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Journal of Applied Biopharmaceutics and Pharmacokinetics, 2013, 1, 5-11 5

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Inhibitory Potentials of Five Phytoestrogens from Pueraria candollei var. mirifica on CYP1A1 and CYP1A2 Proteins in Mouse Liver Microsomes and in silico

Waranya Chatuphonprasert1,2, Kanokwan Jarukamjorn1,*, Waraporn Putalun1 and Thaweesak Juengwattanatrakul3

1Research Group for Pharmaceutical Activities of Natural Products using Pharmaceutical Biotechnology

(PANPB), Faculty of Pharmaceutical Sciences, National Research University-Khon Kaen University, Khon Kaen 40002, Thailand

2Faculty of Medicine, Mahasarakham University, Mahasarakham 44000, Thailand

3Faculty of Pharmaceutical Sciences, Ubon Ratchathani University, Ubon Ratchathani 34190, Thailand

Abstract: Pueraria candollei var. mirifica (PM) is a Thai traditional medicinal plant for rejuvenation and estrogen replacement therapy in menopausal women. CYP1A1 and CYP1A2 proteins are the members of hepatic cytochrome P450 (CYP) enzymes to activate a procarcinogen, in which ethoxyresorufin O-demethylase (EROD) and

methoxyresorufin O-demethylase (MROD) activities are the specific markers for CYP1A1 and CYP1A2, respectively. In the present study, the effects of five phytoestrogens isolated form the bark of PM tuberous roots namely miroestrol, deoxymiroestrol, khawkhurin, isomiroestrol, and methoxyisomiroestrol, on EROD and MROD activities were examined in

mouse hepatic microsomes, compared to a typical CYP1A1/2 inducer and substrate beta-napthoflavone (BNF). The bindings of these five compounds to either CYP1A1 or CYP1A2 enzymes were analyzed using molecular docking with homology modeling technique. Rank of the median inhibitory concentration (IC50) of these compounds on EROD activity

corresponded to that of MROD, namely BNF > miroestrol > kwakhurin > deoxymiroestrol > methoxymiroestrol> isomiroestrol, respectively. Interestingly, the binding pose energy of these compounds to CYP1A1 and CYP1A2 proteins were consistent to those of inhibitory effects on EROD and MROD activities. The observations suggested for the first

time that the active phytoestrogens from PM possessed inhibitory potentials on CYP1A1 and CYP1A2 via EROD and MROD activities, respectively. Furthermore, the binding energy of the compounds to CYP1A1 and CYP1A2 proteins might be a useful tool to predict the effects of a compound on these two CYP enzymes.

Keywords: Pueraria candollei var. mirifica, phytoestrogen, miroestrol, kwakhurin, CYP1A1, CYP1A2.

1. INTRODUCTION

Cytochrome P450 monooxygenase (CYP) is a

supergene family of enzymes involved in the

metabolism of numerous endogenous and exogenous

compounds [1]. CYP plays important roles in the

metabolism of many drugs and in the activation of

several chemical toxicants and carcinogens in both

humans and animals [2]. The subfamily 1A of CYP

(CYP1A) consists of two enzymes: CYP1A1 and

CYP1A2. CYP1A1 is not significantly expressed in the

liver but constitutively expressed in several other

extrahepatic tissues, whereas CYP1A2 is constitutively

and inducibly expressed specifically in the liver [3].

CYP1A inactivates some chemical carcinogens and

environmental contaminants by converting the

substrates to more polar metabolites, resulting in

increased excretion. In contrast, this metabolic

activation may generate other potent carcinogens. For

example, catalyzing the oxygenation of carcinogenic

polycyclic aromatic hydrocarbons [4] which are found in

*Address correspondence to this author at the Faculty of Pharmaceutical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand; Tel/Fax: +66-43-202305; E-mail: [email protected]

combustion products [5], and the conversion of

heterocyclic aromatic amines/amides to epoxide and

other electrophilic reactive species (ultimate

carcinogens) cause DNA or protein adducts, which

lead to tumor formation and toxicity [6]. The activities of

CYP1A1 and CYP1A2 are widely measured as a rate

of the O-dealkylation of 7-ethoxyresorufin (ER) and 7-

methoxyresorufin (MR) for EROD and MROD,

respectively [7].

Pueraria candollei var. mirifica (PM) is a Thai

traditional medicinal plant for rejuvenation and estrogen

replacement therapy in menopausal women. The

extensive researches have informed the

pharmacological effects of this plant, such as

stimulating effects on the luteinizing hormone (LH) and

the follicle-stimulating hormone (FSH) in

gonadectomized rats [8], inhibitory effect on ovulation

in monkeys [9], and anti-oxidation properties in

ovariectomized mice [10]. There are several

phytoestrogens from tuberous roots of PM, i.e.,

miroestrol, isomiroestrol, and deoxymiroestrol, and

isoflavonoids, i.e., puerarin, daidzin, daidzein, genistin,

and genistein [11-12]. The crude extract of PM inhibited

MROD activity in rats [13]. Moreover, miroestrol and

6 Journal of Applied Biopharmaceutics and Pharmacokinetics, 2013, Vol. 1, No. 1 Chatuphonprasert et al.

deoxymiroestrol suppressed CYP1A2 mRNA and

MROD activity in mouse livers [14]. However, the

information of others phytoestrogens from PM is still

incomplete. Therefore, impacts of five phytoestrogens

namely miroestrol, deoxymiroestrol, khawkhurin,

isomiroestrol, and methoxyisomiroestrol, on EROD and

MROD activities were examined in mouse liver

microsomes, compared to a typical CYP1A1/2 inducer

and substrate beta-napthoflavone (BNF). In addition,

docking analysis of these five compounds with either

CYP1A1 or CYP1A2 models were determined. These

data might be helpful in further understanding the role

of PM in phytoestrogen supplement therapy.

2. MATERIALS AND METHODS

2.1. Materials

Beta-naphthoflavone (BNF), resorufin,

ethoxyresorfin, and methoxyresorufin were purchased

from Sigma Chemicals (St Louis, MO, USA). The

tuberous roots of Pueraria candollei var. mirifica (PM)

were collected in Ubon Ratchathani, Thailand, in March

2010. Reference specimens (NIPSKKU007-010) were

deposited at the Herbarium of the Faculty of

Pharmaceutical Sciences, Khon Kaen University,

Thailand. Five phytoestrogens including miroestrol,

deoxymiroestrol, khawkhurin, isomiroestrol, and

methoxyisomiroestrol were extracted and purified from

the tuberous roots of PM as described [10,15]. NMR

identifications were performed, and the results were

compared with authentic standards provided Dr.

Chaiyo Chaichantipyuth, Chulalongkorn University,

Thailand.

2.2. Animal Treatment and Preparation of Liver Microsomes

The seven-week-old male ICR mice were

intraperitoneally administered beta-naphthoflavone

(BNF; 30 mg/kg/day) in corn oil for three consecutive

days. Mice were treated according to a research

protocol approved by the Animal Ethics Committee for

Use and Care of Khon Kaen University, Khon Kaen,

Thailand (Approval No. AEKKU01/2554). The mice

were killed 24 h after the last treatment, and the livers

were immediately excised to prepare microsomes as a

source of the cytochrome P450 enzymes [16]. Briefly,

the livers were sliced using scissor on the ice and

homogenized in 1.15% potassium chloride in the ice-

cooled bath. The liver homogenate was centrifuged at

10,000 g for 10 min at 4°C. The supernatant was

collected for ultra-centrifugation at 104,000 g for 60

min at 4°C. The pellet of microsome was reconstituted

with cold distilled water. The protein concentration of

microsome was determined by the method of Bradford

[17].

2.3. Determination of Ethoxy- (EROD) and Methoxy- (MROD) Resorufin O-Dealkylations

The assessment of EROD and MROD activities

were performed by the method of Sakuma et al. [18]

with modifications. Briefly, a reaction mixture containing

an aliquot of five phytoestrogens or BNF (concentration

ranged from 25 to 1,000 g/ml), 3mM Tris–HCl (pH

7.8), 50 mM NADPH, 5 mg protein of liver microsomes,

and 0.625 mM ethoxyresorufin or methoxyresorufin, in

a final volume of 200 ml was incubated at 37°C. The

formation of resorufin was immediately analyzed by

spectrofluorometry with an excitation wavelength of

520 nm and an emission wavelength of 590 nm,

compared with the resorufin standard [17]. The median

inhibitory concentration (IC50) of each phytoestrogen

was extrapolated using the Probit analysis with the

SPSS 11.5 software [19].

2.4. Homology Modeling and Docking Analysis

The three-dimensional structures of mouse

CYP1A1 and CYP1A2 were constructed using a

homology modeling method. Human microsomal

cytochrome P450 1A2 protein (PDB code: 2HI4) was

selected to be the template because of its highest

identity (69%) and positive matching (83%) for mouse

CYP1A1 and 73% identity and 88% positive matching

for mouse CYP1A2 from SWISS-MODEL analysis [20].

The primary amino acid sequences of mouse CYP1A1

(NP_001129531.1) and CYP1A2 (NP_034123.1) were

fixed to the template using Swiss-PdbViewer 4.0.1, to

generate the mouse CYP1A1 and CYP1A2 model. The

three-dimensional (3D) structures of BNF and the five

phytoestrogen including kwakhurin, miroestrol,

deoxymiroestrol, isomiroestrol, and

methoxyisomiroestrol were constructed and justified for

docking analysis using ArgusLab 4.0.1 (available on

the World Wide Web). All compounds were analyzed

using a docking box 40 40 40 angstroms centered

at the approximate center of mouse CYP1A1 or

CYP1A2 models. We employed the GAdock docking

engine, a genetic algorithm search technique

implemented in ArgusLab [21]. To set up the docking

parameters, calculations were made with the following

values: population size 100, generations 10,000,

mutation rate 0.02, grid resolution 0.4, and flexible

ligand mode. Other parameters were kept with the

Inhibitory Potentials of Five Phytoestrogens Journal of Applied Biopharmaceutics and Pharmacokinetics, 2013, Vol. 1, No. 1 7

default setting. After docking, structures of CYP1A1 or

CYP1A2 and ligands were identified for binding site, H-

bond, and pseudobind using Swiss-PdbViewer 4.0.1

and UCSF Chimera software [22].

3. RESULTS

3.1. Effects of Phytoestrogens on EROD and MROD Activities

EROD and MROD activities were marker enzymatic

reactions for functional works of CYP1A1 and CYP1A2

protein, respectively. Table 1 displayed the IC50 of

compounds on EROD and MROD activities in vitro in

liver microsome. BNF, a typical inducer and substrate

of CYP1A, showed the lowest IC50 for both EROD and

MROD. Inhibitory effects of phytoestrogens were

miroestrol > kwakhurin > deoxymiroestrol >

methoxyisomiroestrol > isomiroestrol in both EROD

and MROD activities. Among these five phytoestrogens

from PM, miroestrol showed the highest potential to

inhibit EROD and MROD activities. Therefore, it is

interesting to further compare the effects of these five

compounds on CYP1A1 and CYP1A2 protein in silico

using molecular docking.

3.2. Molecular Docking of BNF and Five Phytoestrogens from PM to Mouse CYP1A1 and CYP1A2

The ligand binding pose energy between

compounds and mouse CYP1A1 protein was showed

in Table 2. The strength of ligand interaction with

mouse CYP1A1 was miroestrol > kwakhurin > BNF >

deoxymiroestrol > methoxyisomiroestrol > isomiroestrol

with binding pose energy -12.68, -10.13, -9.47, -9.27, -

Figure 1: The structure of five phytoestrogens from Pueraria candollei var. mirifica and beta-napthoflavone.

Table 1: IC50 Values of BNF and Phytoestrogens Isolated from P. candollei var. mirifica on EROD and MROD Enzymes Activities

IC50a ( g/ml)

Compounds EROD

b MROD

b

BNFc < 0.001 0.020 + 0.001

Miroestrol 57.29 + 5.791 19.24 + 0.913

Deoxymiroestrol 128.6 + 12.40 518.4 + 22.30

Kwakhurin 70.55 + 14.11 332.0 + 22.13

Isomiroestrol 543.2 + 88.00 5933 + 366.1

Methoxyisomiroestrol 144.6 + 19.40 1216 + 461.5

aIC50 (median inhibitory concentration) values are expressed as the means+SD (n=4-5) from triplicate independent experiments.

bEROD, ethoxyresorufin O-deethylase; MROD, methoxyresorufin O-demethylase.

cBNF, beta-naphthoflavone, is a specific substrate of enzyme reactions responsible for EROD and MROD, and employed as a positive control.


8.37, and -8.20 kcal/mol, respectively. The order of

binding pose energy corresponded with their inhibitory

potencies on EROD activity, except BNF (Table 1). The

active sites of each ligand are showed in Figure 2.

Within 3 angstrom, BNF was surrounded with TYR263

(H-bond), LYS267, THR313, ILE312, and LYS123

residues (Figure 2A) while kwakhurin was with

THR117, TYR114, LEU118, THR120, LYS 256, and

TYR263 residues (Figure 2B). Miroestrol was

surrounded with CYS461 (H-bond), THR325 (H-bond),

PHE380, PHE454, LEU453, and ALA329 (Figure 2C).

Deoxymiroestrol was encircled with THR126 (H-bond),

GLY320, ILE390, PHE228, ASP324, and SER225

(Figure 2D). Isomiroestrol and methoxyisomiroestrol

were occupied in the similar region, consisting of

TYR263 (H-bond), ASP260 (H-bond), and ASN121

residues (Figure 2E-2F).

Table 2: Ligand Binding Pose Energy Between BNF Phytoestrogens Isolated from P. candollei var. mirifica with CYP1A1 or CYP1A2 Proteins

Ligand binding pose energy (kcal/mol)a

Compounds CYP1A1 CYP1A2

BNF -9.470 -13.34

Kwakhurin -10.13 -7.234

Miroestrol -12.68 -7.551

Deoxymiroestrol -9.270 -7.112

Isomiroestrol -8.201 -6.759

Methoxyisomiroestrol -8.373 -6.808

aThe value of ligand binding pose energy between each compound to CYP1A1 or CYP1A2 expressed the best from triplicate independent experiments.

Figure 2: The docking calculation and binding sites of BNF or the five phytoestrogens and mouse CYP1A1 protein. Mouse CYP1A1 model was docked with BNF (A), kwakhurin (B), miroestrol (C), deoxymiroestrol (D), isomiroestrol (E), and methoxyisomiroestrol (F) using ArgusLAb 4.0.1 program as described in section 2.4. Binding site of each compound was clarified using Swiss-PdbViewer 4.0.1 and UCSF Chimera software. The magenta color displayed the residues within 3 angstrom closed to each ligand. The blue dash line represented the H-bond while yellow lines were other bonds.


The ligand binding pose energy between

compounds and mouse CYP1A2 protein was showed

in Table 2. The strength of ligand interaction with

mouse CYP1A2 was BNF >> miroestrol > kwakhurin >

deoxymiroestrol > methoxyisomiroestrol > isomiroestrol

with binding pose energy -13.34, -7.55, -7.23, -7.11, -

6.81, and -6.76 kcal/mol, respectively. The order of

binding pose energy corresponded with their inhibitory

potencies on MROD activity (Table 1). The active sites

of each ligand are showed in Figure 3. Within 3

angstrom, BNF was surrounded with LEU330, TRP334,

TYR376, PHE425, and PHE423 residues with several

pseudobond between carbons atom (yellow line)

without H-bond (Figure 3A) while kwakhurin was with

GLU416, VAL424, and PHE423 residues (Figure 3B).

Miroestrol was surrounded with THR319, VAL320,

VAL380, THR383, LEU448, GLY450, and CYS456 (H-

bond) (Figure 3C). Deoxymiroestrol was encircled with

THR65 (H-bond), ARG66 (H-bond), LEU62, TRP410,

PHE423, and TYR376 (Figure 3D). Isomiroestrol was

occupied with PHE423 and PRO422 residues (Figure

3E). Methoxyisomiroestrol was surrounded with

LYS440, LEU371, and VAL446 (Figure 3F).

These observations suggested that differences of

structures and active sites affected the binding energy

between the ligands and mouse CYP1A1 or CYP1A2,

leading to varied inhibitory effects on EROD and

MROD activities, respectively. H-bond did not show

significant relationship with the ligand binding energy.

However, the numerous pseudobonds (C-C, C-O, and

others) might be a key factor determined the strength

between a ligand and protein (Figure 3A).

4. DISCUSSIONS

Activities of CYP1A1 and CYP1A2 are widely

measured as a rate of EROD and MROD [7]. CYP1A1

is involved in the carcinogenesis process [23] while

CYP1A2 is involved in metabolism of N-heterocyclics

amine and arylamines. Emerging evidence from

Cyp1a1(-/-) knockout mice has demonstrated hepatic

Figure 3: The docking calculation and binding sites of BNF or the five phytoestrogens and mouse CYP1A2 protein. Mouse CYP1A2 model was docked with BNF (A), kwakhurin (B), miroestrol (C), deoxymiroestrol (D), isomiroestrol (E), and methoxyisomiroestrol (F) using ArgusLAb 4.0.1 program as described in section 2.4. Binding site of each compound was clarified using Swiss-PdbViewer 4.0.1 and UCSF Chimera software. The cyan color displayed the residues within 3 angstrom closed to each ligand. The white dash line represented the H-bond while yellow lines were other bonds.


CYP1A1 and CYP1A2 are very important in

detoxication [24-25]. Furthermore, extensive

researches reported that CYP1A1 and CYP1A2 were

regulated via the aryl hydrocarbon receptor (AhR) [23].

The crude extract of PM decreased MROD activity in

rats [13], accordance with the study of Udomsuk [14],

in which miroestrol and deoxymiroestrol suppressed

CYP1A2 mRNA and MROD activity in mouse livers.

This is the first time to report the effects of miroestrol

and deoxymiroestrol on EROD activity. In addition,

kwakhurin, isomiroestrol, and methoxyisomiroestrol

possessed the inhibitory effects on both EROD and

MROD activities. Deoxymiroestrol suppressed the

expression of AhR and CYP1A1 mRNA in primary

mouse hepatocytes [26]. Therefore, the inhibitory

effects of these five phytoestrogens from PM on EROD

and MROD activities might associate with AhR. The

relationship between CYP1A and cancer risk has been

widely noted [27-28].

The crystal structure of human CYP1A2 (PDB:

2HI4) and molecular docking was a useful tool to

predict the interaction between an herbal compound

and CYP1A2 protein [29]. The homology model of

CYP1A1 from human, developed on the basis of

template crystal structure of human microsomal

CYP1A2 (PDB: 2HI4), and the binding of a ligand with

the model of CYP1A1 was developed for searching of

anticancer agents [30]. Until now, there is no report

regarding the qualitative structure activity relationship

(QSAR) approach of phytoestrogens from PM. We

found that the binding pose energy of these five

compounds and the model of CYP1A1 and CYP1A2

were consistent with their inhibitory effects on EROD

and MROD, though, the binding pose energy of BNF

and CYP1A1 model was weak, in contrast to the IC50

on EROD activity. The different binding sites with

different compounds might be reasons for this

phenomenon. However, the binding pose energy

between phytoestrogens and the CYP1A1 model was

related to the EROD inhibition. The binding pose

energy of BNF to the CYP1A2 model was very low

(Table 2), correlated to the several pseudobonds in the

complex (Figure 3A). Miroestrol showed the highest

potency to inhibit and bind to CYP1A1 and CYP1A2

protein. Hence, the OH-group at C-14 position might

play the key role for CYP1A inhibition. The loss of OH-

group in deoxymiroestrol significantly changed the

inhibitory effects on both EROD and MROD activities.

Furthermore, a substitute group (-OH or -CH3) at C-7

position of isomiroestrol and methoxyisomiroestrol

decreased the inhibitory effects on EROD and MROD

as well as the binding energy with CYP1A model.

However, the structure of kwakhurin was not similar to

others. The good inhibitory effect of kwakhurin might be

explained by its planar structure, leading to be easily

approach to CYP1A protein. Thus, the QSAR study of

these five phytoestrogens with other models and

methods is further required.

These observations suggested that the five

phytoestrogens from PM might potentially decrease the

risk of carcinogenesis due to inhibition of CYP1A

oxidative metabolic activity pathway. Moreover, the

molecular docking and the binding pose energy of a

compound to CYP1A1 and CYP1A2 proteins might be

a useful tool to predict the effect of the compound on

these two CYP enzymes.

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Received on 10-05-2013 Accepted on 08-06-2013 Published on 12-07-2013

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