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Journal of Applied Biopharmaceutics and Pharmacokinetics, 2013, 1, 5-11 5
© 2013 Pharma Professional Services
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 Journal of Applied Biopharmaceutics and Pharmacokinetics, 2013, Vol. 1, No. 1 Chatuphonprasert et al.
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.
Inhibitory Potentials of Five Phytoestrogens Journal of Applied Biopharmaceutics and Pharmacokinetics, 2013, Vol. 1, No. 1 9
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.
10 Journal of Applied Biopharmaceutics and Pharmacokinetics, 2013, Vol. 1, No. 1 Chatuphonprasert et al.
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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