JOURNAL OF MEDICINAL FOOD

J Med Food 11 (4) 2008, 623–628

© Mary Ann Liebert, Inc. and Korean Society of Food Science and Nutrition
DOI: 10.1089/jmf.2007.0050

Pomegranate Juice Inhibits Sulfoconjugation in Caco-2 Human

Colon Carcinoma Cells
Ayako Saruwatari, Shigeaki Okamura, Yoko Nakajima, Yuji Narukawa,
Tadahiro Takeda, and Hiroomi Tamura
Kyoritsu University of Pharmacy, Minatoku, Tokyo, Japan*

ABSTRACT Several fruit juices have been reported to cause food–drug interactions, mainly affecting cytochrome P450 ac-
tivity; however, little is known about the effects of fruit juices on conjugation reactions. Among several fruit juices tested (ap-
ple, peach, orange, pineapple, grapefruit, and pomegranate), pomegranate juice potently inhibited the sulfoconjugation of 1-
naphthol in Caco-2 cells. This inhibition was both dose- and culture time-dependent, with a 50% inhibitory concentration
(IC50) value calculated at 2.7% (vol/vol). In contrast, no obvious inhibition of glucuronidation of 1-naphthol in Caco-2 cells
was observed by any of the juices examined. Punicalagin, the most abundant antioxidant polyphenol in pomegranate juice,
was also found to strongly inhibit sulfoconjugation in Caco-2 cells with an IC50 of 45 M, which is consistent with that of
pomegranate juice. These data suggest that punicalagin is mainly responsible for the inhibition of sulfoconjugation by pome-
granate juice. We additionally demonstrated that pomegranate juice and punicalagin both inhibit phenol sulfotransferase ac-
tivity in Caco-2 cells in vitro, at concentrations that are almost equivalent to those used in the Caco-2 cells. Pomegranate
juice, however, shows no effects on the expression of the sulfotransferase SULT1A family of genes (SULT1A1 and SULT1A3)
in Caco-2 cells. These results indicate that the inhibition of sulfotransferase activity by punicalagin in Caco-2 cells is re-
sponsible for the reductions seen in 1-naphthyl sulfate accumulation. Our data also suggest that constituents of pomegranate
juice, most probably punicalagin, impair the enteric functions of sulfoconjugation and that this might have effects upon the
bioavailability of drugs and other compounds present in food and in the environment. These effects might be related to the
anticarcinogenic properties of pomegranate juice.

KEY WORDS: • Caco-2 • pomegranate • sulfoconjugation

INTRODUCTION vascular diseases.2 It also elicits anti-inflammatory and an-

ticarcinogenic effects.3 Knowledge of these beneficial ef-
T HE POMEGRANATE (Punica granatum L.) has been
revered through the ages for its medicinal properties.1
Preparations of different parts of the plant—flower, fruit
fects of pomegranate has precipitated its use worldwide, al-
though several other fruits have also been reported to cause
food–drug interactions. In their previous studies, Hidaka et
juice, rind, and bark—have been traditionally used to treat
al.4,5 also reported that pomegranate inhibits cytochrome
a wide variety of conditions, although most commonly for
P450 (CYP) 3A activity in vitro and in vivo.
gastroenterological ailments. The edible parts of the pome-
We previously reported that herbal teas, coffee, and
granate fruit comprise 80% juice and 20% seed and are very
turmeric inhibit phase II conjugation reactions, particularly
rich in polyphenolic flavonoids. The soluble polyphenol
sulfoconjugation, in Caco-2 human colon carcinoma cells,
content of the pomegranate varies within a range of
a cell line model of the human intestinal epithelium.6–9 It
0.2–1.0% and includes mainly anthocyanins, catechins, el-
has also been shown that phase II conjugation activity in the
lagitannins, and both gallic and ellagic acids.2 It has been
intestinal epithelium affects the bioavailability of drugs and
reported that pomegranate shows antioxidant activity, re-
other environmental xenobiotics.10 Thus, it is of great in-
sulting in beneficial health effects such as inhibition of low-
terest and some importance to monitor the possible interac-
density lipoprotein oxidation and decreased risk of cardio-
tion of fruit juice intake and conjugation reactions in the in-
testine. During the course of our current investigations of
the effects of fruit juices upon conjugation reactions in Caco-
Manuscript received 2 March 2007. Revision accepted 8 August 2007.
2 cells, we found that the most potent inhibitory effects oc-
Address reprint requests to: Hiroomi Tamura, Faculty of Pharmacy, Keio University, 1- curred with pomegranate juice. We herein describe the de-
5-30, Shibakoen, Minatoku, Tokyo 105-8512, Japan, E-mail: tamura-hr@pha.keio.ac.jp
*Kyoritsu University of Pharmacy merged with Keio University in April 2008 and is now tails of our analysis of the interactions between pomegranate
Faculty of Pharmacy, Keio University. and conjugation reactions in Caco-2 cells.

623
624 SARUWATARI ET AL.

MATERIALS AND METHODS

Materials
Pomegranate juice (product of Iran) was obtained com-
mercially from Zakuro-ya (Fukuoka, Japan), and other fruit
juices were obtained commercially from Kirin Beverages
(Tokyo, Japan). 1-Naphthyl sulfate, 1-naphthyl glucuronide,
and tetrabutylammonium hydrogen sulfate were purchased
from Sigma Chemical Co. (St. Louis, MO). Acetonitrile was
purchased from Wako Chemicals (Tokyo). Reagents for
polymerase chain reaction (PCR) were obtained from Ap-
plied Biosystems, Inc. (Foster City, CA). Caco-2 cells were
obtained at passage 40 from the RIKEN Cell Bank (Tsukuba,
Japan).

Cell culture
Caco-2 cells were grown in 12-well plates (IWAKI,
Tokyo) in 1 mL of Minimum Essential Medium, supple-
mented with 10% fetal bovine serum, 2 mM glutamine, 10
U/mL penicillin, 10 U/mL streptomycin, and additional non-
essential amino acids. The cells were seeded at a concen-
tration of 5  105 cells/mL and grown until confluence (5–6
days) in a 37°C incubator, in a humidified atmosphere con-
taining 5% CO2. Cells were then further cultivated for up
to 3 weeks. The medium was changed every 4–5 days.
Isolation of punicalagin
Pomegranate juice (250 mL) was concentrated in vacuo
to produce a syrup (223.5 g), which was then subjected to
column chromatography on Diaion™ HP-20 resin (Mit-
subishi Chemical Co., Tokyo) and eluted with water fol-
lowed by methanol. The methanol eluate (3.96 g) was pre-
cipitated into diethyl ether, and the resulting precipitate (3.32
g) was chromatographed on a Lobar RP-18 column (Merck,
Darmstadt, Germany) using a solvent A–solvent B gradient
system to give four fractions (solvent A, 0.1% trifluoroacetic
acid; solvent B, acetonitrile/acetic acid/0.1% trifluoroacetic
acid, 25:20:55 by volume). Fraction 1 (383.4 mg) was pu-
rified by preparative high-performance liquid chromatogra-
phy (HPLC) on a Capcellpak C18 column (Shiseido, Tokyo)
eluted with the solvent A to B gradient system to give puni-
calagin (15.4 mg, 0.007%). The structure of punicalagin was
then identified by spectral analysis and compared with pub-
lished information (Fig. 1).11
Analyses of 1-naphthyl sulfate and glucuronide
Quantitation of 1-naphthol conjugates was performed as
described previously.6 Briefly, 1-naphthol (200 M) was
added to the medium, after which the cells were incubated
further at 37°C. Aliquots (50 L) of medium were then re-
moved at various time points, and 30-L aliquots of these
mixtures were filtered and injected into an HPLC apparatus
equipped with an ODS column (Chromolith Performance RP-
18e, 100  4.6 mm, Merck). The mobile phase consisted of
FIG. 1. Chemical structure of punicalagin.
10 mM tetrabutylammonium hydrogen sulfate in water and
acetonitrile (72.5:27.5 vol/vol), and the flow rate was 1.0
mL/minute with a column temperature of 30°C. Elution was
monitored at 285 nm. The retention times for 1-naphthol, 1-
naphthyl sulfate, and 1-naphthyl glucuronide were determined
to be 11.4 minutes, 24.0 minutes, and 3.4 minutes, respec-
tively. The standard curves for 1-naphthyl sulfate and glu-
curonide were linear up to 200 M. The effects of pome-
granate and other constituents on the conjugation reactions
were monitored by adding these compounds to the culture
medium of Caco-2 cells. Fifty percent inhibitory concentra-
tion (IC50) values for the concentration–activity curves were
calculated using a curve-fit program for Windows.
Cytosolic extract preparation from Caco-2 cells
Caco-2 cells (1–2  107) were removed from the culture
dishes (75 mm2), washed with phosphate-buffered saline,
and then homogenized in 1 mL of buffer A (50 mM Tris-
HCl [pH 7.5], 250 mM sucrose, 0.1 mM EDTA, 3 mM 2-
mercaptoethanol, 0.1 mM phenylmethylsulfonyl fluoride, 5
g/mL antipain, and 5 g/mL pepstatin). The debris was re-
moved by centrifugation at 3,000 g for 15 minutes, after
which the supernatant was centrifuged at 105,000 g for 60
minutes. The clear lysate was used as the cytosolic extract
in subsequent experiments.
Assay of phenol sulfotransferase (P-ST) activity
Sulfotransferase activity within the cytosolic fractions
was determined using adenosine 3’-phosphate 5’-phos-
 POMEGRANATE JUICE INHIBITS SULFOCONJUGATION
pho[35S]sulfate ([35S]PAPS) as the sulfate donor and 1-
naphthol for P-ST activity as the sulfate acceptor, accord-
ing to a slight modification of the procedure described pre-
viously by Foldes and Meek.12 In brief, the reaction mixture
(250 L) contained 10 mM phosphate buffer (pH 7.4), 50
M 1-naphthol, 5.0 M [35S]PAPS (0.4 Ci), and cytoso-
lic extract (15 g of proteins). The mixture was incubated
at 37°C for 30 minutes (P-ST), and the reaction was stopped
by addition of 50 L of cold 0.1 M barium acetate. Excess
[35S]PAPS was precipitated by addition of 50 L of both
0.1 M Ba(OH)2 and 0.1 M ZnSO4 and removed by cen-
trifugation at 12,000 g for 5 minutes. This precipitation pro-
cedure was then repeated, and the remaining supernatant
(300 L) was transferred to a 3-mL liquid scintillation tube
to determine radioactivity levels. Control reactions were es-
tablished by omitting the acceptor substrate from the mix-
ture.
Analysis of SULT gene expression
Total RNA was isolated from cultured cells by guani-
dinium thiocyanate-phenol-chloroform extraction. First-
strand cDNA was synthesized from 10 g of total RNA
by 1 unit of Moloney murine leukemia virus reverse tran-
scriptase with oligo(dT) primers, according to the manu-
facturer’s protocol. PCR was performed using this cDNA
as a template, with AmpliTaq® Gold polymerase
(PerkinElmer, Waltham, MA). The PCR primers used to
amplify human SULT and UGT cDNAs were designed
from published sequences. The PCR conditions (35 cy-
cles) were as follows: 1 minute at 94°C, 1.5 minutes at
54–58°C, and 2 minutes at 72°C. Quantitative real-time
(RT)-PCR was performed with an ABI-Prism 7700 ther-
mal cycler using a SYBR® Green PCR core reagent kit
(Applied Biosystems, Warrington, UK). Samples were de-
natured at 94°C for 10 minutes, and cDNA products were
amplified with 40 cycles of denaturation at 94°C for 30
seconds and then annealing and extension at 60°C for 60
FIG. 2. Effects of various fruit juices on conjugation activity
in Caco-2 cells. Caco-2 cells were incubated with 1-naphthol
(200 M) in the presence or absence (control) of different fruit
juices (apple, peach, orange, pineapple, grape fruit, or pome-
granate; 5% [vol/vol]) for 24 hours. The determined quantities
of the 1-naphthyl sulfates (solid columns) and glucuronidates
(open columns) are expressed as percentages of the controls.
All values represent the means of three experiments with stan-
dard deviations. The value for sulfoconjugation of pomegran-
ate was significantly different from those of the control and of
the other juices: *P  .05.
625
seconds. Calculations of the initial amounts of mRNA
were performed according to the cycle threshold
method.13 The mRNA levels were normalized to -actin
levels, which had been quantified by RT-PCR.
Statistics
Data were analyzed by Student’s t test. Values of P  .05
were considered statistically significant.
RESULTS
Effects of different fruit juices on conjugation reactions
in Caco-2 cells
To investigate the possible effects of fruit juices on con-
jugation reactions in the intestinal epithelium, we used Caco-
2 cells, a model of the human intestinal epithelium, and mea-
sured the effects of several fruit juices (5% [vol/vol]) on
both sulfation and glucuronidation within a 24-hour period.
As shown in Figure 2, pomegranate juice had the most po-
tent inhibitory effects on sulfoconjugation in Caco-2 cells,
whereas no significant effects on glucuronidation were ob-
served for any of the fruit juices tested. Pomegranate juice
also inhibits sulfoconjugation in Caco-2 cells in a dose-de-
pendent manner, as shown in Figure 3A, with an IC50 of
2.7% (vol/vol).
Effects of punicalagin on conjugation reactions
in Caco-2 cells
Pomegranate juice was previously shown to have potent
antioxidant, anti-atherosclerotic, and anti-inflammatory ac-
tivities, which are attributed to its high polyphenol con-
tent.14,15 The most abundant of these polyphenols is puni-
calagin, an ellagitannin that has been implicated as the
bioactive constituent responsible for 50% of the potent an-
tioxidant activity of pomegranate juice.14 To elucidate
whether punicalagin is also responsible for the inhibition of
626 SARUWATARI ET AL.
sulfoconjugation that we observed in Caco-2 cells, we iso-
lated this compound from pomegranate juice, as described
in Materials and Methods. As shown in Figure 3C, puni-
calagin strongly inhibited the sulfoconjugation of 1-naph-
thol in Caco-2 cells, whereas no obvious effects could be
observed for glucuronidation (Fig. 3D). The IC50 value for
this inhibition was calculated to be 45 M (n  2).
Effects of pomegranate juice and punicalagin on P-ST
activity in Caco-2 cells
To determine the mechanism of sulfoconjugation inhibi-
tion by pomegranate juice and punicalagin, we measured
their effects on P-ST activity in the cytosol of Caco-2 cells.
As shown in Figure 4, both inhibit P-ST activity in a dose-
dependent manner. We determined the IC50 values in this
case to be 1.6% for pomegranate and 12.4 M for puni-
calagin. In addition, Lineweaver-Burk plots revealed that the
FIG. 3. Effects of pomegranate juice and punicala-
gin on conjugation in Caco-2 cells. Caco-2 cells were
incubated with 1-naphthol and different concentra-
tions of (A and B) pomegranate juice or (C and D)
punicalagin. The levels of 1-naphthyl (A and C) sul-
fate and (B and D) glucuronidate were determined
by analytical HPLC, as described in Materials and
Methods.
mode of inhibition is of a mixed type for both agents
(Fig. 5).
Effects of pomegranate juice on gene expression
of the SULTs and breast cancer-resistant protein
(BCRP) in Caco-2 cells
Recent studies have demonstrated that antioxidative
polyphenols can affect several drug-metabolizing enzymes
in mammalian cells, via the reduction or induction of their
gene expression.16,17 We thus investigated the effects of
pomegranate juice on the expression of SULT genes. In hu-
mans, several subfamilies of SULT genes have been iden-
tified,18 from which we selected SULT1A1 and SULT1A3
because of their substrate specificities. The expression lev-
els of each gene were monitored by RT-PCR after the treat-
ment of Caco-2 cells with 0–5% pomegranate juice for 24
hours. As shown in Figure 6, however, no obvious changes
FIG. 4. Effects of pomegranate juice and punicalagin on
the P-ST activity of Caco-2 cells. The cytosolic sulfotrans-
ferase activities toward 50 M 1-naphthol were measured in
the presence of (A) pomegranate juice or (B) punicalagin, as
described in Materials and Methods.
 POMEGRANATE JUICE INHIBITS SULFOCONJUGATION
FIG. 5. Inhibitory effects of pomegranate juice and puni-
calagin on P-ST activity of Caco-2 cells. Lineweaver-Burk
plots were generated for cells incubated in the absence ()
or presence () of (A) pomegranate juice (0.8%) or (B) puni-
calagin (1.5 M).
were detectable in the levels of these genes, which was also
confirmed by RT-PCR analysis (data not shown).
BCRP is one of the ABC transporters known to be re-
sponsible for the exclusion of sulfoconjugates from cells.19
Certain polyphenols such as quercetin and genistein have
also been reported to affect the expression of several trans-
porter genes.17,20,21 To examine the possibility that pome-
granate juice suppresses BCRP, we assessed the expression
of this gene in Caco-2 cells treated with pomegranate juice
(0–5%). As shown in Figure 6, however, no changes are ev-
ident in BCRP gene expression levels following this treat-
ment.
DISCUSSION
Since the recognition of its potential therapeutic and
chemopreventive properties, including anti-inflammatory,
anticarcinogenic, and anti-atherogenic activities, the con-
sumption of pomegranate juice has increased worldwide.1–3
In our current report, we show that pomegranate juice also
inhibits sulfoconjugation in the human colon carcinoma cell
line, Caco-2, which is an established human intestinal cul-
ture model (Fig. 1). Sulfate conjugation catalyzed by P-STs
is an important pathway in the metabolism of cate-
cholamines and other phenolic compounds, including a
number of drugs and environmental chemicals.22 Among the
extrahepatic tissues, the intestine has the highest levels of
FIG. 6. Effects of pomegranate juice on the gene expression of sul-
fotransferases SULT1A1 and SULT1A3 and of BCRP in Caco-2 cells.
The expression levels of each gene were determined by RT-PCR, af-
ter treatment of the cells with 0–5% pomegranate juice for 24 hours:
lane 1, no treatment control; lane 2, 1.24% (vol/vol); lane 3, 2.5%
(vol/vol); lane 4, 5% (vol/vol); lane 5, () primer control.
627
P-ST activity, which are known to impact upon the bioavail-
ability of drugs and food constituents.23,24 Hence, our pre-
sent data suggest the possibility that high amounts of pome-
granate juice may interact with drugs that are metabolized
by P-ST in the intestines of certain individuals. Several pre-
vious studies have also demonstrated that pomegranate in-
hibits CYP3A activity both in vitro and in vivo.4,5 However,
based upon our current findings, the IC50 of pomegranate
juice for sulfoconjugation is seven times lower than that of
CYP3A (1.6% vs. 11.3%). Sulfoconjugation may therefore
be more profoundly affected by pomegranate juice. The re-
lationship between the inhibitory activities of drug-metabo-
lizing enzymes and the therapeutic effects of pomegranate
should therefore be clarified further.
We also show from our current data that punicalagin, the
most abundant antioxidant component of pomegranate juice,
strongly inhibits sulfoconjugation activity in Caco-2 cells
(Fig. 3). Punicalagin is also the predominant ellagitannin
present in pomegranate juice and can reach levels as high
as 2,000 mg/L juice.14 At this highest level of punicalagin,
a 2.7% concentration of pomegranate juice (equivalent to its
determined IC50 value for sulfoconjugation inhibition) cor-
responds to 54 mg/L of this ellagitannin, or 50 M, which
is quite consistent with its determined IC50 value as in our
present experiments (45 M). These data further suggest that
the major inhibitory component of pomegranate juice is in-
deed punicalagin.
Pomegranate juice and punicalagin were also both found
to strongly suppress cytosolic P-ST activity in vitro (Fig. 4)
in a mixed-type mode of inhibition. The IC50 values in this
case (1.6% and 12.4 M, respectively) are also very com-
patible with those in Caco-2 cells. In addition, there are no
obvious effects of pomegranate juice on the expression of
the SULT1A family of genes or of the BCRP gene (Fig. 6).
These findings indicate that punicalagin in pomegranate
juice mainly inhibits P-ST activity in Caco-2 cells, result-
ing in a decrease in 1-naphthyl sulfate accumulation in the
culture medium. The possibility that pomegranate juice in-
hibits the transporter activity for 1-naphthyl sulfate should
also be elucidated, although in this regard the expression of
BCRP is unaffected by this fruit, as shown in Figure 6.
It is noteworthy in the context of our present data, how-
ever, that the inhibition of these enzymes in vitro will not
necessarily translate into a positive drug interaction in vivo.
Hidaka et al.5 reported that pomegranate juice influences the
628 SARUWATARI ET AL.
pharmacokinetics of carbamazepine in rats, and they con-
cluded from this that the increase in the area under the curve
of carbamazepine by pomegranate juice may be due to the
inhibition of enteric CYP3A activity. Therefore, in vivo stud-
ies investigating the interactions between pomegranate juice
and drugs that are metabolized by P-ST will be necessary
in the future to determine whether the inhibition of P-ST ac-
tivity by pomegranate juice is in fact clinically relevant.
As sulfoconjugation has been shown to be responsible for
the bioactivation of proximal carcinogens in many studies,
this inhibitory feature of pomegranate juice may be related
to the observed anticancer effects of its consumption. Ad-
ditional characterizations should therefore be carried out to
further clarify the molecular basis of the effects of pome-
granate on conjugation reactions.
ACKNOWLEDGMENTS
This work was supported in part by a Grant-in-Aid from
the Ministry of Education, Culture, Sports, Science and
Technology of Japan.
AUTHOR DISCLOSURE STATEMENT
No competing financial interests exist.
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