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Xenobiotica
the fate of foreign compounds in biological systems
ISSN: 0049-8254 (Print) 1366-5928 (Online) Journal homepage: http://www.tandfonline.com/loi/ixen20
Inhibition behavior of fructus psoraleae’s
ingredients towards human carboxylesterase 1
(hCES1)
Dong-Xue Sun, Guang-Bo Ge, Pei-Pei Dong, Yun-Feng Cao, Zhi-Wei Fu, Rui-
Xue Ran, Xue Wu, Yan-Yan Zhang, Hui-Ming Hua, Zhenying Zhao & Zhong-Ze
Fang
To cite this article: Dong-Xue Sun, Guang-Bo Ge, Pei-Pei Dong, Yun-Feng Cao, Zhi-Wei Fu,
Rui-Xue Ran, Xue Wu, Yan-Yan Zhang, Hui-Ming Hua, Zhenying Zhao & Zhong-Ze Fang (2015):
Inhibition behavior of fructus psoraleae’s ingredients towards human carboxylesterase 1
(hCES1), Xenobiotica, DOI: 10.3109/00498254.2015.1091521
To link to this article: http://dx.doi.org/10.3109/00498254.2015.1091521
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Published online: 11 Nov 2015.
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ISSN: 0049-8254 (print), 1366-5928 (electronic)
Xenobiotica, Early Online: 1–8
!2015 Taylor & Francis. DOI: 10.3109/00498254.2015.1091521
RESEARCH ARTICLE
Inhibition behavior of fructus psoraleae’s ingredients towards human
carboxylesterase 1 (hCES1)
Dong-Xue Sun
1
, Guang-Bo Ge
2
, Pei-Pei Dong
3
, Yun-Feng Cao
4,5
, Zhi-Wei Fu
4,5
, Rui-Xue Ran
6
, Xue Wu
4,5
,
Yan-Yan Zhang
4,7
, Hui-Ming Hua
1
, Zhenying Zhao
8
, and Zhong-Ze Fang
9
1
School of Traditional Chinese Medicine, Shenyang Pharmaceutical University, Shenyang, China,
2
Laboratory of Pharmaceutical Resource
Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China,
3
Institute of Integrative Medicine, College of Pharmacy,
Dalian Medical University, Dalian, China,
4
Joint Center for Translational Medicine, Dalian Institute of Chemical Physics, Chinese Academy of
Sciences and the First Affiliated Hospital of Liaoning Medical University, Dalian, China,
5
Joint Center for Translational Medicine, Dalian Institute of
Chemical Physics, Chinese Academy of Sciences and the Affiliated Zhongshan Hospital of Dalian University, Zhongshan, Dalian, China,
6
School of
Pharmacy, Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), Tianjin Medical
University,
7
The First Affiliated Hospital of Liaoning Medical University, Jinzhou, Liaoning, China,
8
Department of Pharmacy, Tianjin Union Medicine
Centre, Tianjin, China, and
9
Department of Toxicology, School of Public Health, Tianjin Medical University, Heping, Tianjin, China
Abstract
1. Fructus psoraleae (FP) is the dried ripe seeds of Psoralea corylifolia L. (Fabaceae) widely used
in Asia, and has been reported to exert important biochemical and pharmacological
activities. The adverse effects of FP remain unclear. The present study aims to determine the
inhibition of human carboxylesterase 1 (CES1) by FP’s major ingredients, including
neobavaisoflavone, corylifolinin, coryfolin, psoralidin, corylin and bavachinin.
2. The probe substrate of CES1 2-(2-benzoyl-3-methoxyphenyl) benzothiazole (BMBT) was
derived from 2-(2-hydroxy-3-methoxyphenyl) benzothiazole (HMBT), and human liver
microsomes (HLMs)-catalyzed BMBT metabolism was used to phenotype the activity of
CES1. In silico docking method was employed to explain the inhibition mechanism.
3. All the tested compounds exerted strong inhibition towards the activity of CES1 in a
concentration-dependent behavior. Furthermore, the inhibition kinetics was determined for
the inhibition of neobavaisoflavone, corylifolinin, coryfolin, corylin and bavachinin towards
CES1. Both Dixon and Lineweaver–Burk plots showed that neobavaisoflavone, corylifolinin,
coryfolin and corylin noncompetitively inhibited the activity of CES1, and bavachinin
competitively inhibited the activity of CES1. The inhibition kinetic parameters (K
i
) were
calculated to be 5.3, 9.4, 1.9, 0.7 and 0.5 mM for neobavaisoflavone, corylifolinin, coryfolin,
corylin and bavachinin, respectively. In conclusion, the inhibition behavior of CES1 by the
FP’s constituents was given in this article, indicating the possible adverse effects of FP
through the disrupting CES1-catalyzed metabolism of endogenous substances and
xenobiotics.
Keywords
Fructus psoraleae, herb–drug interaction,
human carboxylesterase 1 (CES1), toxicity
History
Received 21 July 2015
Revised 2 September 2015
Accepted 3 September 2015
Published online 9 November 2015
Introduction
Fructus psoraleae (FP) is the dried ripe seeds of Psoralea
corylifolia L. (Fabaceae) widely used in Asia. The biological
and pharmacological functions contain the alleviation of
asthma and diahhrea, treatment of osteoporosis, osteomalacia,
bone fracture, and some kind of skin diseases (Lau et al.,
2014; Li et al., 2014; Wang et al., 2015). Some adverse effects
have been reported with the clinical application of FP,
including FP-induced hepatotoxicity (Cheung et al., 2009).
Human carboxylesterase 1 (CES1), one of the most
important isoforms of carboxylesterases (CEs, E.C. 3.1.1.1),
is mainly expressed in the liver, and also exerts some
expression in intestine, kidney, lung and other organs
(Sanghani et al., 2009). CES1 mainly catalyzes the release
process of alcohol substituent and acyl group from the
substrates (Satoh & Hosokawa, 2006). CES1 exhibits import-
ant lipid metabolism regulation role due to its triglyceride (TG)
and cholesterol ester (CE) hydrolase activity (Ko et al., 2009).
CES1 also catalyzes the biotransformation of many clinical
drugs, such as oseltamivir, dabigatran etexilate, pethidine and
clopidogrel (Laizure et al., 2014; Tarkiainen et al., 2015; Zhang
et al., 1999; Zhu & Markowitz, 2013). The inhibition of CES1
Address for correspondence: Pei-Pei Dong, Institute of Integrative
Medicine, College of Pharmacy, Dalian Medical University, Lvshun
South Road No 9, Dalian 116044, China. E-mail: dongpeipei11@163.com
Zhong-Ze Fang, Department of Toxicology, School of Public Health,
Tianjin Medical University, 22 Qixiangtai Road, Heping District, Tianjin
300070, China. E-mail: fangzhongze@tmu.edu.cn
Downloaded by [Dalian Institute of Chemical Physics] at 21:01 12 November 2015
might disrupt the metabolism of endogenous substances and
xenobiotics. Our previous study has shown that FP and its
major ingredients strongly inhibit the activity of human
carboxylesterase 2 (Li et al., 2015). Therefore, we tried to
find the inhibitors of CES1, and the inhibition of major
constituents from FP towards CES1 was observed.
The present study aims to investigate the inhibition of
CES1 activity by the major ingredients of FP, including
neobavaisoflavone, corylifolinin, coryfolin, psoralidin, cory-
lin and bavachinin.
Materials and methods
Chemicals and reagents
The probe substrate of CES1 2-(2-benzoyl-3-methoxyphenyl)
benzothiazole (BMBT) was derived from 2-(2-hydroxy-3-
methoxyphenyl) benzothiazole (HMBT), and synthesized as
previously described (Liu et al., 2014). About 50 mM Tris–
HCl (pH = 7.4) was obtained from Sigma-Aldrich (St. Louis,
MO). Compounds neobavaisoflavone, corylifolinin, coryfolin,
psoralidin, corylin and bavachinin were purchased from
Sichuan Weikeqi Company (Chengdu, Sichuan, China). The
purity of these compounds was >95%. All other reagents were
of HPLC grade or of the highest grade commercially
available.
Inhibition capability evaluation towards CES1
The incubation mixture for profiling the activity of CES1 was
described as previously described (Liu et al., 2014). In brief,
the incubation system is consisted of 50 mM Tris–HCl
(pH = 7.4), 4 mg/mL of human liver microsomes, the specified
concentration of BMBT, and various concentrations of
compounds from FP. The reactions were initiated through
the addition of BMBT, and terminated through adding the
equal volume of ice-cold acetonitrile. After the centrifugation
at 14 300 rpm for 20 min, the supernatants (10 mL) were
injected into the ultra-performance liquid chromatography
(UPLC) for analysis. UPLC analysis was performed on a
Waters ACQUITY UPLC System equipped with photodiode
array (PDA) detector, and the separation of all the compounds
was carried out using BEH C18 column (2.1 100 mm,
1.7 mm particle size). Mobile phase A was pure water with
formic acid (v/v: 0.2%), and freshly prepared for every
analysis set. Mobile phase B was acetonitrile. The elution
condition was optimized to be 70% phase B, and the flow rate
was 0.2 mL/min. The detection wavelength was 300 nm. The
standard curve was generated by peak area versus the
concentration range of BMBT 0.5–80 mM. The curve was
linear over this concentration range with the r
2
>0.99. We
force the calibration equation through zero because we
assume no HPLC response when no metabolite exists. The
fitting equation was y= 6487.3x. The percentage of relative
standard deviation (% RSD) for precision and accuracy of the
HPLC method was found to be 52%.
Inhibition kinetics determination
The reaction velocity was determined at multiple concentra-
tions of BMBT and the inhibitors. Lineweaver–Burk and
Dixon fitting equations were employed to determine the
inhibition type, and the second plot (drawing using the slope
of lines from the Lineweaver–Burk plot versus the concen-
trations of inhibitors) was used to calculate the inhibition
kinetic parameters (K
i
).
Structure preparation and molecular docking
The crystal structure of human carboxylesterase 1 was
received from Protein Data Bank, and the PDB ID is
2HRR. This structure needed to be optimized via steepest
descent and conjugate gradient method, and then it was used
for molecular docking study. AutoDock Version 4.2 was used
for molecular docking simulation, further exploring the
interactions between ligand and enzyme. Ligands neobavaiso-
flavone, corylifolinin, coryfolin, psoralidin, corylin and
bavachinin were docked into human carboxylesterase 1, and
the binding pocket was centered on the active site of human
carboxylesterase 1. The nonpolar hydrogen atoms of human
carboxylesterase 1 were merged, and this enzyme was added
Kollman charges. The six ligands with nonpolar hydrogen
hydrogens were assigned with Gasteiger charges. The grid
points were set to 70 70 70 with grid point spacing
0.375 A
˚. For simulating the protein-fixed ligand-flexible
docking calculations, the Lamarckian Genetic Algorithm
(LGA) was performed. The population size was set to 50. The
best conformation was selected based on the lowest docking
energy. The interactions including hydrogen bonds and
hydrophobic contacts between ligand and enzyme were
analyzed.
Results
The inhibition of FP’s ingredients towards CES1
About 100 mM of FP’s ingredients was firstly used to screen
the inhibition potential towards the activity of CES1, and the
results were given in Figure 1. All the tested FP’s ingredients
exhibited strong inhibition towards CES1, and the inhibition
capability was Neobavaisoflavone corylin >bavachinin >
coryfolin >corylifolinin >psoralidin. Furthermore, the con-
centration-dependent inhibition of these compounds towards
CES1 was demonstrated (Figure 2).
Figure 1. Initial screening of the inhibition of FP’s ingredients towards
the activity of human carboxylesterase 1 (CES1). About 100 mMof
compounds were used.
2D.-X. Sun et al. Xenobiotica, Early Online: 1–8
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The inhibition kinetic behavior of FP’s ingredients
towards CES1
As shown in Figures 3(A), 4(A), 5(A) and 6(A), the
intersection point was located in the horizontal axis in
Dixon plot, indicating the noncompetitive inhibition of
neobavaisoflavone, corylifolinin, coryfolin and corylin
towards the activity of CES1. Furthermore, the Lineweaver–
Burk plot (Figures 3B, 4B, 5B and 6B) also demonstrated this
finding. For the inhibition of bavachinin towards the activity
of CES1, the intersection point was located in the second
quadrant in Dixon plot (Figure 7A), and the vertical axis in
Lineweaver–Burk plot (Figure 7B), indicating the competitive
inhibition of bavachinin towards CES1. According the second
plot, the fitting equation was y= 0.0073x+ 0.0386 (Figure
3C), y= 0.0053x+0.05 (Figure 4C), y= 0.0138x+ 0.0265
(Figure 5C), y= 0.0393x+0.0279 (Figure 6C) and
y= 0.0156x+ 0.0085 (Figure 7C) for the inhibition of
Figure 3. Inhibition kinetics of neobavaisoflavone towards the activity of human carboxylesterase 1 (CES1). (A) Dixon plot for the inhibition of
neobavaisoflavone towards the activity of CES1; (B) Lineweaver–Burk plot for the inhibition of neobavaisoflavone towards the activity of CES1 and
(C) The second plot for the inhibition of neobavaisoflavone towards the activity of CES1. The second plot was drawn using the slope of lines from
Lineweaver–Burk plot versus the concentrations of compound.
Figure 2. Dose-dependent inhibition of FP’s
ingredients towards the activity of human
carboxylesterase 1 (CES1).
DOI: 10.3109/00498254.2015.1091521 Inhibition of hCES1 by Fructus psoraleae 3
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neobavaisoflavone, corylifolinin, coryfolin, corylin and bava-
chinin towards the activity of CES1. The inhibition kinetic
parameters (K
i
) were calculated to be 5.3, 9.4, 1.9, 0.7 and
0.5 mM (Table 1) for neobavaisoflavone, corylifolinin, cor-
yfolin, corylin and bavachinin, respectively.
Molecular docking to understanding the interaction
mechanism
The binding conformations of the six compounds with CES1
were given in supplemental Figure 1, showing the binding
Figure 5. Inhibition kinetics of coryfolin towards the activity of human carboxylesterase 1 (CES1). (A) Dixon plot for the inhibition of coryfolin
towards the activity of CES1; (B) Lineweaver–Burk plot for the inhibition of coryfolin towards the activity of CES1 and (C) The second plot for the
inhibition of coryfolin towards the activity of CES1. The second plot was drawn using the slope of lines from Lineweaver–Burk plot versus the
concentrations of compound.
Figure 4. Inhibition kinetics of corylifolinin towards the activity of human carboxylesterase 1 (CES1). (A) Dixon plot for the inhibition of corylifolinin
towards the activity of CES1; (B) Lineweaver–Burk plot for the inhibition of corylifolinin towards the activity of CES1 and (C) The second plot for
the inhibition of corylifolinin towards the activity of CES1. The second plot was drawn using the slope of lines from Lineweaver–Burk plot versus the
concentrations of compound.
4D.-X. Sun et al. Xenobiotica, Early Online: 1–8
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Figure 7. Inhibition kinetics of bavachinin towards the activity of human carboxylesterase 1 (CES1). (A) Dixon plot for the inhibition of bavachinin
towards the activity of CES1; (B) Lineweaver–Burk plot for the inhibition of bavachinin towards the activity of CES1 and (C) The second plot for the
inhibition of bavachinin towards the activity of CES1. The second plot was drawn using the slope of lines from Lineweaver–Burk plot versus the
concentrations of compound.
Figure 6. Inhibition kinetics of corylin towards the activity of human carboxylesterase 1 (CES1). (A) Dixon plot for the inhibition of corylin towards
the activity of CES1; (B) Lineweaver–Burk plot for the inhibition of corylin towards the activity of CES1 and (C) The second plot for the inhibition of
corylin towards the activity of CES1. The second plot was drawn using the slope of lines from Lineweaver–Burk plot versus the concentrations of
compound.
DOI: 10.3109/00498254.2015.1091521 Inhibition of hCES1 by Fructus psoraleae 5
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pocket in CES1 for these compounds is composed of amino
acids residues Asp90, Lys92, Ala93, Gly94, Gln95, Leu96,
Leu97, Ser98, Phe101, Gly141, Gly142, Gly143, Leu144,
Met145, Val146, Glu220, Ser221, Ala222, Gly223, Gly224,
Glu225, Ser226, Der247, Gly248, Val249, Thr252, Val254,
Leu255, Lys302, Phe303, Leu304, Ser305, Leu306, Leu318,
Glu354, Phe355, Leu358, Ile359, Met361, Leu363, Met364,
Ser365, Leu388, Met425, Phe426 and His468. In the binding
pocket of CES1, the hydrogen bonds were formed with
inhibitors neobavaisoflavone, corylifolinin, coryfolin, psora-
lidin, corylin and bavachinin. Residues Ser221, Leu304,
Leu363 and His468 made hydrogen bonds to neobavaiso-
flavone (Figure 8A). CES1 formed two hydrogen bonds with
corylifolinin via residues Ala93 and Ser221 (Figure 8B).
Residues Leu304 formed one hydrogen bond with coryfolin
(Figure 8C). The amino acids residues Ser221 and Leu304
in CES1 formed two hydrogen bonds with psoralidin
(Figure 8D). Residue Ser221 formed one hydrogen bond
with corylin (Figure 8E). Residue Ala93 formed one hydrogen
bond with bavachinin (Figure 8F). Besides the hydrogen
bonds, a set of residues formed hydrophobic contacts with
inhibitors in the binding pocket of CES1. Among these,
fourteen residues formed hydrophobic interactions with
neobavaisoflavone, including residues Ala93, Gly143,
Ser221, Val254, Leu255, Leu304, Leu318, Ile359, Leu363,
Met364, Leu388, Met425, Phe426 and His468. Corylifolinin
made hydrophobic contacts with residues Ala93, Leu97,
Gly143, Val146, Ser221, Val254, Leu255, Leu304, Ile359,
Leu363 and Phe426. Coryfolin formed hydrophobic inter-
actions with thirteen residues, including residues Ala93,
Leu97, Phe101, Gly142, Gly143, Val146, Ser221, Leu304,
Leu358, Ile359, Leu363, Met364 and His468. Psoralidin
formed hydrophobic contacts with residues Ala93, Leu97,
Gly142, Gly143, Val146, Thr252, Val254, Leu255, Leu304,
Ile359, Leu363, Met364, Met425 and Phe426. Corylin formed
hydrophobic contacts with only nine residues, including
Lys92, Ala93, Leu96, Leu97, Gly142, Val146, Leu304, Ile359
and Leu363. In addition, bavachinin formed hydrogen bonds
with residues Ala93, Leu97, Gly143, Val146, Ser221, Glu225,
Thr252, Val254, Leu255, Leu304, Leu318, Ile359, Leu363,
Met425 and Phe426 (Figure 9).
Discussion
The safety of herbs is drawing more and more attentions with
the more and more popularity, including the toxicity of herbs
themselves and possible co-administration risk. Our present
study demonstrated the strong inhibition of major ingredients
of FP towards CES1. The compounds neobavaisoflavone,
Figure 8. The formation of hydrogen bonds between CES1 and neobavaisoflavone (A), corylifolinin (B), coryfolin (C), psoralidin (D), corylin (E) and
bavachinin (F).
Table 1. The inhibition kinetic types and parameters, and the proposed
threshold of total systemic maximum plasma concentration (C
max
)for
DDI of five bioactive compounds in FP towards CES1.
Compound name
Inhibition
type
Inhibition
parameter (mM)
Threshold
for C
max(mM)
Neobavaisoflavone Noncompetitive 5.3 0.53
Corylifolinin Noncompetitive 9.4 0.94
Coryfolin Noncompetitive 1.9 0.19
Corylin Noncompetitive 0.7 0.07
Bavachinin Competitive 0.5 0.05
The calculation of threshold was based on the [I]/K
i
>0.1 standard.
6D.-X. Sun et al. Xenobiotica, Early Online: 1–8
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corylifolinin, coryfolin, psoralidin, corylin and bavachinin
made hydrogen bonds and hydrophobic interactions with
CES1 in the active pocket. Among these, Ser221 formed
hydrogen bond with inhibitors neobavaisoflavone, corylifoli-
nin, psoralidin and corylin. It is noteworthy that residue
Ser122 belongs to the catalytic triad of CES1, which is
important to the catalytic activity of enzyme (Fleming et al.,
2007). Hence, these four compounds might inhibit the activity
of enzyme via the interference to the binding of ligand with
enzyme. Hydrophobic residue Leu304 formed hydrogen bond
with neobavaisoflavone; in addition, hydrophobic residue
Ala93 formed hydrogen bonds with corylifolinin and
bavachinin, implying that the inhibitors could disturb the
binding environment of ligand to enzyme. In the binding
pocket of inhibitors to enzyme, all these inhibitors formed
contacts with hydrophobic residues Ala93, Leu304, Ile359
and Leu363, suggesting that these inhibitors may impact
the hydrophobic environment in the binding pocket of ligand
to enzyme.
The mice with CES1 knockout developed obesity, fatty
liver, hyperinsulinemia and insulin insensitivity, highlighting
the important of CES1 in the regulation of lipid metabolism
(Muller et al., 2003). Additionally, CES1 plays an important
role in the metabolism of glucose, demonstrated by the
negative regulation of over-expression of CES1 towards
the glucose levels in plasma (Xu et al., 2014). Therefore,
the present study indicated the importance to further moni-
toring the lipid metabolism disruption in the patients taking
FP. Additionally, the herb–drug interaction should be also
paid more attention for the co-administration of FP and drugs
mainly undergoing CES1-mediated metabolism.
Lineweaver–Burk plot was selected to get inhibition
kinetic type. For Hanes–Woolf plot, [S]/v (vertical axis)
was drawn versus [S] (horizontal axis). For Eadie–Hofstee
plots, v (vertical axis) was drawn versus v/[S] (horizontal
axis). For these two plot methods, two variables were
included in an axis (vertical axis or horizontal axis), which
might result in larger deviation of the data. Although
Lineweaver–Burk plot also has some disadvantages (e.g.
gradient distortion, large CV at low substrate concentration),
it is the most convenient method for inhibition kinetic
determination, and these disadvantages can be avoided
through optimization of substrate concentration and more
accurate determination of reaction velocity at low substrate
concentration. Different inhibition types were found for the
inhibition of FP’s ingredients towards CES1.
Neobavaisoflavone, corylifolinin, coryfolin and corylin
exhibited noncompetitive inhibition towards CES1, and
bavachinin exerted competitive inhibition towards CES1.
Competitive inhibition can be avoided when the concentration
of substrate increased. However, noncompetitive inhibition
cannot be eliminated through the elevated concentration of
substrates. Therefore, for bavachinin, drug–drug interaction
might be eliminated through increasing the concentration of
substrates mainly undergoing CES1-catalyzed metabolism.
In contrast, drug–drug interaction cannot be avoided for
Figure 9. The hydrophobic interactions between CES1 and inhibitors neobavaisoflavone, corylifolinin, coryfolin, psoralidin, corylin and bavachinin.
DOI: 10.3109/00498254.2015.1091521 Inhibition of hCES1 by Fructus psoraleae 7
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neobavaisoflavone, corylifolinin, coryfolin and corylin
through increasing the concentration of substrates mainly
undergoing CES1-catalyzed metabolism. It should be noted
some of these compounds have also been reported to inhibit
the activity of human carboxylesterase 2 (Li et al., 2015),
indicating the none selectivity for the inhibition of FP’s
ingredients towards CES isoforms.
To complete the translation function, the in vivo concen-
tration to result in the drug–drug interaction was given based
on the standard threshold of [I] (the in vivo concentration of
inhibitors)/K
i
(in vitro inhibition kinetic parameters) values
([I]/K
i
50.1, low possibility; 0.15[I]/K
i
51, medium possibil-
ity; [I]/K
i
>1, high possibility). The threshold values for total
systemic maximum plasma concentration (C
max
) were
calculated to be 0.53, 0.94, 0.19, 0.07 and 0.05 mMfor
neobavaisoflavone, corylifolinin, coryfolin, corylin and bava-
chinin, respectively.
In conclusion, the inhibition behavior of CES1 by the FP’s
constituents was given in this article, indicating the possible
adverse effects of FP through the disrupting CES1-catalyzed
metabolism of endogenous substances and xenobiotics.
Declaration of interest
The authors report no conflict of interests. This work was
supported by the National Natural Science Foundation of
China (No. 81202586, 81202587, 81202588 and 81303146),
Tianjin Project of Thousand Youth Talents, and Tianjin city
funded international projects to culture selected outstanding
postdoctoral.
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Supplementary material available online
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