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Experimental Therapeutics |
Medical Research Council Toxicology Unit [C. I., D. J. L. J., R. V., C-K. L., J-L. L., L. H., S. P., R. J., A. G.] and Department of Oncology [M. W., W. P. S.], University of Leicester, Leicester LE1 9HN, and School of Pharmacy and Pharmaceutical Sciences, De-Montfort University, Leicester LE1 9BH [S. O.], United Kingdom
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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B at the level of the
NIK/IKK
/ß signaling complex (11)
. In cell incubations
in vitro these effects of curcumin were observed in the
10-5–10-4 M
concentration range. The bioavailability of curcumin in rodents has
been shown to be low (12
, 13)
. In a recent study, an oral
dose of 1 g/kg administered to mice yielded a peak plasma level of only
0.5 µM (13)
. There is preliminary
evidence derived from a clinical pilot study that suggests that the
systemic availability of curcumin is also poor in humans, because oral
doses of 4–8 g generated peak plasma levels of as little as 0.41–1.75
µM (14)
. These findings cast doubt
on the assumption that consumption of curcumin as a drug or food
constituent furnishes levels of compound in blood and tissues
sufficient to elicit biological effects associated with
chemoprevention, and they render rational selection of a potentially
chemopreventive dose difficult. It is conceivable that curcumin is
biotransformed to species that are responsible for, or contribute to,
its chemopreventive efficacy. The metabolism of curcumin in humans is
poorly understood. In rodents its major metabolic pathway involves
successive reduction via dihydrocurcumin and tetrahydrocurcumin to
hexahydrocurcumin (see Fig. 1
) and conjugation of mainly tetrahydrocurcumin and hexahydrocurcumin
with glucuronic acid (13
, 15)
. The liver is the primary
organ that generates metabolites from drugs and other xenobiotics.
Early studies suggest that curcumin undergoes extensive metabolism in
rat hepatocytes in vitro, although the metabolic products
were not identified (16)
. The rat has served extensively
as an experimental model in the evaluation of the ability of curcumin
to prevent carcinogen-induced cancer (3
, 4) . In view of
the paucity of the existing data on curcumin metabolism, we tested the
hypothesis that curcumin is biotransformed similarly by human and rat
liver. To that end, hepatocytes obtained from humans and rats were
incubated with curcumin, and their metabolites were identified.
Curcumin was also administered to rats via the i.v. and p.o. routes,
and its plasma metabolites were compared with those found in
suspensions of liver cells. Finally, to investigate whether the
identified metabolites possess pharmacological properties germane to
chemoprevention, we compared their ability with that of curcumin to
inhibit phorbol ester-induced COX-2 expression in human colon cells as
reflected by PGE2 levels.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Cells and Animals.
Nonmalignant HCECs (18)
were obtained from Dr. A. Pfeifer
(Nestlé Research Institute, Lausanne, Switzerland). These cells
were passaged in B50 medium (Biofluids Inc., Rockville, MD) containing
BSA, bovine pituitary extracts, retinoic acid, vitamin C, and
dexamethasone. Male (180–200 g) or female (160–180 g) F344 rats were
purchased from Charles River UK Ltd. (Margate, Kent, United Kingdom) or
Harlan UK Ltd. (Bicester, Oxon, United Kingdom). Rats that were
maintained in a purpose-built animal house in negative pressure
isolators (19–23°C) under a 12-h light/dark cycle received RM1
rodent maintenance diet (SDS, Kent, United Kingdom) and water ad
libitum. Experiments using animals were conducted as stipulated by
Project License 80/1250 granted to the Medical Research Council
Toxicology Unit by the United Kingdom Home Office, and the experimental
design was vetted and approved by the Leicester University Ethical
Committee for Animal Experimentation.
Isolation of Human and Rat Hepatocytes.
Isolation of hepatocytes from humans or rats was performed by the
collagenase perfusion method of Berry and Friend (19)
according to the protocol described by Seglen (20)
.
Healthy liver tissue resected from four Caucasian patients with
secondary hepatic tumors (two females, 38 and 61 years old; two males,
51 and 53 years old) were obtained from the United Kingdom Human Tissue
Bank (Leicester, United Kingdom). Patients had not received medication
known to interfere with liver metabolic activity. Following removal of
the liver from the body, cannulas were immediately inserted into four
to five large blood vessels of the lobe, which was immediately perfused
in theater with kidney perfusion medium (500 ml) and transported in
this fluid on ice. On arrival in the laboratory, the liver was
transferred to a custom-built stainless steel tank and perfused for
20–30 min with liver perfusion medium maintained at 37°C to remove
blood. The liver was then perfused with liver digestion media for
approximately 45 min. The digested liver lobe was transferred to a tray
containing liver suspension medium (DMEM supplemented with human serum
albumin 2%), and the tissue was gently disrupted to release cells.
Undigested tissue was removed by passing the cell suspension through a
series of sieves (successive mesh size: 1 mm, 0.5 mm, and 100 µm).
For the isolation of rat liver cells, male F344 rats (180–220 g) were
anesthetized with pentobarbitone, and the liver was perfused (5 min;
rate, 50 ml/min) via the inferior portal vein with HBSS (containing 1
mM EGTA), which had been presaturated with carbogen
(oxygen/CO2 5%). The liver was digested using
collagenase (100 mg/liter) and calcium chloride (332 mg/liter) in HBSS.
Tissue was gently disrupted and washed through a sieve (100-µm mesh
size) with liver suspension medium. Human or rat cells, thus, obtained
were washed three times and centrifuged (3 min, 50 x g, 4°C). Cells were counted using a hemocytometer
immediately following isolation. Hepatocyte viability determined by the
trypan blue exclusion assay was routinely 80% or above. Hepatocytes in
suspension were maintained on ice for a maximum of 30 min before use.
Incubations with Hepatocytes.
Freshly isolated hepatocytes (2 x 106 cells per ml) were suspended in liver
suspension medium (2 ml) and incubated in a slowly shaking incubator
(37°C). Curcumin dissolved in DMSO was added to furnish a final
concentration of 100 µM. The concentration of DMSO
(maximally 0.1% v/v) in the incubate did not interfere with cell
viability. Control incubates included curcumin with heat-inactivated
hepatocytes or hepatocytes incubated with the vehicle only. Incubations
were terminated after 5, 30, 60, and 120 min by placing vials on dry
ice. During the longest incubation period (2 h) cell viability
decreased to between 60% and 40% of initial values (trypan blue
exclusion test). Before HPLC analysis, suspensions were rapidly
defrosted, immediately extracted twice with ethyl acetate (twice volume
of sample), and mixtures were centrifuged (2800 x g, 4°C, 15 min). The organic layers were removed,
combined, and evaporated to dryness under nitrogen. Samples were
reconstituted in acetonitrile and immediately analyzed by HPLC. In
control experiments, the ability of hepatocytes to conjugate the model
substrate umbelliferone was assessed and found to be intact
(21)
.
Metabolism Studies in Vivo.
Female F344 rats received curcumin either p.o. (gavage, 500 mg/kg;
vehicle, DMSO; dosage volume, 2.0 ml/kg) or i.v. (40 mg/kg; vehicle,
glycerol formal; dosage volume, 1.0 ml/kg). The p.o. dose level was
chosen because it is approximately equivalent to a daily dose of
curcumin when ingested with the diet at 1%, a concentration that has
been frequently used in intervention studies. The i.v. dose chosen was
the highest feasible dose formulated in a solvent suitable for
injection. Animals were subjected to terminal anesthesia
(halothane/nitrous oxide), and blood was removed by cardiac puncture 30
min and 1, 2, 6, 12, and 24 h (p.o. administration) or 5 and 30
min and 1 and 6 h (i.v. administration) after dosing. Blood was
also obtained from animals that had received vehicle only. Blood was
transferred into heparinized centrifuge tubes, and plasma was obtained
by centrifugation (1100 x g, 4°C, 25 min).
Aliquots of plasma were extracted with twice the volume of ethyl
acetate, or mixed with four times the volume of a mixture of
DMSO:methanol (1:4). The mixtures were centrifuged (1000 x g, 15 min), and the supernatant was removed. In the
case of the ethyl acetate extract, the organic layer was evaporated
under nitrogen. Extraction efficiencies from plasma using the ethyl
acetate extraction method for curcumin, hexahydrocurcumin, and curcumin
sulfate were determined by HPLC (see below) as 95 ± 4%, 70 ± 5%, and 49 ± 9%,
respectively. Recovery of curcumin in the case of treatment with
DMSO:methanol was 70 ± 5% (mean ± SD,
n = 3–6 in all these studies). Extraction
efficiencies from hepatocyte suspensions were identical to those
determined for plasma.
HPLC Analysis.
A reversed-phase HPLC method was used to determine the quantity of
curcumin and its putative metabolites that is similar but not identical
to that described before (13)
. A Varian Prostar (230
model) solvent delivery system coupled to a UV-visible detector (310
model) and autosampler (model 410) and a Symmetry Shield RP 18 column
(150 x 3.9 mm; Waters) were used. Detection of
curcumin, curcumin sulfate, and curcumin glucuronide was achieved at
420 nm, whereas tetrahydrocurcumin, hexahydrocurcumin, and
hexahydrocurcuminol were analyzed at 280 nm.
Tetra-(m-hydrophenyl)-chlorin was used as an internal standard. Samples
were reconstituted in acetonitrile:water (1:1), and the injection
volume was 50 µl. A linear gradient of 5–45% acetonitrile in 0.01%
ammonium acetate (pH 4.5) was used for 30 min, followed by an increase
over 20 min to 95% acetonitrile (flow rate, 1 ml/min). The retention
times quoted in the results and in Table 1
were obtained using these conditions. The limits of detection of
curcumin, tetrahydrocurcumin, and hexahydrocurcumin in plasma and
hepatocyte suspensions were between 5 and 10 nM. In the
case of curcumin, the quantitative method was validated using a
2.7-µM solution yielding intra- and interday coefficients
of variation of 5.1% and 9.8%, respectively (n = 4), and a limit of quantitation of 
20
nM. Curcumin calibration curves spanned the
concentration range of 20 nM to 40
µM.
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).
Synthesis of Hexahydrocurcuminol.
An equimolar amount of sodium borohydride was added to
hexahydrocurcumin (3 mM) dissolved in methanol. HPLC
analysis (detection at 280 nm) showed that after 2 h at ambient
temperature all of the hexahydrocurcumin had reacted. Methanol was
removed by evaporation under nitrogen, and the residue was
reconstituted in water (2 ml) and adjusted to pH 4.5. The product was
extracted with ethyl acetate, and the solvent was evaporated under
nitrogen. The structural identity of the product as hexahydrocurcuminol
was confirmed by mass spectrometry (see "Results" and Table 1
).
Mass Spectrometry.
Mass spectrometry was performed on a Quattro Bio-Q tandem
quadruple mass spectrometer upgraded to Quattro MK II
specifications (Micromass, Altrincham, Cheshire, United Kingdom) with a
pneumatically assisted electrospray interface. Samples were analyzed in
negative ion mode. The temperature was maintained at 120°C, the
operating voltage of the electrospray capillary was 3.88 kV and the
cone voltage 32 V. Tandem mass spectrometric experiments were conducted
using argon as the collision gas and a collision energy of 25 eV.
Samples were dissolved in water:methanol (1:1) and introduced into the
mass spectrometer via flow injection using a Varian 9012 Solvent
delivery system (Varian, Walton-on-Thames, United Kingdom) and a
Rheodyne 7125 injector (Cotatai, CA). HPLC conditions were as
described under HPLC analysis above, except that the linear gradient
program was: acetonitrile (5- 45%) in 0.01% ammonium acetate (pH 4.5)
for 60 min (rather than 30 min), followed by an increase for 20 min to
95% acetonitrile (flow rate, 1 ml/min). These are the conditions of
the chromatogram shown in Fig. 4
, and they differ from those shown in
Fig. 2
. The flow was split so that only 115 µl was introduced into the mass
spectrometer. In some experiments, the solution was introduced by
continuous infusion using a Harvard Apparatus model 22 syringe pump
(Harvard Apparatus, South Natick, MA) pumped at a flow rate of 10
µl/min.
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RESULTS |
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25 and 31 min, consistent with curcumin sulfate and glucuronide,
respectively (see below). HPLC analysis using detection at 280 nm
yielded at least four metabolite peaks; the two major ones were
characterized by retention times of 22.5 and 24.4 min (Fig. 2)
. Both
species were found in hepatocytes from humans (Fig. 2A)
and
rats (Fig. 2B)
, and they were absent from chromatograms of
hepatocyte incubations from which curcumin had been omitted. The peak
characterized by the retention time of 24.4 min coeluted with authentic
hexahydrocurcumin, and mass spectrometric analysis of a dried residue
of the eluent was collected at the pertinent retention time confirmed
its identity (Table 1)
. The other major metabolite with a retention
time of 22.5 min afforded a molecular ion of m/z 375 on mass
spectrometric analysis (Table 1)
, thus containing two mass units more
than hexahydrocurcumin. In a separate experiment, authentic
hexahydrocurcumin was incubated with rat hepatocytes and rapidly
metabolized to the species characterized by a retention time of 22.5
min and the molecular ion m/z 375. These findings are consistent with
the possibility that the metabolite was generated from curcumin via
hexahydrocurcumin. Furthermore, the same molecule was generated
chemically on treatment of hexahydrocurcumin with the reducing agent
sodium borohydride. We infer from these results that the second major
hepatocytic metabolite of curcumin is hexahydrocurcuminol (Fig. 1)
.
Fig. 3
shows the time course of disappearance of curcumin and concurrent
generation of its two major metabolites in suspensions of rat
hepatocytes. The ratio of integrated peak areas of hexahydrocurcumin
over hexahydrocurcuminol after incubation of rat or human hepatocytes
with curcumin for 2 h furnished values of 1.0 ± 0.1 in the case of rat hepatocytes as compared with 3.2 ± 0.6 (mean ± SD, n = 3
for each) for human hepatocytes. Taken together, the results obtained
in experiments with hepatocytes demonstrate, first, that metabolic
reduction of curcumin to hexahydrocurcumin is rapid, followed by the
reduction of the carbonyl moiety to hexahydrocurcuminol and, second,
that overall reduction of curcumin to hexahydrocurcuminol, the ultimate
reduction product of curcumin, occurs more extensively in rat than in
human hepatocytes.
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. Both species persisted in
the plasma after p.o. dosing for up to 6 h. The concentrations of
conjugates measured at 30 min and 6 h after p.o. administration
were between 1.7 and 1.5 µM for curcumin
glucuronide and between 0.21 and 0.35 µM for
curcumin sulfate (mean of three experiments in each case). At later
time points, curcumin conjugates were detectable but at levels below
the limit of quantitation. The third major metabolite in the extract of
plasma decreased in size during incubation of plasma extracts with
ß-glucuronidase with concomitant increase of the curcumin sulfate
peak. It was also decreased on incubation with arylsulfatase with
concomitant elevation of the curcumin glucuronide peak (data not
shown). Mass spectral analysis with ion-selected monitoring furnished a
molecular ion of m/z 622. These results characterize this metabolite as
curcumin glucuronide sulfate. Further chromatographic analysis of the
plasma extracts by ion-selected monitoring yielded peaks with m/z 367,
373, 375, and 549, in addition to the curcumin conjugate peaks,
consistent with the presence of curcumin, hexahydrocurcumin,
hexahydrocurcuminol, and hexahydrocurcumin glucuronide, respectively
(Fig. 4)
. Finally, for unambiguous identification, curcumin glucuronide and
curcumin sulfate were synthesized using UDP glucuronic acid plus
bacterial glucuronyltransferase and triethylamine sulfur trioxide,
respectively. On HPLC analysis these molecules afforded peaks with
retention times identical to those of the two curcumin conjugates
identified in rat plasma after oral dosing (data not shown). They also
furnished mass spectral fragmentation patterns compatible with those
obtained from the conjugates isolated from the rat plasma (Table 1)
.
These curcumin conjugates were also observed after i.v. administration
of curcumin (Fig. 5A)
. Parent drug disappeared very rapidly, and, at 30 min
after i.v. administration, curcumin levels were below the limit of
quantitation (Fig. 5B)
. Curcumin conjugates were present at
levels near the limit of detection at the 1 h time point, but they
were not evident at 6 h.
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shows that curcumin decreased PMA-inducible PGE2
production down to almost preinduction levels. Tetrahydrocurcumin,
hexahydrocurcumin, and curcumin sulfate reduced it by 31%, 37%, and
22%, respectively. Hexahydrocurcuminol was devoid of inhibitory
activity. In a confirmatory Western analysis using a COX-2 monoclonal
antibody, curcumin was shown to reduce PMA-induced COX-2 protein
expression consistently by 60–70%. In contrast, the curcumin
metabolites interfered with COX-2 protein induction only weakly or not
at all (data not shown).
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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hexahydrocurcumin is rapid, and the
overall rate of curcumin reduction seems slower in human than in rat
liver cells; (c) the predominant metabolites of curcumin in
rat plasma in vivo are curcumin glucuronide and curcumin
sulfate, whereas hexahydrocurcumin and hexahydrocurcuminol, the major
metabolites of curcumin in hepatocyte suspensions, occur only in small
amounts in rat plasma after curcumin administration; (d)
curcumin metabolites are markedly less able to inhibit inducible COX-2
expression than their metabolic progenitor.
Whereas tetrahydrocurcumin, hexahydrocurcumin, and curcumin glucuronide
have been described as products of the metabolic reduction of
curcumin in rodents before (13
, 15)
, this is the first
study that describes hexahydrocurcuminol and curcumin sulfate as
curcumin metabolites. Hexahydrocurcuminol occurs naturally in the
rhizomes of the ginger plant Zingiber officinale
(24)
and of Curcuma xanthorrhiza
(17)
, the latter of which is, together with Curcuma
longa, the major plant source of curcumin. Our results suggest
that curcumin glucuronide and curcumin sulfate are generated only in
small amounts in hepatocytes, whereas they are abundant in rat plasma
after administration of curcumin. This discrepancy is consistent with
the hypothesis that they are generated, at least in part,
extra-hepatically, probably in the gastrointestinal tract
(25)
. The metabolic conversions described here and their
interelationship are described in Fig. 7
: the figure shows that curcumin undergoes metabolism to its sulfate and
glucuronide and sulfate-glucuronide conjugates. The liver reduces
curcumin to hexahydrocurcumin and hexahydrocurcuminol, probably via the
intermediacy of dihydrocurcumin and tetrahydrocurcumin, two species
that were identified in mice (13)
, but not in the present
study in rat plasma or rat and human hepatocytes. Dihydrocurcumin,
tetrahydrocurcumin, and hexahydrocurcumin generate glucuronides, all
three of which were characterized in mice (13)
, and
hexahydrocurcumin glucuronide was also found here in rats.
Hexahydrocurcuminol constitutes the ultimate product of curcumin
reduction, and it is conceivable that it is also a substrate of
conjugating enzymes. However, identification of hexahydrocurcuminol
glucuronide or hexahydrocurcuminol sulfate has thus far been elusive.
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are pharmacological deactivation pathways. Information as to
the biological potency of curcumin metabolites is scarce. Only
tetrahydrocurcumin has previously been subjected to comparative
pharmacological studies. It was found to be more potent than curcumin
in the carrageenin-induced rat paw edema test for anti-inflammatory
activity (26)
, and at least as potent an antioxidant as
curcumin in rabbit erythrocyte membrane ghosts and rat liver microsomes
in vitro (27
, 28)
. In contrast,
tetrahydrocurcumin was much less potent than curcumin as inducer of
quinone reductase in cells in vitro (29)
or as
inhibitor of 12-O-tetradecanoylphorbol-13-acetate-induced
tumor promotion in mouse skin (30)
. Our results intimate
that the unsaturated nature of the diarylheptanoid chain and free
phenolic moieties may be pivotal pharmacophoric features of molecules
related to curcumin for optimal inhibition of COX-2 expression, the
in vitro paradigm of chemopreventive activity chosen here. The prolonged presence in rat plasma of curcumin glucuronide and curcumin sulfate after oral administration as described here may be the corollary of slow absorption of curcumin from the gastrointestinal tract and/or of its intrahepatic circulation. This contention is consistent with results of a recent drug distribution study in mice (13) . It suggests low, probably subefficacious, curcumin levels in a variety of tissues, which amounted to between 1 nmol/g in brain and 72 nmol/g in liver 1 h after an i.p. dose of 100 mg/kg of the drug. The intestine was the exception in that it contained 300 nmol/g tissue. The results presented here, together with information published previously, suggest that curcumin taken p.o. might prevent cancer of the colon more effectively than malignancies in other tissues. This conclusion provides a rationale for trials of curcumin to be conducted with the aim of preventing human colorectal cancer.
In conclusion, the results described here shed new light on the role of the liver in the metabolic fate of curcumin because they suggest that hepatic metabolism of curcumin is a pharmacological deactivation step. Overall, the results buttress the rationale for clinical evaluation of curcumin in the chemoprevention of human colorectal cancer. The relevance of the findings discussed here for humans who consume curcumin will eventually be established in clinical studies of curcumin, in which pharmacokinetic and pharmacodynamic parameters will be correlated.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported in part by core funding from the
Medical Research Council and a Medical Research Council postgraduate
studentship (to C. I.). 
2 To whom requests for reprints should be
addressed, at Medical Research Council Toxicology Unit, University of
Leicester, Hodgkin Building, P.O. Box 138, Leicester LE1 9HN, United
Kingdom. Phone: 44-116-252-5618; Fax: 44-116-252-5616; E-mail: ag15{at}le.ac.uk
3 The abbreviations used are: COX, cyclooxygenase;
HCEC, human colonic epithelial cell; HPLC, high-performance liquid
chromatography; PGE2, prostaglandin E2; PMA,
phorbol-12-myristate-13-acetate.
Received 6/13/00. Accepted 11/29/00.
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 N. Li, X. Chen, J. Liao, G. Yang, S. Wang, Y. Josephson, C. Han, J. Chen, M.-T. Huang, and C. S. Yang Inhibition of 7,12-dimethylbenz[a]anthracene (DMBA)-induced oral carcinogenesis in hamsters by tea and curcumin Carcinogenesis, August 1, 2002; 23(8): 1307 - 1313. [Abstract] [Full Text] [PDF]
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 S. Somasundaram, N. A. Edmund, D. T. Moore, G. W. Small, Y. Y. Shi, and R. Z. Orlowski Dietary Curcumin Inhibits Chemotherapy-induced Apoptosis in Models of Human Breast Cancer Cancer Res., July 1, 2002; 62(13): 3868 - 3875. [Abstract] [Full Text] [PDF]
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S. Perkins, R. D. Verschoyle, K. Hill, I. Parveen, M. D. Threadgill, R. A. Sharma, M. L. Williams, W. P. Steward, and A. J. Gescher Chemopreventive Efficacy and Pharmacokinetics of Curcumin in the Min/+ Mouse, a Model of Familial Adenomatous Polyposis Cancer Epidemiol. Biomarkers Prev., June 1, 2002; 11(6): 535 - 540. [Abstract] [Full Text] [PDF]
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C. R. Ireson, D. J. L. Jones, S. Orr, M. W. H. Coughtrie, D. J. Boocock, M. L. Williams, P. B. Farmer, W. P. Steward, and A. J. Gescher Metabolism of the Cancer Chemopreventive Agent Curcumin in Human and Rat Intestine Cancer Epidemiol. Biomarkers Prev., January 1, 2002; 11(1): 105 - 111. [Abstract] [Full Text]
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S. M. Plummer, K. A. Hill, M. F. W. Festing, W. P. Steward, A. J. Gescher, and R. A. Sharma Clinical Development of Leukocyte Cyclooxygenase 2 Activity as a Systemic Biomarker for Cancer Chemopreventive Agents Cancer Epidemiol. Biomarkers Prev., December 1, 2001; 10(12): 1295 - 1299. [Abstract] [Full Text] [PDF]
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 A. Asai and T. Miyazawa Dietary Curcuminoids Prevent High-Fat Diet-Induced Lipid Accumulation in Rat Liver and Epididymal Adipose Tissue J. Nutr., November 1, 2001; 131(11): 2932 - 2935. [Abstract] [Full Text] [PDF]
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R. A. Sharma, H. R. McLelland, K. A. Hill, C. R. Ireson, S. A. Euden, M. M. Manson, M. Pirmohamed, L. J. Marnett, A. J. Gescher, and W. P. Steward Pharmacodynamic and Pharmacokinetic Study of Oral Curcuma Extract in Patients with Colorectal Cancer Clin. Cancer Res., July 1, 2001; 7(7): 1894 - 1900. [Abstract] [Full Text] [PDF]
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R. A. Sharma, C. R. Ireson, R. D. Verschoyle, K. A. Hill, M. L. Williams, C. Leuratti, M. M. Manson, L. J. Marnett, W. P. Steward, and A. Gescher Effects of Dietary Curcumin on Glutathione S-Transferase and Malondialdehyde-DNA Adducts in Rat Liver and Colon Mucosa: Relationship with Drug Levels1 Clin. Cancer Res., May 1, 2001; 7(5): 1452 - 1458. [Abstract] [Full Text]
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