Phytochemistry Letters 4 (2011) 3033

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Phytochemistry Letters
journal homepage: www.elsevier.com/locate/phytol

Cytochrome P450 2D6 inhibitory constituents of Lunasia amara

Subehan, Naoto Takahashi, Shigetoshi Kadota, Yasuhiro Tezuka *
Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan

A R T I C L E I N F O A B S T R A C T

Article history: From a MeOH extract of Lunasia amara, which showed the cytochrome P450 2D6 (CYP2D6) inhibition, 14
Received 22 June 2010 acridone alkaloids including two new alkaloids [5-hydoroxygraveoline (1) and 8-methoxyifaiamine
Received in revised form 21 October 2010 (2)] were identied. Among the 14 acridone alkaloids, 5-hydoroxygraveoline (1) and lunamarine (3)
Accepted 23 October 2010
showed moderate inhibition selective for CYP2D6, with IC50 values of 4.7 mM and 1.8 mM, respectively.
Available online 5 November 2010
2010 Phytochemical Society of Europe. Published by Elsevier B.V. All rights reserved.

Keywords:
Lunasia amara
Rutaceae
Acridone alkaloids
Cytochrome P450 2D6 (CYP2D6)
Herbdrug interaction

1. Introduction products makes it important to understand the potential interac-

Cytochrome P450s (CYPs) are the principal enzymes responsi-
ble for the oxidative metabolism of drugs and other xenobiotics, as
well as several endogenous substances in mammalian tissues.
Drug metabolism plays a critical role in the termination of drug
action and inuences the resident time of toxic chemicals within
the body. Thus, the effects of oxidations by CYPs can be manifested
in poor drug bioavailability and various acute and chronic
toxicities, including birth defects, cancer susceptibility, and
adverse drug interactions (Guengerich, 2001).
In human liver microsomes, CYP3A4 is the most abundant
enzyme. Recent investigations have revealed that more than 50% of
drugs used clinically are oxidized by CYP3A4, and about 30% of
drugs are metabolized by CYP 2D6 (CYP2D6) (Rendic and di Carlo,
1997). Inhibition of these enzymes is presumably the major
mechanism responsible for several drugdrug interactions. Fur-
ther, an inhibitor can also be used as a drug-sparing agent when
taken concomitantly with conventional medicines, to decrease the
dosage and nancial cost of expensive drug regimes (Clarke and
Jones, 2002).
Most of conventional pharmacokinetic literature deals with
drugdrug interactions, but recently interactions between herbal
agents and prescription drugs have drawn attention (Izzo, 2004).
These interactions occur since herbs are often self-administered
along with therapeutic drugs. The popularity of herbal medicinal
* Corresponding author. Tel.: +81 76 434 7627; fax: +81 76 434 5059.
E-mail address: tezuka@inm.u-toyama.ac.jp (Y. Tezuka).
tions between them and prescribed drugs, because almost all
herbal medicines contain a mixture of pharmacologically active
constituents. Indeed, several reports have demonstrated that
natural compounds and herbal products may cause pharmacoki-
netic interactions with Western drugs used clinically when they
are administered simultaneously (Nebel et al., 1999; Taylor and
Wilt, 1999).
We previously reported the CYP3A4 inhibitory constituents of
Kampo medicinal herbs, Schizandra Fructus (Iwata et al., 2004a)
and Evodia Fructus (Iwata et al., 2005); and the Indonesian Jamu
herbal medicines, Zingiber aromaticum (Usia et al., 2004), Piper
cubeba (Usia et al., 2005a), Cinnamomum burmani (Subehan et al.,
2008), and Foeniculum vulgare (Subehan et al., 2007). In addition,
we also reported the CYP2D6 inhibitory constituents of Cathar-
anthus roseus (Usia et al., 2005b) and Piper nigrum (Subehan et al.,
2006).
In our continuing study on the mechanism-based inhibition of
Indonesian medicinal plants, we found the MeOH extract of
Lunasia amara Blanco (Rutaceae) inhibited CYP2D6 (IC50 9.1 mg/
mL). L. amara is a popular traditional medicine, used extensively in
Indonesia either as a sole extract or in a mixture of several herbs for
the treatment of swollen limbs, skin diseases, and inamed or
irritated eyes, while the wood decoction is known as an
aphrodisiac in South Sulawesi Province (PT Eisai Indonesia,
1995). Lunacridine from L. amara has been reported to be a
DNA-intercalating topoisomerase II inhibitor (Prescott et al., 2007),
but there is no report on CYP2D6 inhibitory constituents of this
plant. In our continuing research, we examined the active
constituents of L. amara, which we report in this study.

1874-3900/$ see front matter 2010 Phytochemical Society of Europe. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.phytol.2010.10.006
[()TD$FIG] Subehan et al. / Phytochemistry Letters 4 (2011) 3033 31

Table 1
1 13
H (400 MHz) and C (100 MHz) NMR data for new acridone alkaloids 1 and 2 in
CDCl3.

1 2
1 13 1 13
H C H C

1 8.86 br s
2 155.2 s 160.9 s
3 6.20 s 111.0 d 116.9 s
4 181.9 s 162.7 s
5 162.9 s 7.29 d (8.0) 110.0 d
6 6.85 d (8.1) 108.9 d 7.10 t (8.0) 121.6 d
Fig. 1. Structures of new acridone alkaloids. 7 7.56 t (8.1) 134.3 d 6.94 d (8.0) 114.6 d
8 6.87 d (8.1) 104.6 d 145.7 s
4a 114.0 s 129.6 s
2. Results and discussion 8a 142.9 s 112.5 s
10 129.0 s
20 6.85 d (1.8) 122.7 d 4.61 q (6.6) 91.5 d
The bark of L. amara was extracted with MeOH, and the MeOH 30 148.1 s 44.2 s
extract was subjected to column chromatography to give two new 40 149.0 s 1.49 s (3H) 20.3 q
acridone alkaloids, 5-hydroxygraveroline (1) and 8-methoxyif- 50 6.94 d (8.1) 108.8 d 1.27 s (3H) 25.6 q
60 6.88 dd (8.1, 1.8) 108.9 d 1.45 d (6.6) (3H) 14.5 q
aiamine (2), together with 12 known ones (Fig. 1). The known
NCH3 3.60 s (3H) 38.0 q
alkaloids were identied by analyzing their spectral data and OCH3 3.86 s (3H) 56.0 q
comparing them with those found in the literatures. They were OCH2O 6.08 s (2H) 101.8 t
lunamarine (3) (Goodwin et al., 1959a), ifaiamine (4) (Chamber- OH 14.70 s
lain and Grundon, 1971), orixalone A (5) (Ito et al., 2004), Assignments are based on COSY, HMQC, and HMBC experiments.
lunidonine (6) (Ruegger and Stauffacher, 1963), lunacridine (7)
(Barr et al., 1994; Brown et al., 1980), lunidine (8) (Ruegger and
Stauffacher, 1963), N-methylindersine (9) (Kamperdick et al., Compound 2 was isolated as a colorless amorphous solid having
1999), lunacrine (10) (Goodwin et al., 1959b; Ramesh et al., 1984), a molecular formula of C15H16NO3. Its IR spectrum showed
balfourodine (11) (Brown et al., 1980), lunine (12) (Goodwin et al., absorptions corresponding to NH (3400 cm1) and carbonyl
1959b), lunasine (13) (Price, 1959), and balfourodinium (14) groups (1650 cm1). The 1H NMR spectrum of 2 revealed signals
(Rideau et al., 1979). due to three aromatic protons (dH 7.29, d, J = 8.0 Hz; dH 7.10, t,
Compound 1 was obtained as yellow powder, having a J = 8.0 Hz; dH 6.94, d, J = 8.0 Hz), two quaternary methyls (dH 1.49,
molecular formula of C17H13NO4. The 1H NMR spectrum of 1 1.27, both 3H, s), and an (O)CHCH3 group (dH 4.61, q, J = 6.6 Hz;
showed signals due to six aromatic protons and an isolated olenic dH 1.45, d, J = 6.6 Hz), together with those of a methoxyl (dH 3.86,
proton (dH 6.20, s) together with those of a hydrogen-bonded 3H, s) and an amino proton (dH 8.86, br s) (Table 1). The 13C NMR
hydroxyl (dH 14.70, s), a methylenedioxy (dH 6.08, s, 2H), and a spectrum showed 15 carbon signals including three sp2 methines,
methyl (dH 3.60, s) group. The 13C NMR spectrum of 1 showed 17 two oxygen-substituted sp2 quaternary carbons, three sp2 quater-
carbon signals consisting of seven sp2 methines, three oxygen- nary carbons, an oxygen-substituted methine, a quaternary sp3
substituted sp2 quaternary carbons, four sp2 quaternary carbons, a carbon, and three methyls, together with those of a methoxyl (dC
methylenedioxy carbon (dC 101.8, t), a N-methyl carbon (dC 38.0, 56.0, q) and a carbonyl carbon (dC 162.7, s) (Table 1). These signals
q), and a carbonyl carbon (dC 181.9, s). Analysis of the COSY suggested that 2 was a quinolone alkaloid similar to ifaiamine (4)
correlations indicated that the six aromatic protons consist of a (Chamberlain and Grundon, 1971), but 2 differed from 4 due to the
1,2,3-trisubstituted benzene ring (dH 7.56, t, J = 8.1 Hz; dH 6.87, d, presence of a methoxyl group at C-5 or C-8 and the lack of the N-
J = 8.1 Hz; dH 6.85, d, J = 8.1 Hz) and a 1,2,4-trisubstituted benzene methyl group of 4. Then, the HMBC correlations H-6/C-4a, H-6/C-8,
ring (dH 6.94, d, J = 8.1 Hz; dH 6.88, dd, J = 8.1, 1.8 Hz; dH 6.85, d, H-5/C-8a, and OCH3/C-8 conrmed the location of the methoxyl
J = 1.8 Hz) (Table 1). These spectral data suggested that compound group at C-8. These and other HMBC correlations conrmed the
1 was likely a quinolone alkaloid similar to lunamarine (3) isolated structure of 2 (Fig. 3). We could not determine the absolute
from the same extract, except for the presence of an oxygen- stereochemistry at C-20 due to the small amount obtained.
substituent at C-5 or C-8 instead of that at C-7 in 3. The presence of However, 2 should have the same absolute stereochemistry as 4
the signal due to the hydrogen-bonded hydroxyl proton (dH 14.70, because 2 showed the same levorotatory optical rotation ([a]D
s) suggested the locations of the hydroxyl and the carbonyl groups 308). Thus, compound 2 was concluded to be N-demethyl-8-
at C-5 and C-4, respectively, which was conrmed by the HMBC methoxyifaiamine.
correlations (Fig. 2). Thus, compound 1 was determined to be 5- All compounds isolated were tested for their inhibitory
hydroxygraveroline. activities on CYP3A4 and CYP2D6. Among the 14 compounds

[()TD$FIG] [()TD$FIG]

Fig. 2. Selected HMBC and COSY correlations for 1. Fig. 3. Selected HMBC and COSY correlations for 2.
32 Subehan et al. / Phytochemistry Letters 4 (2011) 3033
Table 2
Inhibitory activities (IC50 mM) of isolated alkaloids in the metabolism mediated by
CYP3A4 and CYP2D6.
Compound IC50 (mM)
CYP3A4
1 >100
2 32.5
3 46.8
4 69.7
5 >100
6 23.9
7 >100
8 71.1
9 47.8
10 57.6
11 >100
12 46.9
13 >10
14 61.7
Ketoconazolea 0.2
Quinidinea
a
Positive controls.
tested, 1 and 3 showed moderate inhibition selective for CYP2D6,
with IC50 values of 4.7 and 1.8 mM, respectively (Table 2). It is
known that substrates for CYP2D6 contain a basic nitrogen atom at
57 A from the oxidation site and that the aromatic rings are
coplanar (Meyer et al., 1986; Wolff et al., 1985). Moreover, many
potent CYP inhibitors are nitrogen-containing drugs, including
imidazole, pyridines, and quinolines, which can inhibit CYP
through binding to the prosthetic heme iron or to the lipophylic
region of the protein (Lin and Lu, 1998). On the other hand, the
methylenedioxyphenyl ring could be metabolized by CYP2D6 to
generate carbene intermediates, which can then form a strong
covalent complex with iron center of the heme in cytochromes
(Bertelsen et al., 2003; Murray, 2000). Thus, the presence of the
quinolone group and/or the methylenedioxyphenyl ring in 1 and 3
might be correlated with CYP inhibition.
3. Experimental
3.1. General
Optical rotation was measured with a JASCO DIP-140 digital
polarimeter. HR-FAB-MS was recorded on a JEOL JMS-700T mass
spectrometer using glycerol as matrix. The 1H and 13C NMR
spectra were recorded at 400 MHz and 100 MHz, respectively, on
a JEOL JNM-LA400 spectrometer. Chemical shifts are reported in d
(ppm) using TMS as internal standard and coupling constants (J)
were measured in Hz. Column chromatography was carried out on
silica gel (70230 mesh, Kanto Chemical Co. Ltd., Tokyo, Japan).
Medium pressure liquid chromatography (MPLC) was conducted
with a Buchi MPLC apparatus on silica gel. Normal or reversed-
phase TLC was performed on Merck precoated silica gel 60F254
plates or on Merck RP-18F254 plates, and spots were visualized by
using ceric sulfate spray reagent. All reagents used were analytical
grade.
3.2. Plant material
Wood and bark of L. amara Blanco was obtained at Gadjah Mada
University, Yogyakarta, Indonesia, in September 2007, and was
identied by Mr. Sri Suhadiyah, Sulawesi Biodiversity Foundation,
Makassar, Indonesia. A voucher sample (TMPW25679) is held at
the Museum for Materia Medica, Analytical Research Center for
Ethnomedicines, Institute of Natural Medicine, University of
Toyama, Toyama, Japan.
3.3. Extraction and isolation
Fresh wood and bark of L. amara (4 kg) were crushed, extracted
with MeOH, evaporated under reduced pressure followed by
CYP2D6 lyophilization to give a MeOH extract (128 g). Part of the MeOH
4.7
extract (20 g) was subjected to silica gel column chromatography
>100 with a CHCl3MeOH solvent system, yielding seven fractions [fr. 1:
1.8 CHCl3 eluate, 836 mg; fr. 2: CHCl3MeOH (90:10) eluate, 1.6 g; fr. 3:
>100 CHCl3MeOH (80:20) eluate, 343 mg; fr. 4: CHCl3MeOH (70:30)
>100
eluate, 5.4 g; fr. 5: CHCl3MeOH (60:40) eluate, 3.3 g; fr. 6: CHCl3
>100
95.5 MeOH (60:40) eluate, 2.5 g; fr. 7: MeOH eluate, 5.5 g]. Fraction 2 was
>100 separated by repetitive normal-phase prep. TLC with hexaneEtOAc
>100 (7:3) to afford 5-hydroxygraveroline (1, 3.0 mg), orixalone A (5,
>100 15.2 mg), lunidonine (6, 15.0 mg), and N-methylindersine (9,
>100
21.9 mg). Fraction 3 was puried repeatedly by normal-phase prep.
21.8
7.6 TLC with EtOActoluene (1:5) to give ifaiamine (4, 32.8 mg),
14.5 lunacridine (7, 3.5 mg), lunidine (8, 17.0 mg), and 9 (34.2 mg), while
fraction 4 was repeatedly subjected to normal-phase prep. TLC with
0.05
EtOActoluene (2:8) to give 8-methoxyifaiamine (2, 4.0 mg), 4
(6.9 mg), 9 (13.9 mg), lunacrine (10, 31.4 mg), and lunine (12,
3.5 mg). Fraction 5 was separated by MPLC on silica gel with CH2Cl2
MeOH (060% of MeOH), followed by normal-phase prep. TLC with
CH2Cl2MeOH (88:12), reversed-phase prep. TLC with acetoneH2O
(2:1), and/or normal-phase prep. TLC with CH2Cl2MeOHNH3
(85:15:2), to give lunamarine (3, 3.2 mg) and balfourodine (11,
14.7 mg). Fraction 6 was puried by a combination of normal-phase
prep. TLC with CH2Cl2MeOH (85:15) and reversed-phase prep. TLC
with CH3CNH2O (2:3) to give lunasine (13, 25.9 mg) and
balfourodinium (14, 12.3 mg).
3.3.1. 5-Hydroxygraveroline (1)
Yellow powder; HR-FAB-MS m/z 296.0890 [M+H]+ (calc. for
C17H14O4N, 296.0923); 1H and 13C NMR (400 MHz and 100 MHz,
CDCl3): Table 1.
3.3.2. N-Demethyl-8-methoxyifaiamine (2)
Colorless amorphous solid; a24 
D  30 (c 0.25, CHCl3); HR-FAB-
MS m/z 260.1322 [M+H] (calc. for C15H18NO3, 260.1287); 1H and
+
13
C NMR (400 MHz and 100 MHz, CDCl3): Table 1.
3.4. CYP inhibition assay
[O-Methyl-14C]dextromethorphan (55 mCi/mmol, radiochemi-
cal purity > 99%) and [N-methyl-14C]erythromycin (55 mCi/mmol,
radiochemical purity > 99%) were purchased from American
Radiolabeled Chemicals, Inc. (St. Louis, MO, USA). b-Nicotinamide
adenine dinucleotide phosphate (NADP+, oxidized form), glucose-
6-phosphate (G-6-P), and G-6-P dehydrogenase were purchased
from Oriental Yeast Co., Ltd. (Tokyo, Japan). Human liver
microsomes (HLM) were obtained from XenoTech, LCC (Lenexa,
KS, USA) and stored at 80 8C prior to use.
Inhibitory activity on the metabolism mediated by CYP2D6 and
CYP3A4 was determined using a radiometric measurement of
[14C]formaldehyde formed by the reaction with [O-methyl-14C]-
dextromethorphan or [N-methyl-14C]erythromycin as a substrate
(Iwata et al., 2004b). Briey, in disposable culture tubes
(13  100 mm; Iwaki, Tokyo, Japan) containing phosphate buffer
(0.1 M, pH 7.4), 50 mL of HLM (4 mg protein/mL), sample, and
puried water were added in 500 mL of total incubation volume.
After a preincubation for 5 min in shaking water bath at 37 8C, the
reaction is initiated by addition of 50 mL of the NADPH-generating
system (4.2 mg/mL of NADP+ in a solution of 100 mM G-6-P,
100 mM MgCl2, and 10 U/mL G-6-P dehydrogenase). Substrate
solution (50 mL) was added and incubated for 20 min (for CYP2D6)
or for 10 min (for CYP3A4) in a shaking water bath at 37 8C. The
reaction was stopped by addition of 125 mL of 10% trichloroacetic
 Subehan et al. / Phytochemistry Letters 4 (2011) 3033
acid, and the solution was centrifuged at 3000 rpm for 10 min at
room temperature. The supernatant was applied to Envi-carb solid
phase extraction columns (Supelco, PA, UK) and was eluted with
two volumes of ultrapure water (2  500 mL). After adding 10 mL
of Clear-sol I (Nacalai Tesque, Inc., Kyoto, Japan), the eluted
radioactivity was quantied by liquid scintillation counting LS
6500 (Beckman, CA, USA). Correction was made for radioactivity
eluted from control incubation in which HLM and NADPH-
generating systems had been omitted. The assays were performed
in triplicate for all test specimens, and remaining activity was
analyzed using the WinNonlin software (ver.3.1; Pharsight
Corporation; Mountain View, CA, USA).
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