant cells (Efferth et al. 2008). The amount of miltirone in Danshen extracts produced by solvent varied around 0.1-0.4 mg/g dried herb due to different growth conditions of the plant and extraction methods (Cao et al. 2008). This amount was about 10% of that of tanshinone IIA which is the most abundant tanshinone in Danshen (Sun et al. 2011). The total chemical synthesis of miltirone has also been carried out and characterized for its development as a potential drug candidate (Huang et al. 2006).

Cytochrome P450 enzymes (CYPs) such as CYP1A2, 2C9, 2D6 and 3A4 collectively metabolize over 90% of the current drugs. The overall contribution in drug metabolism is estimated as followed: CYP1A2 (4%), 2C9 (10%), 2D6 (30%) and 3A4 (50%) (Purnapatre et al. 2008). These CYP450s are, therefore, important in metabolism-based drug-drug/herb-drug interactions. Previous metabolic studies with model probe substrates of the CYP isoforms have shown that major tanshinones, including tanshi-none 1, tanshinone 11A, cryptotanshinone and dihydrotanshinone, inhibited the metabolism of human CYP1A2, CYP2C9, CYP2D6 and CYP3A4 in varying degree (Wang et al. 2010; Zhou et al. 2012b). These tanshinones are considered as the main ingredients in Danshen preparations for the contribution of CYPs inhibition (Zhou et al. 2012a). Since miltirone, as a new chemical entity with drug-likeness, is structurally similar to these tanshinones, its metabolism-based drug-drug interactions should be considered at the early stage of drug development (Baranczewski et al. 2006). The aim of this study was to investigate the CYPs-mediated metabolism-based interactions of miltirone on CYP1A2, CYP2C9, CYP2D6 and CYP3A4, with their model probe substrates phenacetin, tolbutamide, dextromethorphan and testosterone in pooled human liver microsomes (HLMs), respectively. The drug-drug interaction potential of miltirone was compared with those of major tanshinones. The modes of inhibition were characterized by enzyme kinetic study, where appropriate, and further ligand-binding information was provided by molecular docking analysis which also be useful for elucidating the structure-activity relationships of tanshinones on CYPs inhibition.

Material and methods

Materials and reagents

Miltirone (purity >98%) was purchased from Sichuan Weikeqi Biological Technology Co., Ltd. (Sichuan, China), which was validated with the authentic standard from Hong Kong Jockey Club Institute of Chinese Medicine (Hong Kong, China). Acetonitrile (ACN, HPLC grade) was supplied by Labscan Analytical Sciences (Bangkok, Thailand). All model probe substrates and their metabolites, [beta]-nicotinamide adenine dinucleotide phosphate (NADP), glucose-6-phosphate (G-6-P), glucose-6-phosphate dehydrogenase (G-6-P-D), and other unspecified reagents were from Sigma Chemical CO. (St. Louis, MO, USA). Histologically normal liver tissues were individually isolated from resected tissues of Chinese patients (eighteen male, five female) with hepatocellular carcinoma, after they had received curative hepatectomy at Prince of Wales Hospital, Hong Kong. The pooled human liver microsomes (HLMs) were prepared as previous study (Wang and Yeung 20111)). This study was approved by the Local Ethics Committee with consents from patients following the Declaration of Helsinki.

Incubation conditions

The inhibitory effects of miltirone on the activities of CYP1A2, CYP2C9, CYP2D6 and CYP3A4 were investigated with individual probe substrates in pooled HLMs via four reactions including phenacetin 0-deethylation, tolbutamide hydroxylation, dextromethorphan 0-demethylation and testosterone 6[beta]-hydroxylation, respectively. Probe substrates were dissolved in methanol as stock solutions (10 mM), while miltirone was dissolved in DMSO for stock solution (10 mM). All of them were diluted to the final concentrations with incubation buffer, and final concentrations of organic solvents were below 1%. Incubation buffer (0.05 M Tris/KCI, pH 7.4) contained a NADPH-regenerating system with NADP (1.3 mM), G-6-P (3.3 mM), G-6-P-D (0.4 Unit/m1) and magnesium chloride (3.3 mM). Incubation buffer was preincubated for 3 min at 37 C, and then 20 min incubations for CYP3A4 or 60 min for other CYPs were started with addition of HLMs (0.8 mg/ml) in a final concentration of 0.25 ml via a thermomixer (Eppendorf, Germany) at 800 rpm and 37 [degger]C. Equal volume of chilled ACN was used to terminate reactions. All reactions were performed in triplicate.

Samples preparation

After incubation, the samples were centrifuged at 10,000 rpm for 10 min. The respective supernatant was added with 10 [micro]l of the internal standards, including warfarin (100 [micro]g/m1 in methanol) for CYP1A2 and CYP3A4, chlorpropamide (50 [micro]g/m1 in methanol) for CYP2C9, and chlorpheniramine (100[micro]/ml in 0.01 M NCI) for CYP2D6. The supernatant mixture was subsequently extracted with ethyl acetate in thermomixer at 1400 rpm for 30 min, and then centrifuged at 5000 rpm for 5 min. After the organic layer was dried, methanol (60 [micro]l) was used to resuspend the residues for CYP1A2 and CYP3A4, while the mixture (60 [micro]l) of [H.sub.2]0 (pH 2.7, adjusted by [H.sub.3] P[O.sub.4]) and ACN (1:2.4) was for CYP2C9 and CYP2D6.

HPLC analysis

Validated HPLC-DAD analysis was performed using the Agi-lent 1100 HPLC system (CA. USA) equipped with a quaternary pump, an online degasser, an autosampler and a diode array detector (Feng et al. 2012). In brief, an Alltech Alltima [C.sub.18] column (250 mm x 4.6 mm, 5 [micro]m) was for the assessments of CYP1A2 and CYP3A4 activities at 248 nm and 235 nm, respectively. The mobile phase was constitutive of (A) acetic acid in water (1.5%, pH 4.7) and (B) ACN at a flow rate of 0.7 ml/min in a gradient elution: 0-4 min, 20% B; 4-5 min, 20-60% B; 5-7 min, 60-80% B; 7-15 min, 80% B. An Allsphere ODS-2 column (250 mm x 4.6 mm, 5 [micro]m) was used to detect CYP2C9 activities with isocratic elution using a mixed mobile phase with 40% ACN and 60% sodium acetate (10 mM) in water (pH 4.3) at a flow rate 010.6 ml/min and a wavelength of 230 nm. An Agi-lent ZORBAX Eclipse XDB-[C.sub.8] column (150 mm x 4.6 mm, 5[micro]m) was used for measuring CYP2D6 activities at a wavelength of 220 nm. The mobile phase consisted of 30% ACN and 70% triethylamine (0.1%)-water (pH 3.0, adjusted by perchloric acid) at a flow rate of 0.5 ml/min. 50 [micro]lof each sample was subjected to HPLC analysis.

CYPs inhibition and enzymatic kinetic study

Inhibition assessments (IC50) on CYP450 isoforms in pooled HLMs were performed with a fixed concentration of model probe substrates (50 [micro]M) and a series of concentrations of miltirone ranging from 0-10[micro]M for CYP1A2, 0-2011M for CYP2C9, 0-100[micro]M for CYP2D6 and CYP3A4, respectively. Meanwhile, the other inhibition parameters, including inhibition types and inhibition constant ([K.sub.i]) values, were measured with a series of concentrations of probe substrates (25-200 [micro]M) and miltirone (0-100 [micro]M), respectively.

Molecular docking analysis

Mode of inhibition of miltirone on these CYPs was further assessed by molecular docking analysis with the software AutoDock Vina v.1.0.2 (Trott and Olson 2010). The crystal structures of human CYP450s were obtained from the Protein Data Bank as followed: CYP1A2 (PDB code 2HI4) in complex with alpha-naphthoflavone, a specific inhibitor (Sansen et al. 2007); CYP2C9 (PDB code 1R90) in complex with flurbiprofen, a probe substrate (Wester et al. 2004): CYP2D6 (PDB code 3QM4) in complex with prinomastat, a substrate and potent inhibitor (Wang et al. 2012): CYP3A4 (PDB code 1W0F) in complex with progesterone, a probe substrate (Williams et al. 2004). The docking parameters were set as previous study with default values, and the sizes of grid boxes were set as 20A x 20A x 20A for encompassing CYPs' active cavities (Zhou et at. 2012b). The binding modes of miltirone with lowest binding free energy to the active cavities of CYPs were selected for further confirmation of clocking conformation, with probe substrates in the metabolism conformation. The simulation results were illustrated by PyMOL Molecular Graphics System v.1.3 (Schrodinger, LLC) and Discovery Studio Visualizer (Accelrys, Inc., CA).

Data analysis

Data were presented as the mean [+ or -] standard error of mean (S.E.M.), and analyzed by one-way ANOVA followed by Bunnett's Post Hoc test. p values less than 0.05 were considered statistically significant. IC50 values were calculated from non-linear regression analysis with Prism v.5.0 (GraphPad Software, CA). Graphical inspection from different plots was used to illustrate the inhibition constants ([K.sub.i]) and modes of miltirone to different CYP450 enzymes (Feng et al. 2012). These plots included Primary Lineweaver-Burk Plot (obtained by reciprocal of reaction velocities versus reciprocal of substrate concentrations), Dixon plot (obtained by reciprocal of reaction velocities versus inhibitor concentrations), Secondary Lineweaver-Burk plot for [K.sub.i] (obtained by the slopes of the regression lines in the Primary Lineweaver-Burk plot versus inhibitor concentrations), Secondary Lineweaver-Burk plot for [alpha][K.sub.i] (obtained by y-intercepts of the regression lines in Primary Lineweaver-Burk plot versus inhibitor concentrations), Secondary Dixon plot (obtained by the slopes of the regression lines in the Dixon plot versus reciprocal of substrate concentrations). For graphical inspection, Primary Lineweaver-Burk plot and Dixon plot are firstly used for the confirmation of the competitive type. Otherwise, wheny-intercept in Secondary Dixon plot is greater than zero, mixed inhibition (competitive and non-competitive) is observed; wheny-intercept is at the origin, competitive inhibition is observed (Segel 1975). Meanwhile, [alpha] [not equal to] ([K.sub.i] [alpha][K.sub.i]) also displays mixed type inhibition (Shou et al. 2001).

Results

CYPs inhibition and enzymatic kinetic study

Inhibition of miltirone on human CYP isoforms was summarized in Table 1. Miltirone (0-100 [micro]M) concentration-dependently inhibited the formation of metabolites from model probe substrates of CYP1A2, CYP2C9, CYP2D6 and CYP3A4, respectively. The I[C.sub.50] values of miltirone on CYP1A2 and CYP2C9 activities were 1.73 pt.M and 8.61 [micro]M, respectively. Miltirone slightly inhibited the activities of CYP2D6 and CYP3A4 with I[C.sub.50] values of 24.25 [micro]M and 35.09 [micro]M, respectively. Miltirone concentration-dependently decreased the ratios of the metabolite and probe substrate of each CYP450 isoform (Fig. 2).

Table 1 Inhibitory parameters ([micro]M) of miltirone
on human CYP450 isoforms (n =3).

CYP         Miltirone
isoforms
            I[C.sub.50] [K.sub.i]   [alpha][K.sub.i]   Inhibition mode

1A2               1.73       3.17               1.72   Mixed

2C9               8.61       1.48                  -   Competitive

2D6             30.20       24.25               33.01  Mixed

3A4             33.88       35.09               12.04  Mixed

-.Not be determined.


To investigate the mechanism(s) of inhibition of miltirone on the CYP450 isoforms, concentrations of the model probe substrates for each CYP450 isoform were used. From the Primary Lineweaver-Burk plots (Figs. 3a, 5a and 6a) and Dixon plots (Figs. 3b, 5b and 6b), the straight lines intersected on the second quadrant or negative x-axis, which indicated competitive or mixed inhibitions of miltirone on CYP1A2, CYP2D6 and CYP3A4; From the Secondary Dixon plots (Figs. 3c, 5c and 6c), the straight lines intersected on the positive y-axis, which suggested mixed inhibitions of miltirone on CYP1A2, CYP2D6 and CYP3A4. Therefore, the mixed type inhibitions of miltirone were observed on CYP1A2-mediated phenacetin hydroxylation, CYP2D6-mediated dextromethorphan 0-demethylation and CYP3A4-mediated testosterone 63-hydroxylation. For CYP2C9-mediated tolbutamide hydroxylation, the straight lines intersected in the first quadrant of Primary Lineweaver--Burk plots (Fig. 4a) and positive y-axis of Dixon plots (Fig. 4b), but Secondary Lineweaver-Burk plot for aKi and Secondary Dixon plot cannot be plotted. These showed a competitive inhibition of miltirone on CYP2C9 activity.

The K1 values of miltirone on CYP1A2, CYP2C9, CYP2D6 and CYP3A4 were obtained from the Secondary Lineweaver-Burk plot for Ki with values of 3.17[micro]M, 1.48 [micro]M, 24.25 [micro]M and 35.09 [micro]M, respectively. From the Secondary Lineweaver-Burk plot for aKi, crKi values of miltirone on CYP1A2, CYP2D6 and CYP3A4 were 1.72 33.01 pM and 12.04 [micro]M, respectively. Since a values of CYP1A2 ([alpha] = 1.84), CYP2D6 ([alpha] = 0.73) and CYP3A4 ([alpha] = 2.91) were unequal to 1, the mixed type inhibitions of miltirone to CYP1A2, CYP2D6 and CYP3A4 were obtained, which were consistent with the results in above-mentioned graphical inspections.

Molecular docking study

Molecular docking analysis on the interactions of miltirone to CYP1A2, CYP2C9, CYP2D6 and CYP3A4 were performed to confirm the drug binding conformation. Miltirone bound to the active cavity of human CYP1A2 (PDB code 2HI4) with the binding energy of -11.1 kcal/mol, while phenacetin acted in a similar position with the binding energy of -7.3 kcal/mol (Fig. 7a and Table 2). A previous study has shown that the amino acid residues, including Thr124, P1ie125, Phe226, Phe260, G1y316, and A1a317, in the active site of CYP1A2 are responsible for ligand binding (Yang et al. 2012). As shown in Fig. 7e, two residues (Phel 25 and Phe226) of these key residues are critical for the binding of miltirone. Ring B and ring C of miltirone had strong Pi-Pi stacking interaction with Phe226 in the distances of about 4.8 and 5.8 A, respectively. Ring B also interacted with Phe125 through Pi-Pi stacking interaction in a distance of 3.8 A. Meanwhile, C-3 provided a sigma-Pi interaction with Phe226 in a distance of 3.6A. These interactions took responsibility to the inhibition of miltirone on CYP1A2-mediated phenacetin O-deethylation.

Table 2 Logarithm of free binding energies (kcal/mol) of miltirone
to the active cavities of human CYP1A2 (PDB code 2HI4), CYP2C9
(PDB code 1R90), CYP2D6 (PDB code 3QM4) and CYP3A4 (PDB code IMF).
The metabolized positions of probe substrates were within
closer distances to the heme iron.

CYP isoforms   Miltirone  Probe substrates. (a)

1A2                -11.1                    -73
2C9                 -8.2                   -7.2
2D6                -10.4                   -7.9
3A4                 -9.3                   -9.7

(a.) Phenacetin for CYP1A2, tolbutamide for CYP2C9,
dextromethorphan for CYP2D6 and testosterone for CYP3A4.


For docking to CYP2C9, the crystal structure of CYP2C9 (PDB code 1R90) was used. As shown in Fig. 7b and Table 2, miltirone bound to the same binding site as tolbutamicle in the active cavity of CYP2C9, while miltirone had higher binding affinity (-8.2 kcal/mol) than tolbutamide (-7.2 kcal/mol). As shown in Fig. 7f, the ketone group at C-12 position of miltirone interacted with the side chain of Arg108, the key residue for ligand binding in CYP2C9-1R90 (Polgar et al. 2007), via hydrogen bonding interaction within distance of 2.8 A. Further, miltirone and tolbutamide shared similar conformation in another crystal structure of CYP2C9 (PDB code 10G5) (data not shown), but not in the allosteric site that bound S-warfarin (Williams et al. 2003). All these suggested miltirone bound to tolbutamide-binding site in human CYP2C9.

The molecular docking analysis showed that miltirone bound to the active cavity of CYP2D6 (PDB code 3QM4) with binding affinity of -10.2 kcal/mol in the same position as dextromethorphan whose binding affinity was -7.9 kcal/mol (Fig. 7c and Table 2). As shown in Fig. 7g, ring B and ring C of miltirone interacted with Phel 20, a key amino acid residue of CYP2D6 for ligand binding (McLaughlin et al. 2005), via Pi-Pi stacking interaction in distances of 3.9A and 4.1 A, respectively. Meanwhile, miltirone also interacted via van der Waals with G1u216, Asp301, and Phe483 which locate in the substrate-binding site (Ito et al. 2008).

As shown in Fig. 7d, the docking results indicated that miltirone bound to CYP3A4 (PDB code 1W0F) in a similar way to testosterone in the active cavity of human CYP3A4. Miltirone interacted via Van der Waals with Phe57, Arg212, Phe215, Thr309, Ala370, Arg372 and Met371, and via polarity with Gly481 and Phe213 (Fig. 711). The binding affinity of miltirone (-9.3 kcal/mol) was lower than that of testosterone (-9.7 kcal/mol) (Table 2). Hence, miltirone had a weaker affinity than testosterone in binding to the active cavity of CYP3A4.

Discussion

In the present study, the potential metabolism-based drug-drug interactions of miltirone were investigated. The inhibitions of miltirone on four major CYP450 isoforms, including CYP1A2, CYP2C9, CYP2D6 and CYP3A4, were observed in varying degree in pooled HLMs (Table 1). Molecular docking analysis also provided some information on structure-activity relationships for the CYPs inhibition by tanshinones.

From previous study, tanshinone I, tanshinone 11A and cryp-totanshinone were moderate inhibitors of human CYP1A2 with IC; values of 2.16 [micro]M, 1.45 [micro]M and 1.88 [micro]M, respectively, while dihydrotanshinone was a strong inhibitor of CYP1A2 (Ki = 0.53 [micro]M) (Wang et al. 2010). In this study, miltirone was also found as a moderate inhibitor (Ki =3.17 [micro]M) mainly via strong Pi-Pi stacking interactions with Phel 25 and Phe226 in the active cavity of CYP1A2 (Fig. 7a and e). These further confirmed the potential herb-drug interactions between tanshinones and CYP1A2-metabolized drugs. Since Phe125 and Phe226 are the key residues for CYP1A2 ligand binding (Yang et al. 2012), benzene rings of tanshinones should be an important factor for Pi-Pi stacking interactions with these two amino acid residues. It was, therefore, suggested that the abi-etane type-diterpene quinones sharing rings A, B and C were potent CYP1A2 inhibitors, and ring D did not play an important role in tanshinones-mediated CYP1A2 inhibition.

As shown in previous study, only dihydrotanshinone was considered to be a moderate inhibitor ([K.sub.i] = 1.92 [micro]M), as the source of Danshen extracts-mediated CYP2C9 inhibition, while other three tanshinones were weak inhibitors with high Ki values as followed: tanshinone 1, 51.2 [micro]M; tanshinone 11A, 61.6 [micro]M; cryptotanshinone, 22.9 p.M (Wang et al. 2010). The structural difference of tanshi-none land clihydrotanshinone is only the presence of double bond at C-15 position of the furan ring (ring D), which was supposed to cause the differences in their inhibitions of CYP2C9 and CYP3A4 (Wang and Yeung 2011b). Miltirone showed moderate inhibition on CYP2C9 (Ki = 1.48[micro]M) through interaction via hydrogen bonding with Arg108 in the active cavity of CYP2C9 (Fig. 7b and f). Without ring D, miltirone also provided high binding affinity via ketone group at C-12 position with Arg108. It should be speculated that the ketone groups of other tanshinones may interact with Arg108, the key contributor for substrates/inhibitors binding of CYP2C9 (Polgar et at. 2007).

Previous study showed that only dihydrotanshinone moderately inhibited CYP2D6 with K1 value of 2.53 [micro]M, but the Ki values of tanshinone I, tanshinone HA and cryptotanshinone cannot be determined (Zhou et al. 2012b). Dihydrotanshinone also moderately inhibited CYP3A4 ([K.sub.i] = 2.1[micro]M), but the effects of tanshinone I, tan-shinone IIA and cryptotanshinone were very weak ([K.sub.i] > 86.9 [micro]M) (Wang et al. 2010). In this assay, miltirone weakly inhibited CYP2D6 ([K.sub.i] = 24.25 [micro]M) via Pi-Pi stacking interaction with Phe120 (Fig. 7c and g). This interaction was similar to that of dihydrotanshinone. It is, therefore, supposed that other tanshinones interacting with Phe120 in CYP2D6 crystal structure have inhibition potential on CYP2D6 activity, when performing molecular docking-based virtual screening. Miltirone weakly inhibited CYP3A4 (K1 = 35.09 [micro]M) and interacted with the amino residues of the active site via Van der Waals and polarity (Fig. 7d and h). The weak inhibitions by miltirone on CYP2D6 and CYP3A4 indicated that miltirone, as a minor portion, did not significantly involve in the inhibition on these two enzymes by Danshen extracts as shown previously (Wang and Yeung 2011a, 2012; Zhou et al. 2012b). Taken together, our results demonstrated that moderate drug-drug interactions of miltirone with clinically used drugs metabolized by CYP1A2 and CYP2C9 should be considered. Miltirone caused a lesser degree of drug-drug interactions than dihydrotanshinone with CYP2D6- and CYP3A4-metabolized drugs.

Conflict of interest

The authors have no conflict of interest to disclose.

* Corresponding author.

** Corresponding author. Tel.: +852 39436884: fax: +852 26035139.

E-mail addresses: zhouxuelin@cuhk.edu.hk. peterxlzhou@gmail.com (X. Zhou), yiuwakwan@cuhk.edu.hk (Y.W. Kwan).

0944-7113/$--see front matter [C] 2012 Elsevier GmbH. All rights reserved. http://dx.doi.org/10.1016/j.phymed.2012.09.021

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Xuelin Zhou (a),(*), Yan Wang (a), Tao Hu (a), Penelope M.Y. Or (a), John Wong (b), Yiu Wa Kwan (a),**, David C.C. Wan (a), Pui Man Hoi (c), Paul B.S. Lai (d), John H.K. Yeung (a)

(a.) School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T. Hong Kong, China

(b.) Department of Surgery. Prince of Wales Hospital, Shatin, N.T., Hong Kong, China

(c.) Institute of Chinese Medical Sciences. University of Macau, Macao. China

(d.) Department of Surgery. Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T. Hong Kong, China
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Author:Zhou, Xuelin; Wang, Yan; Hu, Tao; Or, Penelope M.Y.; Wong, John; Kwan, Yiu Wa; Wan, David C.C.; Hoi,
Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
Article Type:Report
Date:Feb 15, 2013
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