Selective Inhibitory Effect of Osthenol on Human Cytochrome 2C8

Article abstract of DOI:10.1002/bkcs.11479

Osthenol is a furanocoumarin with anti-tumor, anti-inflammatory, and anti-viral activity. It is present in various citrus juices and fruits; however, its inhibitory effects on cytochrome P450 (CYP) enzyme activity, in the context of herb–drug interaction (HDI) prediction, have not been previously studied. In this study, osthenol was chemically synthesized in order to identify potential HDIs. Its inhibitory effect on eight CYP isoforms and the underlying mechanism of inhibition were investigated by using cocktail assays and liquid chromatography-tandem mass spectrometry in pooled human liver microsomes. The inhibitory effect of osthenol on CYP2C8-catalyzed paclitaxel hydroxylation was selective and dose-dependent, but not time-dependent. The IC₅₀ value was 2.8 μM. Additionally, osthenol displayed mixed mode inhibition with a relatively low Ki value of 0.96 μM, which is indicative of the potential for HDIs with co-administered CYP2C8 substrates. To the best of our knowledge, this is the first report of selective inhibition of CYP2C8 by osthenol.

Full text of DOI:10.1002/bkcs.11479

Article
DOI: 10.1002/bkcs.11479
BULLETIN OF THE
P. J. Cho et al.
KOREAN CHEMICAL SOCIETY
Selective Inhibitory Effect of Osthenol on Human Cytochrome 2C8
*
*
Pil Joung Cho, WoongShik Nam, Doohyun Lee, Taeho Lee, and Sangkyu Lee
BK21 Plus KNU Multi-Omics based Creative Drug Research Team, College of Pharmacy and Research
Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Republic of Korea.
*E-mail: tlee@knu.ac.kr; sangkyu@knu.ac.kr
Received December 29, 2017, Accepted April 18, 2018, Published online May 23, 2018
Osthenol is a furanocoumarin with anti-tumor, anti-inflammatory, and anti-viral activity. It is present in
various citrus juices and fruits; however, its inhibitory effects on cytochrome P450 (CYP) enzyme activ-
ity, in the context of herb–drug interaction (HDI) prediction, have not been previously studied. In this
study, osthenol was chemically synthesized in order to identify potential HDIs. Its inhibitory effect on
eight CYP isoforms and the underlying mechanism of inhibition were investigated by using cocktail
assays and liquid chromatography-tandem mass spectrometry in pooled human liver microsomes. The
inhibitory effect of osthenol on CYP2C8-catalyzed paclitaxel hydroxylation was selective and dose-depen-
dent, but not time-dependent. The IC50 value was 2.8 μM. Additionally, osthenol displayed mixed mode
inhibition with a relatively low Ki value of 0.96 μM, which is indicative of the potential for HDIs with
co-administered CYP2C8 substrates. To the best of our knowledge, this is the first report of selective inhi-
bition of CYP2C8 by osthenol.
Keywords: Osthenol, Furanocoumarin, CYP2C8, Paclitaxel, Human liver microsomes
Introduction
effect on cytochrome P450 (CYP) 3A4, which has been
shown to alter the pharmacokinetics of many drugs, includ-
ing midazolam, cyclosporine, and nifedipine.9,10
In addition, 8-methoxypsoralen (methoxsalen), a naturally
occurring furanocoumarin with photosensitizing properties,
was demonstrated to have a clinically significant interaction
with cyclosporine by potently inhibiting CYP3A4.11 More-
over, marmelosin, a furanocoumarin isolated from Aegle
marmelos, reversibly and non-competitively inhibited
CYP1A2.12
The interaction between furanocoumarins and drugs may
be based on a selective inhibitory effect on a specific CYP
isoform. This is too broad and unclear. I would recommend
revising this to osthenol, a furanocoumarin, is abundant in
a variety of citrus juices and fruits to be more specific and
consistent with the data provided in the abstract. Although
many pharmacological effects of osthenol have been
reported, its inhibitory effects on CYP enzyme activity, in
the context of potential HDI prediction, have not been stud-
ied thus far. In this study, we chemically synthesized and
examined the selective inhibitory effect of osthenol on
CYP2C8 in pooled human liver microsomes (HLMs), and
we evaluated its reversible mixed mode inhibition.
Osthenol, an active component of Angelicae dahuricae
radix (Angelica; known as Bai Zhi in Korea), is a furano-
coumarin and a C8-prenylated derivative of umbelliferone,
from which angelicin derivatives are obtained.1,2 It is also a
metabolite of osthole, a major component of Cnidium mon-
nieri.3 Angelicae dahuricae radix is traditionally used to
treat patients with rheumatism arthralgia because of its anti-
inflammatory activity. It is a wild species of Angelica and
native to Siberia, the far east of Russia, Mongolia, north-
eastern China, Japan, Korea, and Taiwan.4
Osthenol, known for its pharmacological effects (e.g.,
anti-tumor, anti-inflammatory, and anti-viral activity),3,5–7
inhibited mouse skin tumor promotion in an in vivo two-
stage carcinogenesis test and exhibited highly potent inhibi-
tory activity against 5-alpha-reductase type I in LNCaP
cells, both indicative of its anti-tumor effects.2,6 In addition,
osthenol inhibited concanavalin A-induced hepatitis in mice
and the activity of 5-lipoxygenase and cyclooxygenase
in vitro.7,8
Herb–drug interactions (HDIs) are evaluated to determine
the safety of co-administration of drugs and medicinal herbs.
An increase in the consumption of herbal preparations has
been associated with increased side effects or toxicity of
co-administered drugs because these herbal medicines
dramatically alter drug pharmacokinetics. In particular, fura-
nocoumarin derivatives are known to be responsible for
HDIs. For example, grapefruit juice, which contains the
furanocoumarin derivatives bergapten, bergamottin, and
60,70-dihydroxybergamottin, displayed a strong inhibitory
Experimental
Materials and Methods. All chemicals were of reagent
grade and were used as purchased. The reactions were moni-
tored via thin-layer chromatography analysis by using Merck
silica gel 60 F-254 thin-layer plates (Billerica, MA, USA).
Flash column chromatography was conducted on a Merck
Bull. Korean Chem. Soc. 2018, Vol. 39, 801–805
© 2018 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Wiley Online Library
801

Article
BULLETIN OF THE
ISSN (Print) 0253-2964 | (Online) 1229-5949
KOREAN CHEMICAL SOCIETY
(1.0 mL), followed by a Grubbs second-generation catalyst
(6.4 mg, 7.5 μmol). The reaction mixture was stirred at
room temperature for 90 min. The solvent was removed
and the residue was purified via flash silica gel column
chromatography (hexane/EtOAc, 3:1) to produce acetylated
osthenol (4) (102 mg, 75%) as a white solid: 1H NMR
(500 MHz, CDCl3) δ 7.67 (d, J = 9.5 Hz, 1H), 7.34 (d, J =
8.4 Hz, 1H), 7.01 (d, J = 8.4 Hz, 1H), 6.39 (d, J = 9.5 Hz,
1H), 5.14 (t, J = 6.6 Hz, 1H), 3.49 (d, J = 7.1 Hz, 2H),
2.35 (s, 3H), 1.82 (s, 3H), 1.68 (s, 3H).
Ac2O
AcO
O
O
HO
O
O
pyridine
rt, 2 h
quant.
2
3
Grubbs II,
2-methylbut-2-ene
CH2Cl2
75%
rt, 90 min
NaOH(aq)
7-Hydroxy-8-(3-Methylbut-2-en-1-Yl)-2H-Chromen-
2-one (1)2. To a solution of 8-(3-methylbut-2-en-1-yl)-
2-oxo-2H-chromen-7-yl acetate (4) (82 mg, 0.30 mmol) in
MeOH (3 mL), 0.5 M NaOH (1.2 mL, 0.6 mmol) was
HO
O
O
AcO
O
O
MeOH
rt, 3 h
97%
4
1
ꢀ
added at 0 C. The reaction mixture was stirred at room
Scheme 1. Synthesis of osthenol (1). Osthenol (purity >99%)
was synthesized from 8-allyl-7-hydroxy-2H-chromen-2-one (2)
in a three-step sequence and purified before use.
temperature for 3 h, adjusted with 1 N HCl solution, and
extracted twice with CH2Cl2. The combined organic layers
were dried over MgSO4, filtered, and concentrated under
reduced pressure. The residue was purified through flash
silica gel column chromatography (hexane/EtOAc, 3:1) to
produce osthenol (1) (67 mg, 97%) as a white solid.
silica gel 60 (230–400 mesh) column. H and l3C nuclear
1
magnetic resonance (NMR) spectra were recorded in δ units
relative to a deuterated solvent (CDCl3), used as an internal
reference, with a Bruker 500 MHz NMR instrument (Bruker,
MA, USA). The mass spectra (MS) were recorded at 70 eV
by using electron impact (EI) spectrometry. The known com-
pound 8-allyl-7-hydroxy-2H-chromen-2-one (2) was pre-
pared using the same procedure in a two-step sequence from
umbelliferone.13 Osthenol (purity >99%) was synthesized
from compound 2 in a three-step sequence and purified
before use (Scheme 1). The following spectral data were
determined for osthenol (7-hydroxy-8-(3-methylbut-2-en-
1-yl)2H-chromen-2-one): 1H NMR (500 MHz, CDCl3) δ
7.63 (d, J = 9.4 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H), 6.81 (d,
J = 8.5 Hz, 1H), 6.34 (s, 1H), 6.24 (d, J = 9.4 Hz, 1H),
5.36–5.22 (m, 1H), 3.61 (d, J = 7.2 Hz, 2H), 1.85 (s, 3H),
1.75 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 161.8, 158.5,
153.3, 144.3, 136.2, 126.7, 120.4, 114.9, 113.3, 112.9,
112.6, 25.9, 22.2, 18.2; MS (EI) m/z 230 ([M]+); purity
>99% as determined via HPLC peak area analysis.
Screening of Selective Inhibitory Effects of Osthenol by
Using a Cocktail Substrate Assay. The inhibitory effects
of osthenol on the activity of eight CYPs were determined
by conducting a cocktail assay in parallel with liquid
chromatography–tandem mass spectrometry (LC–MS/MS)
as previously described.14 Eight different CYP-specific sub-
strates, previously used for cocktail assays, were prepared:
phenacetin (80 μM) for CYP1A2, coumarin (2 μM) for
CYP2A6, bupropion (2 μM) for CYP2B6, paclitaxel
(10 μM) for CYP2C8, diclofenac (10 μM) for CYP2C9,
omeprazole (20 μM) for CYP2C19, dextromethorphan
(50 μM) for CYP2D6, and midazolam (50 μM) for
CYP3A4. The activity of each CYP was determined by
analyzing the generated metabolites via LC–MS/MS in the
multiple reaction monitoring mode.
To screen for inhibitory effects on human CYP activity,
osthenol (0, 5, and 10 μM) was incubated with 0.25 mg/
mL pooled HLMs (150 mixed gender, Sekisui XenoTech,
LLC, Kansas City, KS, USA) in 0.1 M potassium phos-
phate buffer (pH 7.4) and the eight substrates. The reaction
was started by adding the NADPH-regenerating system
(0.1 M glucose 6-phosphate [Sigma-Aldrich, St. Louis,
MO, USA]), 10 mg/mL β-nicotinamide adenine dinucleo-
tide phosphate (β-NADPH, Oriental Yeast Co., Ltd.,
Tokyo, Japan), and 1.0 U/mL glucose-6-phosphate dehy-
drogenase (Sigma-Aldrich). After incubation for 60 min,
the reaction was terminated by adding 100 μL acetonitrile
containing 0.1% formic acid and 5 μM reserpine (internal
standard, IS). The solution was mixed and centrifuged at
13 000 ×g for 10 min, and 5 μL of the supernatant was
injected onto a C18 column for LC–MS/MS analysis.
8-Allyl-2-Oxo-2H-Chromen-7-Yl Acetate (3).
Acetyl
anhydride (0.14 mL, 1.5 mmol) at 0 ꢀC was added to a
solution of 8-allyl-7-hydroxy-2H-chromen-2-one (2)1
(202 mg, 1.0 mmol) in ꢀpyridine (5 mL). The reaction mix-
ture was stirred at 25 C for 2 h and the volatiles were
removed through evaporation. The residue was purified via
flash silica gel column chromatography (hexane/EtOAc,
3:1) to produce acetylated product 3 (245 mg, quant.) as a
white solid: 1H NMR (500 MHz, CDCl3) δ 7.68 (d,
J = 9.5 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.04 (d,
J = 8.4 Hz, 1H), 6.39 (d, J = 9.5 Hz, 1H), 5.88 (ddt,
J = 16.5, 10.1, 6.3 Hz, 1H), 5.12–4.99 (m, 2H), 3.56 (d,
J = 6.3 Hz, 2H), 2.34 (s, 3H).
8-(3-Methylbut-2-en-1-Yl)-2-Oxo-2H-Chromen-7-Yl
Acetate (4). 2-Methyl-2-butene (4 mL, 36.8 mmol) was
added to a solution of 8-allyl-2-oxo-2H-chromen-7-yl
acetate (3) (122 mg, 0.50 mmol) in degassed CH2Cl2
Determination of Inhibition Mode of Osthenol in HLMs.
To determine the inhibition pattern of osthenol on
CYP2C8, assays with and without preincubation were com-
pared. A mixture of osthenol (0–40 μM) and 0.25 mg/mL
Bull. Korean Chem. Soc. 2018, Vol. 39, 801–805
© 2018 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.bkcs.wiley-vch.de
802

BULLETIN OF THE
Article
Inhibition of CYP2C8 by Osthenol
KOREAN CHEMICAL SOCIETY
Table 1. Screening of selective inhibitory effects of osthenol on 8 CYP activities in human liver microsomes.a
Relative activity (%)
Osthenol
Substrate
Conc.
Substrate reaction probe
CYP isoform
(μM)
5 μM
10 μM
Phenacetin O-deethylation
Coumarin 7-hydroxylation
Bupropion hydroxylation
Paclitaxel 6-hydroxylation
Diclofenac 4-hydroxylation
Omeprazole 5-hydroxylation
Dextromethorphan O-deethylation
Midazolam 10-hydroxylation
a
CYP1A2
CYP2A6
CYP2B6
CYP2C8
CYP2C9
CYP2C19
CYP2D6
CYP3A4
80
4
76.0
70.4
78.7
48.7
48.8
82.9
84.7
82.2
54.2
65.8
51.9
28.9
51.2
93.8
70.1
68.7
20
10
10
20
10
5
The inhibitory effects of osthenol (0, 5, 10 μM) on the activity of eight CYP isoforms in HLMs were determined using a cocktail probe. Data
are the mean values of duplicate experiments.
of HLMs in 0.1 M potassium phosphate buffer (pH 7.4)
was preincubated for 0 or 20 min, and the NADPH-
regenerating system was added to start the reaction. The
reactions were terminated after incubation for 60 min at
Results
To identify potential HDIs, osthenol was chemically synthe-
sized as described in Scheme 1. A cocktail assay coupled with
an LC–MS/MS system was utilized to determine whether
osthenol selectively inhibited any CYP isoforms in pooled
HLMs. As shown in Table 1, osthenol strongly inhibited
CYP2C8-mediated paclitaxel hydroxylation to less than 50%
at 5 μM and exerted dose-dependent effects. Osthenol also
showed weak inhibitory effects on CYP1A2-catalyzed phen-
acetin O-deethylation, CYP2B6-catalyzed bupropion hydrox-
ylation, and CYP2C9-mediated diclofenac 40-hydroxylation
in pooled HLMs.
ꢀ
37 C by adding 100 μL acetonitrile containing 0.1% for-
mic acid and 5 μM reserpine. Other procedures were con-
ducted as described above. The inhibitory potentials were
compared by determining the IC50 values (concentration of
inhibitor that results in 50% inhibition of enzyme activity)
obtained from plots of the percentage activity versus log
[I] concentration.
To calculate the Ki of CYP2C8-catalyzed paclitaxel
hydroxylation by osthenol, paclitaxel (2.5, 5, 10, and
20 μM) was incubated with osthenol (0, 5, 10, 20, and
40 μM) in 0.1ꢀM potassium phosphate buffer (pH 7.4) for
60 min at 37 C. The inhibition pattern was investigated
from the Michaelis–Menten saturation curve, Lineweaver–
Burk plot, and secondary plotting. The Ki value was
obtained from the secondary plots based on the slopes of
the Lineweaver–Burk plots.
To investigate the inhibitory mechanism of osthenol, the
IC50 values from time- and dose-dependent experiments
were compared (Figure 1). The IC50 values after preincuba-
tion for 0 and 20 min were 2.8 and 1.7 μM, respectively;
No preincubation
20 min preincubation
100
80
60
40
20
0
Instruments. All measurements were performed by using
LC–MS/MS in multiple reaction monitoring mode on an
Accela™ LC system coupled to a TSQ Vantage triple
quadrupole mass spectrometer (Thermo Fisher Scientific,
Inc., Waltham, MA, USA) equipped with an HESI-II spray
source. Electrospray ionization was performed in positive
mode at a spray voltage of 3500 V. Nitrogen was used as
the sheath and auxiliary gases at optimal values of 45 and
20 (arbitrary units), respectively. Theꢀvaporizer and capil-
lary temperatures were 150 and 300 C, respectively. For
LC analysis, an Inertsil® ODS-2 (3 μm, 2.1 × 150 mm)
column (GL Sciences, Inc., Torrance, CA, USA) was used.
The mobile phase consisted of acetonitrile (mobile phase
A) and water (mobile phase B), both containing 0.1% for-
IC50: 2.8 µM
IC50: 1.7 µM
0.1
1
10
100
Osthenol (µM)
Figure 1. Effect of 20 min preincubation of osthenol (0–40 μM)
on CYP2C8-catalyzed paclitaxel hydroxylation in 0.25 mg/mL
pooled HLMs (without preincubation (●) or with preincubation
(○)). Inhibitory potentials were compared using the IC50 values
obtained from plots of the percentage activity versus log
[I] concentration. The data are the mean values from duplicate
experiments.
ꢀ
mic acid, at a flow rate of 0.22 mL/min at 30 C. Multiple
reaction monitoring was used to detect CYP isozyme-
specific marker metabolites to determine CYP activity.15
Bull. Korean Chem. Soc. 2018, Vol. 39, 801–805
© 2018 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.bkcs.wiley-vch.de
803

BULLETIN OF THE
Article
Inhibition of CYP2C8 by Osthenol
KOREAN CHEMICAL SOCIETY
the IC50 value was not significantly altered with preincuba-
tion, indicating that osthenol is a dose-dependent, but not
time-dependent, reversible inhibitor of CYP2C8 in HLMs.
The inhibition mode of osthenol on CYP2C8 activity
was determined graphically from a Michaelis–Menten satu-
ration curve and Lineweaver–Burk plot against inhibitor
concentration (Figure 2). In the Michaelis–Menten plot, a
decrease in Vmax and Km values indicated mixed mode inhi-
bition of CYP2C8-mediated paclitaxel hydroxylation by
osthenol (Figure 2(a)). The mechanism of CYP2C8 inhibi-
tion by osthenol was confirmed by using a Lineweaver–
Burk plot (Figure 2(b)). At low concentrations (0–20 μM),
osthenol displayed mixed mode inhibition; at higher con-
centrations, osthenol displayed a pattern of competitive
inhibition. Finally, osthenol was found to be a reversible
mixed mode inhibitor with a Ki value of 0.96 μM, as calcu-
lated from the secondary plot for CYP2C8 (Figure 2(c)).
15
12
9
(a)
Osthenol 0 µM
Osthenol 5 µM
Osthenol 10 µM
Osthenol 20 µM
Osthenol 40 µM
6
3
0
0
5
10
15
20
25
Paclitaxel (µM)
2.0
(b)
Osthenol 0 µM
Osthenol 5 µM
Osthenol 10 µM
Osthenol 20 µM
Osthenol 40 µM
Discussion
1.5
1.0
0.5
This study demonstrated the selective inhibition of
CYP2C8 by osthenol in HLMs. Osthenol displayed revers-
ible and mixed mode inhibition, as determined in a cocktail
assay coupled with an LC–MS/MS system. Osthenol
decreased CYP2C8 activity with a Ki value of 0.96 μM.
CYP2C8 was recently established as an important drug-
metabolizing enzyme.16 CYP2C8 accounts for approxi-
mately 6–7% of the total hepatic CYP enzymes and is an
important component of drug–drug interactions via drug
response linked to pharmacogenetic polymorphism.17
CYP2C8 is involved in metabolizing more than 100 drugs,
including those with anti-cancer, anti-diabetic, anti-malar-
ial, and lipid-lowering effects.16 For example, CYP2C8 is
responsible for the metabolism of over 70% of amodiaquine
N-deethylation, cerivastatin 6-hydroxylation, enzalutamide
hydroxylation and N-demethylation, and pioglitazone
hydroxylation reactions.18–20
For reversible inhibitors, a strong inhibitory effect of
compounds on specific CYP enzymes in vitro does not
always correspond to an inhibitory effect in vivo and there-
fore does not result in HDIs. Although montelukast and
zafirlukast strongly inhibited CYP2C8 in vitro, with con-
centrations supporting an IC50 of <3 μM in recombinant
CYP2C8 and HLM, they did not affect the pharmacokinet-
ics of CYP2C8 substrates in vivo.21 The absence of an
effect in vivo is likely explained by the extensive plasma
protein binding (>99%), low systemic concentrations, and
genetic polymorphism. However, some natural compounds
that inhibit CYP2C8 in vitro have also shown interactions
in vivo.
0.2
-0.1
0.0
0.1
0.2
0.3
0.4
0.5
-1
1/paclitaxel (µM)
(c)
4
3
2
1
0
Ki : 0.96 µM
0
10
20
30
40
50
Osthenol (µM)
Figure 2. Michaelis–Menten saturation curve (a), Lineweaver-
Burk plot (B), and secondary plot (C) for inhibition of
CYP2C8-catalyzed paclitaxel hydroxylation by osthenol in pooled
HLMs. Paclitaxel (2.5, 5, 10, and 20 μM) was incubated with
osthenol (0, 5, 10, 20, and 40 μM) in 0.1 M potassium phosphate
For example, the green tea catechin (−)-epigallocatechin-
3-gallate inhibited CYP2C8 with a Ki of 6.8 μM,22 and a pos-
sible HDI was reported for those who consume more than
1.8 L of green tea daily.22 Moreover, this compound signifi-
cantly modulated the bioavailability of diltiazem, verapamil,
tamoxifen, simvastatin, 5-fluorouracil, nicardipine, quetiapine,
ꢀ
buffer (pH 7.4) for 60 min at 37 C. The Ki value was obtained
from the secondary plots based on the slopes of the Lineweaver-
Burk plots. The data are the mean values from duplicate
experiments.
Bull. Korean Chem. Soc. 2018, Vol. 39, 801–805
© 2018 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.bkcs.wiley-vch.de
804

BULLETIN OF THE
Article
Inhibition of CYP2C8 by Osthenol
KOREAN CHEMICAL SOCIETY
4. C. Wang, J. Sun, H. Li, X. Yang, H. Liu, J. Chen, J. Nat.
Med. 2016, 70, 563.
5. C. Ito, M. Itoigawa, M. Ju-ichi, N. Sakamoto, H. Tokuda,
H. Nishino, H. Furukawa, Planta Med. 2005, 71, 84.
6. E. K. Seo, K. H. Kim, M. K. Kim, M. H. Cho, E. Choi,
K. Kim, W. Mar, Planta Med. 2002, 68, 162.
7. J. H. Liu, S. Zschocke, E. Reininger, R. Bauer, Planta Med.
1998, 64, 525.
8. T. Okamoto, S. Yoshida, T. Kobayashi, S. Okabe, Jpn.
J. Pharmacol. 2001, 85, 95.
sunitinib, clozapine, and nadolol both clinically and in ani-
mals.23 As osthenol has shown to be strong inhibitor of
CYP2C8 than (-) -epigallocatechin-3-gallate, osthenol might
show herb-drug interaction in humans and animals.
Osthenol is also a stronger CYP2C8 inhibitor than quer-
cetin, which is one of the earliest detected in vitro inhibitors
of CYP2C8.24,25 Quercetin has previously shown an HDI
with doxorubicin, cyclosporine, and etoposide.26 Therefore,
when patients are administered herbal medicinal foods
derived from A. dahuricae, they should be warned of the
potential for drug interactions.
9. S. Arora, I. Taneja, M. Challagundla, K. S. Raju, S. P. Singh,
M. Wahajuddin, Toxicol. Lett. 2015, 239, 1.
10. P. C. Ho, D. J. Saville, S. Wanwimolruk, J. Pharm. Pharm.
Sci. 2001, 4, 217.
11. M. Rheeders, M. Bouwer, T. C. Goosen, J. Clin. Pharmacol.
2006, 46, 768.
12. V. K. Manda, B. Avula, A. G. Chittiboyina, I. A. Khan,
L. A. Walker, S. I. Khan, Xenobiotica 2016, 46, 117.
13. J. Magolan, M. J. Coster, J. Org. Chem. 2009, 74, 5083.
14. J. Sim, H. W. Jang, M. Song, J. H. Kim, S. H. Lee, S. Lee,
Food Chem. Toxicol. 2014, 69, 276.
An HDI may depend on the plasma concentration of the
specific compound after absorption. An increase in plasma
concentration, particularly from high doses or when the
herb has accumulated, may be linked to an HDI. Although
the pharmacokinetic parameters of osthenol are unknown,
studies of the inhibitory effect of natural compounds on
CYP activity are important for preventing side effects or
toxicities of co-administered drugs.
In conclusion, we found strong and selective inhibitory
effects of osthenol on CYP2C8-catalyzed paclitaxel
hydroxylation in HLMs and investigated potential HDIs
associated with osthenol by evaluating its inhibitory effects
on CYP2C8 in HLMs. Future studies should be conducted
to evaluate the inhibitory effect of osthenol in vivo to pre-
dict osthenol–drug interactions.
15. M. Song, M. Hong, M. Y. Lee, J. G. Jee, Y. M. Lee,
J. S. Bae, T. C. Jeong, S. Lee, Food Chem. Toxicol. 2013,
59, 549.
16. J. T. Backman, A. M. Filppula, M. Niemi, P. J. Neuvonen,
Pharmacol. Rev. 2016, 68, 168.
17. B. Achour, J. Barber, A. Rostami-Hodjegan, Drug Metab.
Dispos. 2014, 42, 1349.
18. X. Q. Li, A. Bjorkman, T. B. Andersson, M. Ridderstrom,
C. M. Masimirembwa, J. Pharmacol. Exp. Ther. 2002,
300, 399.
19. J. S. Wang, M. Neuvonen, X. Wen, J. T. Backman,
P. J. Neuvonen, Drug Metab. Dispos. 2002, 30, 1352.
20. J. A. Gibbons, M. de Vries, W. Krauwinkel, Y. Ohtsu,
J. Noukens, J. S. van der Walt, R. Mol, J. Mordenti,
T. Ouatas, Clin. Pharmacokinet. 2015, 54, 1057.
21. T. Jaakkola, J. T. Backman, M. Neuvonen, M. Niemi,
P. J. Neuvonen, Eur. J. Clin. Pharmacol. 2006, 62, 503.
22. S. Misaka, K. Kawabe, S. Onoue, J. P. Werba, M. Giroli,
S. Tamaki, T. Kan, J. Kimura, H. Watanabe, S. Yamada,
Drug Metab. Pharmacokinet. 2013, 28, 244.
Acknowledgments. This research was supported by the
Kyungpook National University Research Fund, 2017.
Conflict of interest. We wish to confirm that there are no
known conflicts of interest associated with this publication
and that no significant financial support has been received
for this work that could have influenced its outcome.
References
1. F. Karamat, A. Olry, R. Munakata, T. Koeduka,
A. Sugiyama, C. Paris, A. Hehn, F. Bourgaud, K. Yazaki,
Plant J. 2014, 77, 627.
2. Y. Chen, G. Fan, B. Chen, Y. Xie, H. Wu, Y. Wu, C. Yan,
J. Wang, J. Pharm. Biomed. Anal. 2006, 41, 105.
23. A. A. Albassam, J. S. Markowitz, Planta Med. 2017, 83, 496.
24. Y. Gao, D. Liu, H. Wang, J. Zhu, C. Chen, Xenobiotica
2010, 40, 467.
3. X. Lv, C. Y. Wang, J. Hou, B. J. Zhang, S. Deng, Y. Tian,
S. S. Huang, H. L. Zhang, X. H. Shu, Y. H. Zhen, K. X. Liu,
J. H. Yao, X. C. Ma, Xenobiotica 2012, 42, 1120.
25. A. Rahman, K. R. Korzekwa, J. Grogan, F. J. Gonzalez,
J. W. Harris, Cancer Res. 1994, 54, 5543.
26. N. R. Srinivas, Phytother. Res. 2015, 29, 1679.
Bull. Korean Chem. Soc. 2018, Vol. 39, 801–805
© 2018 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.bkcs.wiley-vch.de
805