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Medical Research Council Toxicology Unit, University of Leicester, Leicester LE1 9HN, United Kingdom [E. A. H., P. A. D., A. G.], and Jodrell Laboratory, Royal Botanic Gardens Kew, Richmond, Surrey TW9 3AB, United Kingdom [T. K., M. S. J. S.]
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Clinically, chemopreventive agents that suppress tumor development are of primary interest, because they might counteract cancers even in tissues in which carcinogenic initiation has already occurred. A number of mechanisms have been proposed by which such agents suppress tumors, but they all culminate in interference with proliferation and survival of initiated cells. In the light of these considerations, we decided to study the potential colon- and breast tumor-suppressive properties of rice further. Specifically, we wanted to test the hypotheses that: (a) rice contains substances that interfere with the proliferation or colony-forming ability of breast or colon cells; and (b) there is a difference between white and brown rice in terms of antiproliferative or anticlonogenic properties. Because the extracts of brown rice bran did indeed inhibit cell growth, they were chemically analyzed and found to contain phenolic constituents. We investigated the potential role of these phenols in the mediation of the growth inhibition exerted by brown rice bran extract. Overall, the study was designed to contribute to the knowledge base that may eventually lead to the dispensation of rational advice concerning both the potential usefulness of particular diets and the prudence of recommending consumption of specific nutriceuticals isolated from the diet.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Chemicals.
Cell culture medium and reagents were obtained from Life Technologies,
Inc. (Paisley, Scotland), except Vitrogen 100, which was purchased from
Collagen Corp. (Palo Alto, CA), and human fibronectin, which was bought
from Sigma Chemical Co. (Poole, United Kingdom). To test whether the
phenols that we identified in the brown rice fractions (see below) have
cell growth-modulatory properties themselves and may therefore
contribute to the activity of the fractions investigated, we purchased
pure caffeic acid, ferulic acid, p-coumaric acid,
methoxycinnamic acid, sinapic acid, vanillic acid, and protocatechuic
acid to be able to use them in amounts sufficient for assays in cells
in vitro. These phenols, genistein and two reagents used in
the MTS assay, MTS and phenazine methosulfate, were obtained from
Sigma. Brown and white rice varieties were purchased from a local
supermarket.
Preparation of Rice Extract.
Brown or white rice (1.5 kg) was cooked in water (2.7 liter) for 30
min. The rice was cooled, mixed with water, and successively and
exhaustively extracted with diethyl ether, ethyl acetate, and methanol
(twice at 1.5 liter each). Rice bran was prepared by milling brown rice
with a food processor prior to cooking. Bran powder was separated from
the endosperm with a colander (mesh size, 
1 mm). The bran was boiled
in water and extracted as described above. Extracts were concentrated
in vacuo, and the residues were analyzed by HPLC using a
Waters system 600 (with 717 autosampler) linked to a LiChrosphere RP-18
C18 column (250 x 4.6 mm; 5 µm) and a
Waters 996 photodiode array detector. For detection, wavelengths were
scanned between 200 and 400 nm. The mobile phase consisted of 2%
acetic acid in water (eluant A), and methanol:acetic acid:water
(18:1:1; eluant B). A linear gradient was run from 40 to 100% B over
20 min (flow rate, 1 ml/min), followed by 100% B for 5 min, before the
column was reconditioned prior to injection of the next sample.
Chromatographic Separation and Analysis of Fractions.
The ethyl acetate extracts of brown rice or brown rice bran were
chromatographed on an Amberlite XAD-2 styrene-divinylbenzene polymer
column (diameter 5 x 32 cm) and eluted with increasing amounts of
methanol (0–100%) in water. Ten fractions (250 ml each) were
collected and analyzed by HPLC using the eluant as described above. The
first fraction did not contain any detectable peaks and was not tested
further. The subsequent nine fractions afforded HPLC peaks. They will
be referred to as "fractions 1–9." Fractions were eluted with 10%
methanol:water (fraction 1) to 100% methanol (fraction 9). Weights of
fractions 1–9 were 1.42, 0.11, 0.14, 0.88, 0.39, 0.40, 0.39, 0.08, and
0.06 g, respectively. Tentative assignment of chromatographic
peaks in the fractions to compounds was performed on the basis of
chromatographic retention times, UV absorption spectra (using data in a
library of flavonoids at the Jodrell Laboratory providing retention
times and UV absorption maxima), and by cochromatography with authentic
reference compounds. Unambiguous identification was achieved by
quadrupole ion trap mass spectrometry (Finnigan LCQ instrument) in
negative atmospheric pressure chemical ionization mode, linked to the
HPLC-UV detector (set at 260 nm). The HPLC eluant used was 25–100%
methanol in water for 20 min; the flow rate was 1 ml/min. The
[M-H]- ions at the apposite retention times
were subjected to tandem mass spectrometric analysis in which the
appropriate fragments corresponding to
[M-H-CH3]-,
[M-H-OCH3]-, and/or
[M-H-CO2]- were
observed. It has to be pointed out that the HPLC retention times (as
shown in Table 1
) of individual phenols do not reflect accurately the order in which the
phenols eluted from the XAD-2 column as constituents of the fractions,
reflecting chemical differences between the columns used for
fractionation and for HPLC analysis.
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450 g of dried plant
material. Tricin was recrystallized from methanol, and its structure
was confirmed by means of HPLC retention time, UV absorption
(
max in methanol 352, 266, and, 243 nm),
1H NMR, and mass spectra. In the
1H NMR spectrum, tricin (in DMSO-d6,
500 MHz) afforded the following diagnostic resonances (
in ppm):
3.88 (6H, H-3' and -5'), 6.21 (1H, H-6), 6.56 (1H, H-8), 6.96 (1H,
H-3), 7.32 (2H, H-2' and -6'), 9.24 (1H, 4'-OH), 10.73 (1H, 7-OH), and
12.94 (1H, 5-OH). It yielded the following diagnostic mass units
(m/z with abundance expressed as % in parentheses): 329
(100), 119 (23)
, 141 (8)
, 223 (4)
, 299 (4)
, and 157 (3)
.
Assessment of Cell Proliferation and Clonogenicity.
Stock solutions of ethyl acetate extract of brown rice, its
chromatographic fractions or of phenols detected in the fractions were
taken up in DMSO and diluted in HEPES buffer (1 M; pH 7.4),
such that the final concentrations of DMSO and HEPES in the cell
incubations did not exceed 0.02% and 10 mM, respectively,
concentrations that did not alter cell growth or clonogenicity. Effects
of the fractions of the ethyl acetate extract and of the phenols on the
proliferation and clonogenicity of breast and colon cells were
investigated both in high density cultures using the MTS assay and
under low cell density conditions by clonogenic assay. Extracts were
applied at a concentration of 100 µg/ml.
In the MTS assay, six cell types were used, three human breast-derived lines, immortalized HBL 100, tumorigenic MCF 7 and MDA MB 468 cells, and three human colon-derived cell types, immortalized HCEC and tumorigenic SW 480 and HT 29 cells. Cells (750 per well in 0.2 ml of medium) were seeded in 96-well plates and cultured for 4 h prior to treatment. Extract and fractions were added to cellular incubates at 100 µg/ml. Solvent control incubates contained the appropriate mixture of buffer and DMSO. Cells were exposed to test substances for 7 days, after which mitochondrial function of the cells was determined by the MTS assay as described by Malich et al. (19) using 2 h as the time period of incubation with MTS and an automated plate reader set at a wavelength of 490 nm (Labsystems iEMS Reader MF). In this assay, the number of viable cells is reflected by extent of reduction of MTS by intact mitochondria to generate a dye that absorbs at 490 nm.
The effect of test substances on clonogenicity was determined in SW 480 cells (300 per well in 2 ml) and MDA MB 468 cells (200 per well in 2 ml) in six-well plates. Cells were allowed to attach for 4 h prior to exposure to test substances. MDA MB 468 cell cultures contained 50% conditioned medium, as described previously (20) . Phenols were applied either at 50 µM (MDA MB 468 cells) or 200 µM (SW 480 cells), except tricin, which was applied at 50 µM throughout. After an addition of test substance, cells were cultured for 10 days before the colony number was assessed. Cells were washed with PBS, fixed in 100% ethanol, and stained with 25% Giemsa blue solution. Colonies consisting of >10 cells were counted. Colony-forming efficiency of SW 480 and MDA MB 468 cells was 59 ± 16.9% and 58 ± 9.5%, respectively. Genistein (30 µM) was included as a positive control in both assay types.
IC50s (mean ± SD; see Table 4
) were
determined for individual phenols from at least three independent
clonogenic assay experiments in which the following concentrations were
used: caffeic acid at 1, 5, 10, 25, and 50 µM;
protocatechuic acid at 50, 100, 200, and 300 µM in the
MDA MB 468 cells and 10, 20, 40, and 50 µM in the SW 480
cells; tricin at 0.05, 0.1, 0.5, 1.0, and 10 µM in the
MDA MB 468 and 10, 20, 25, 40, and 50 µM in the SW 480
cells. IC50s for each data set were derived from
graphs in which colony number, expressed as percentage of control
incubate, was plotted against phenol concentration.
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and 4
, cell colony numbers are presented as predicted means
as determined by the ANOVA model; the SD of the set is shown on the
control bar only. For Tables 2
and 3
, absorbance values obtained in the MTS assay were analyzed as above,
but results are presented as percentages of control cell cultures
(omitting extracts or phenols).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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. White rice afforded an ethyl acetate extract of similar
weight to that of the brown variety, but it contained only traces of
phenols (Fig. 1A)
. Further extraction of either rice variety
with methanol and subsequent concentration yielded gummy materials,
characteristic of oligo- and polysaccharides. In the case of brown
rice, the methanol extract contained also trace amounts of phenols.
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, which suggests that the bran layer
rather than the rice kernel is the predominant location of phenolic
constituents of rice. The ethyl acetate extract of brown rice or bran
was subjected to column chromatographic fractionation on Amberlite
XAD-2 using methanol:water with increasing concentrations of the former
as eluant. This procedure furnished nine phenol-enriched fractions that
were further analyzed by HPLC. Characterization of compounds associated
with selected peaks in the chromatograms of the fractions was
performed, and the structures of the identified compounds are shown in
Fig. 2
. Precise quantitation of the amounts of each compound in the fractions
was not carried out, but approximate percentage values, with respect to
the weight of the fractions, were computed by integration of the
chromatographic peak areas (Table 1)
. On the basis of the weights of
the fractions collected and the tentative assumption that the recovery
of constituents from the chromatography column was 100%, computation
of the approximate content of these substances in brown rice yields the
following estimated values, expressed as µg per 100 g dry weight
of rice: 66 µg of protocatechuic acid, 390 µg of
p-coumaric acid, 28 µg of caffeic acid, 334 µg of
ferulic acid, 105 µg of sinapic acid, and 7 µg of tricin. It is
pertinent to point out that because the rice was boiled before
extraction, the compounds thus far identified are probably products of
hydrolysis of their glycosidic precursors. The fractions also contained
other compounds at low levels, including flavonoids, which we have not
yet identified.
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. Although it
caused a significant decrease in numbers of MDA MB 468, HBL 100, SW
480, and HCECs, proliferation of MCF 7 or HT 29 cells was not affected.
Four of the nine fractions of the brown rice extract decreased cell
numbers in some but not all cell types (Table 2)
; fraction 1 reduced
numbers of the three breast and SW 480 colon cells, fraction 3 caused a
significant decrease in HBL 100 cells, and the most lipophilic
fractions, 8 and 9, attenuated consistently the number of viable cells
of all six types, thus resembling genistein, which served as positive
control. In contrast, fractions 2–7 increased, rather than decreased,
the numbers of colon cells to a moderate extent over control cell
numbers.
In the clonogenic assay, the unfractionated brown rice bran extract
decreased colony formation in both cell types. Its effect was
particularly potent against MDA MB 468 cells, the colony-forming
ability of which was reduced by 90%, comparable with the efficacy of
genistein (Fig. 3)
. The white rice extract did not affect clonogenicity (result not
shown). The clonogenicity of SW 480 cells was inhibited by all nine
rice fractions, with fractions 4, 5, and 8 being most potent (Fig. 3A)
. Formation of MDA MB 468 cell colonies was decreased by
fractions 4, 5, 8, and 9 of the rice bran extract (Fig. 3B)
.
Effects of Phenols on Number of Viable Cells and Clonogenicity.
The eight phenols that had been identified as constituents of the ethyl
acetate extract of brown rice and rice bran (for structures, see Fig. 2
) were characterized in terms of their antiproliferative and
anticlonogenic potential in comparison with genistein. They were
applied at 50 µM (MTS assay) and 50 and 200
µM (clonogenic assay) and compared with genistein (30
µM). Using the MTS assay, caffeic acid caused a
significant decrease in numbers of viable cells in all six lines except
HBL 100 (Table 3)
. Tricin was active in MDA MB 468, HBL 100, and HT 29
cells but not in MCF 7, HCEC, and SW 480 cells. Ferulic acid decreased
the number of viable HCECs, and methoxycinnamic acid reduced numbers of
both HCEC and HT 29 cells.
In low-density cultures of SW 480 cells, caffeic acid, ferulic acid,
p-coumaric acid, methoxycinnamic acid, sinapic acid,
vanillic acid, protocatechuic acid (all at 200
µM), and tricin (50 µM)
interfered with colony formation (Fig. 4A)
. The clonogenicity of MDA MB 468 cells was inhibited in
response to caffeic acid, ferulic acid, and tricin (50
µM; Fig. 4B
). Table 4
shows the IC50s for inhibition of clonogenicity
for the three most anticlonogenic compounds, caffeic acid,
protocatechuic acid, and tricin. Of these phenols, tricin was the most
potent with IC50s of 16
µM in the colon and 0.6
µM in the breast cell line.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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0.25%
of fraction 8 (see Table 1
). Therefore, the concentration of tricin as
constituent of fraction 8 was 0.7 µM when the fraction
was applied at 100 µg/ml to the cellular incubation. This value is
indeed close to the IC50 of tricin, which was 0.6
µM when it was added as pure compound to the MDA MB 468
cell incubation mixture in the clonogenic assay (see Table 4
).
Furthermore, ferulic acid may have contributed to the anticlonogenicity
of fractions 4 and 5 in both breast and colon cells, and sinapic acid
may have been involved with the inhibiting effect of fraction 7 on the
clonogenicity of SW 480 cells. The interpretation of these findings is
confounded by the fact that fractions 3–7 elevated, rather than
decreased, numbers of viable colon cells (Table 2)
. This result
suggests that the rice bran extract contains both growth-inhibitory and
-stimulatory constituents, intimating the possibility that the
potentially beneficial effect of some of the bran components may be
masked, or counteracted, by the opposite activity of others.
There are some incongruities when the results presented above in the
clonogenic assay are compared with those in the MTS assay. For example,
fractions 4 and 5 interfered with clonogenicity (Fig. 3)
but did not
reduce the numbers of viable cells as measured by the MTS assay (Table 2)
. Likewise, protocatechuic acid at 50 µM was unable to
reduce numbers of viable cells of any of the six types (Table 3)
, but
its IC50 with respect to anticlonogenicity in
SW480 cells was 21.6 µM (Table 4)
. These discrepancies
are consistent with the notion that the growth behavior of cells
cultured at very low density in the clonogenic assay is more
susceptible to cytotoxic and cytostatic stimuli than that of more
densely seeded cells. An illustrative example of this phenomenon is the
susceptibility of lung carcinoma cells toward the growth effects of the
marine compounds bistratene A (23)
and bryostatin 1
(24)
. In contrast, it is more difficult to explain how
fraction 1 reduced the number of viable MDA MB468 cells (Table 2)
without affecting their clonogenicity (Fig. 3)
. Furthermore, there were
inconsistencies concerning the effects of the fractions on the one side
and those of their constituent phenols on the other. For example, the
potent anticlonogenic activity of fractions 4 and 5 against SW480 cells
(Fig. 3)
contrasts with only weak efficacy of methoxycinnamic acid and
ferulic acid (Fig. 4)
, two phenols identified as constituents of these
fractions. Fractions 8 and 9, which contain tricin, inhibited the
viability of SW 480 cells in the MTS assay (Table 2)
, but tricin (50
µM) on its own failed to affect it (Table 3)
. This lack
of correlation between activities of fractions and constituent phenols
suggests that agents other than those characterized above are likely to
contribute to the observed effects of the fractions, and it reinforces
the conclusion that the bran extract contains phytochemicals with
growth-inhibiting and -promoting properties.
One potential role of in vitro experiments of the type
described here is to furnish conjectures as to the potential tissue
specificity of the agents under study. The results outlined above were
obtained in three breast and three colon cell types and allow tentative
suggestions as to potential differences in sensitivity between these
two tissues. The rice bran extract interfered more potently with the
colony formation of the breast than of the colon cells (Fig. 3)
,
whereas the individual fractions were overall more potently
anticlonogenic in the colon cell lines. Nevertheless, there was no such
tissue specificity of extract or fractions in the MTS assay. In the
clonogenic assay, all eight phenols investigated exerted activity
against the colon cells, whereas only three, caffeic acid, ferulic
acid, and tricin, affected the breast cells, albeit at lower
concentrations than those used in the SW 480 cell assay. Protocatechuic
acid and tricin showed the most striking indication of potential tissue
specificity in terms of anticlonogenicity (Table 4)
. The colon cancer
cells were eight times more sensitive to protocatechuic acid than the
breast cells, whereas the breast cancer cells were 25 times more
sensitive toward tricin than the colon cells. In the MTS assay, ferulic
and methoxycinnamic acids reduced the numbers of viable colon cells but
not breast cells. Specificity was not observed when effects of rice
fractions and constituent phenols on the tumorigenic cell types were
analyzed in comparison with those on the immortalized ones.
Of the eight phenols investigated here, the flavone tricin is arguably the most potent anticlonogenic agent in cells of either breast or colon tissue origin. Tricin occurs predominantly as 5-glucoside in the Gramineae (18) , the plant family to which wheat, barley, maize and other grain crops apart from rice belong. It was first isolated from wheat straw almost 70 years ago (25) . Although a plethora of information exists on biological properties pertinent to anticarcinogenesis for flavonoids and isoflavonoids such as genistein and quercetin, there is to our knowledge only one report with reference to tricin, which suggests that tricin isolated from stems of the plant Wikstroemia indica (Thymelaeaceae) possesses antineoplastic activity against the P388 murine leukemia model (26) . The potency of tricin documented here renders it an attractive candidate for elucidation of its cancer chemopreventive efficacy in vivo, especially with respect to breast cancer, and of its biochemical mechanisms, which are unknown.
The results presented here on cell growth modulation by rice
constituents have to be interpreted in the light of the beneficial
effects of rice that have been published before. Rice bran constituents
possess antimutagenic (7, 8, 9)
, antitumor-promoting
(10)
, and cytotoxic (14, 15, 16)
properties.
Among the bioactive constituents are the triterpene cycloartenol
ferulate, which counteracted the tumor-promoting activity of phorbol
ester in the skin of
7,12-dimethylbenz[a]anthracene-initiated mice
(10)
,
(10E,12Z)-9-hydroxy-10,12-octadecadienoic acid
(14)
, and hydrolyzed anthocyanin (16)
, which
were cytotoxic against murine P388 leukemia and HCT-15 cells,
respectively, in vitro, and a dextran-like 
-glucan, which
exhibited antitumor activity against Meth-A fibrosarcoma and Lewis lung
carcinoma grown in mice in vivo (15)
. Rice bran
polysaccharides inhibited gastrointestinal carcinogenicity induced by
N-ethyl-N'-nitrosoguanidine (13)
.
Arabinoxylan hemicellulose, an indigestible rice bran fiber
macromolecule, decreased exposure of rodents to carcinogenic
xenobiotics by facilitating their intestinal excretion
(11)
, and hemicellulose inhibited
1,2-dimethylhydrazine-induced intestinal carcinogenesis in rats
(12)
. Among other agents that have been found in rice and
may conceivably confer cancer chemopreventive activity on this staple
diet are ß-sitosterol (27
, 28)
, phytic acid
(29)
, and tocotrienols and tocopherols (30)
.
The results described here add eight phenols to the list of rice
constituents with potential cancer chemopreventive activity, but it is
important to note that although these agents are discussed here as
constituents of rice, they occur ubiquitously in the plant kingdom.
Are there any conclusions of the results presented above that might be exploited for dietary advice? The results support the hypothesis that brown rice contains substances with putative cancer preventive properties, and that these substances are present at much lower levels in the white variety. Furthermore, the phenols contained in rice bran described here may be associated with cancer chemopreventive activity of brown rice. Thus, the consumption of rice bran or brown rice instead of milled white rice may be advantageous with respect to cancer prevention. This conclusion has to be interpreted in the light of the fact that worldwide the consumption of brown rice is probably minuscule as compared with that of the white variety. The conclusion is consistent with the general realization that consumption of whole grain foodstuffs, including whole-grain bread, pasta, and rice is more beneficial to the maintenance of human health than that of their refined products. In an overview of the epidemiological evidence, whole-grain intake was associated with an odds ratio of <1, suggesting protection in 11 of 12 studies, and whole-grain diets have been suspected to be of particular benefit in the prevention of colorectal, gastric, and endometrial cancers and coronary heart disease (31) . The conclusion also enforces the dietary recommendations proffered by the World Cancer Research Fund and American Institute for Cancer Research, which advocate diets rich in whole-grain and minimally refined cereals (32) .
There are several reasons that underline the tentative nature of the
conclusions drawn from our results: (a) it is possible that
it is the intact rice matrix containing the sum of nutrient and
nonnutrient constituents that is required to confer optimal
chemopreventive activity on brown rice, and this may be diminished or
lost on investigation of fractions or constituents in isolation;
(b) the complete spectrum of growth-inhibitory constituents
contained in brown rice was not elucidated by us. It is therefore
conceivable that agents other than those identified and discussed here
contribute much more potently to the antiproliferative and
anticlonogenic activity of the rice extract than the phenols which were
characterized here, and furthermore, there was evidence of
growth-promoting constituents in rice bran fractions, but we did not
attempt their chemical identification; (c) it is important
to relate, at least putatively, the findings described here to the
in vivo situation in which rice is ingested as part of the
diet. It is exceedingly difficult to estimate the amount of the phenols
that has to be ingested to precipitate growth-arresting effects
in vivo. On the basis of our gross calculation, it is
conceivable that in total 1 mg of the free phenols investigated here
is ingested with 100 g of brown rice. Even assuming satisfactory
bioavailability, the amounts of the individual growth-modulating
phenols, such as for example 28 µg of caffeic acid and 7 µg of
tricin, present in the body after a meal containing 100 g of brown
rice, are unlikely to be sufficient to furnish systemic levels that
elicit effects equivalent to those observed here under highly defined
artificial cell culture conditions. These levels are also markedly
below those of bioactive rice bran constituents that have been
identified previously. These levels are based on a computation taking
into account the amounts that have been isolated and the fact that rice
bran constitutes 15% of the whole grain. For example,
100 g of brown rice yielded 2.1 mg cycloartenol ferulate
(10)
and 1.4 mg of
(10E,12Z)-9-hydroxy-10,12-octadecadienoic acid
(14)
. Nevertheless, it is conceivable that the phenols
characterized here, when present together with each other and with
other rice constituents, affect biological targets synergistically and
thus exert much higher growth-modulating and chemopreventive efficacy
than those observed on assessment of individual compounds. This
consideration may be especially pertinent under conditions of daily
ingestion of these compounds with rice as part of the diet over a long
period of time.
Finally, this type of study can give hints as to potentially useful nutriceuticals isolated from foodstuffs that may prevent cancer. Our results suggest that among the phenols contained in brown rice, tricin might be a prime candidate nutriceutical with colon or particularly breast cancer chemopreventive activity.
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Acknowledgments |
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Footnotes |
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1 This study was supported by a generous grant
from the World Cancer Research Fund. 
2 To whom requests for reprints should be
addressed, at MRC Toxicology Unit, University of Leicester, PO Box 138,
Leicester LE1 9HN, United Kingdom. Phone: 44 (0) 116 2525541; Fax: 44
(0) 116 2525616; E-mail: eah5{at}le.ac.uk
3 The abbreviations used are: HCEC, human colon
epithelial cell; MTS,
3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium;
HPLC, high performance liquid chromatography; NMR, nuclear magnetic
resonance.
Received 12/28/99; revised 8/ 9/00; accepted 8/20/00.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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B activation via the NIK/IKK signalling complex. Oncogene, 18: 6013-6020, 1999.[Medline]
-oryzanol components and simultaneous assessment of tocols in rice bran oil. J. Am. Oil Chem. Soc., 70: 301-307, 1993.
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