The word '"fiber" comes to mind when we think of cereals, whole grains
and health. However, while fiber is important to our health, it is not
the sole ingredient endowed with medicinal value. Other constituents
locked within cereals and grains possess important physiologic and
pharmacologic properties which are being rapidly uncovered by medical
research. This is best exemplified in the case of rice and its
components, which was the focus of an international symposium held last
summer in Kyoto, Japan.

Rice is an important staple cereal of a large fraction of the world's
population. It is primarily consumed after processing as polished
rice. The bran or germ which comprises 10% of whole rice is removed
during the polishing process. However, rice bran is an important source of
rice oil and other phytochemicals which possess antioxidative and
disease-fighting properties. Traditionally, rice-bran products have found
applications in agricultural, food and cosmetic industries. Now, medical
research has unraveled scientific evidence supporting a role for key
components of rice in health maintenance and disease prevention.

Rice-based products drawing much attention of biomedical researchers
include: myo-inositol (a B vitamin), its phosphate-derivative inositol
hexaphosphate (IP6 or phytate), rice-bran oil and polyphenols with
antioxidant function. IP6 is the major form of phosphorylated inositol
present in foods, constituting 1-5% by weight of most cereals, nuts,
oilseeds, legumes and grains. It occurs at 9.5-14.5% by weight in rice
bran. Antioxidative polyphenols in rice bran include ferulic acid, its
esterified derivatives (oryzanols), tocopherols and other phenolic
compounds.

The first international symposium on "Disease Prevention by IP6 and
Other Components of Rice" was held last June in Kyoto. About 520
people convened at this conference devoted to inositol, inositol
hexaphosphate and other components of rice. Some 20 speakers presented
papers on topics ranging from chemistry and mechanisms of action to
anti-cancer effects and other beneficial functions of IP6. About 10
studies were presented on ferulic acid, rice bran oil and other
components of rice. In addition, 65 other papers were presented in
poster sessions as reports of research which complemented above studies.

From the quality of the information presented, it can be said that
increased consumption of rice and its products would result in improved
health, with reduction in heart disease, renal stones and some forms of
cancer.

The symposium was sponsored by Tsuno Foods & Rice which, since 1947, has been
developing and improving ways of using rice bran for industrial manufacture
based on rice oil extraction and refinery. In fact, the symposium was held at
the occasion of the company's 50th anniversary. Its purpose was to foster
exchange of information and ideas about important developments that have
bearing on disease prevention by rice components with medicinal properties.

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Beneficial Effects of IP6 and Inositol

The symposium started with a discussion of chemistry and usage of rice
components. S. Ogawa (Keio University) presented an impressive overview
of chemical structures and uses of myo-inositol and its related
compounds. T. Osawa (Nagoya University) discussed the protective role of rice
antioxidants in oxidative stress and Y. Watanabe (Ehime University, Matsuyama)
reviewed the synthesis of inositol triphosphate and phospholipids.

A large portion of the symposium was devoted to IP6 and its parent
molecule, inositol. It is difficult to summarize all the studies
presented at the conference. This article will touch upon major
findings of relevance to disease prevention and treatment.

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Cancer

Let's consider the advances against cancer. A renowned epidemiologist
reviewed studies linking diet and life style to cancer (S.Sugano, Cancer
Institute, Tokyo). It's been known for sometime that consumption of whole
grains, vegetables and fruits is linked to reduced cancer risk. These foods
are rich in fiber which has been shown to protect against both colonic and
mammary cancer (reviewed by B.S. Reddy and L. A. Cohen, American Health
Foundation, New York). However, as it became apparent at the symposium, fiber
is not the sole anticarcinogen since other substances in fiber-containing
foods also exert protective influences on cancer. Thus, a multinational
epidemiologic study carried out in the mid 1980's had shown that foods rich in
phytate (IP6) but poor in fiber, such as cereals and grains, correlated better
with reduced risk of colon cancer than phytate-poor fiber foods such as fruits
and vegetables (Graf and Eaton, Cancer 1985; 56:717-718). IP6 is a strong
chelating agent and certain metals are known to promote cancer through
generationof reactive free radicals from oxidation of fats. IP6 also plays an
important role in regulating cell proliferation and differentiation.

In 1988, the first two studies were published, reporting inhibitory
effects of purified IP6 on tumor formation in experimental animals. One
study (Shamsuddin et al. Carcinogenesis 9:577-80) showed suppression of
cancer of the large bowel by IP6 and theother study (Jariwalla et al.
Nutr. Res. 8: 813-27) demonstrated reduction of the incidence and size
of soft-tissue tumors (fibrosarcomas) promoted by dietary factors.
Since then, a number of experimental studies have confirmed the
anti-cancer action of IP6 (reviewed by I. Vucenik and A.K.M. Shamsuddin, Univ.
of Maryland, Baltimore). The compound has been shown to inhibit various
rodent and human cancer cell lines in vitro and to protect against growth of
diverse cancers in vivo. Protective effects have been seen against cancers of
the breast, colon, pancreas, liver, skin and connective tissue. In vivo,IP6
not only prevents carcinogen-induced tumor development but it also interferes
with growth of pre-formed, transplanted tumors, suggesting that it may play a
role in both cancer prevention and treatment.

The step at which IP6 acts during tumor development varies depending
upon the type of cancer studied. In colon carcinogenesis, IP6 was shown to
suppress bowel cancer when given before, during and even several months after
carcinogen administration (Shamsuddin and colleagues, Univ. of Maryland).In
a multi-organ rat carcinogenesis model, IP6 administered (as phytic acid)
during the promotion stage suppressed hepatic tumors but had no influence on
development of esophagal, colonic, pancreatic, renal and thyroid tumor lesions
(M. Hirose, National Institute of Health Sciences, Tokyo). In a
two-stage model of carcinogenesis in mouse skin, IP6 inhibited tumor
formation when given during the initiation stage but not during tumor
promotion, indicating differential sensitivity of skin cancer (T. Ishikawa,
Univ. of Tokyo). Clinical studies in humans against different tumor types
would be useful. Awaiting such studies,
what can be said presently is that naturally-occurring salt forms of IP6
appear to be safe in animal studies even when used at higher than
physiologic dosages.

The role of myo-inositol as a chemopreventive agent was also discussed.
It is another phytochemical with low toxicity and ability to inhibit
carcinogenesis in various organs which include mammary gland, colon and
lung. In studies evaluating its chemopreventive activity in lung
carcinogenesis (L. W. Wattenberg, Univ. of Minneapolis, Minnesota), it
was reported that myo-inositol has unusual properties, manifesting a
capacity to prevent lung cancer when given during separate phases of the
carcinogenic process as well as throughout the entire course of the process.
When administered throughout the carcinogenic process, it's effects were found
to be additive. Another study reported on suppression of liver cancer by oral
administration of myo-inositol, thus adding to the diverse spectrum of tumors
affected by this naturally-derived plant constituent (H. Nishino, Kyoto Prefectual
University of Medicine). Myo-inositol has also been reported to enhance the
anti-cancer action of IP6 in other animal studies.

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Mechanism of Cancer Suppression

The mechanism by which IP6 or myo-inositol exert chemopreventive and
anti-cancer effects is not completely understood. IP6 is rapidly
absorbed by cells (in vitro and in vivo) and metabolized to lower
phosphates and inositol (reviewed by Shamsuddin). It has been suggested
that lower inositol phosphates may mediate cancer inhibition, although
direct evidence for this is lacking. Both IP6 and its lower phosphates have
metal chelating activity and may interfere with tumor formation by suppressing
metal catalyzed oxidation of fats. Alternatively, IP6 may block the activity
of key enzyme(s) affecting cell proliferation. One enzyme candidate is PI-3
kinase which plays a central role in signal transduction and cell
transformation triggered by growth factor or tumor promoter. IP6 has been
reported to inhibit PI-3 kinase activity in vitro (Z. Dong, Univ. of
Minnesota, Austin). While this enzyme inhibition may explain the
chemopreventive effect of IP6, it is not known whether it mediates IP6's
effect on pre-existing tumors or
established cancer cells. Other, as yet, unknown mechanism may be
involved in the anti-cancer effect of IP6.

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Heart Disease

The ability of IP6 to reduce hyperlipidemia and protect against
cardiovascular disease (CVD) was also discussed. CVD is associated with high
mortality in Western and other industrialized countries. It is linked to
several risk factors among which is hyperlipidemia -- high levels of
cholesterol and triglycerides in blood.

It has been known that consumption of Bengal gram, a bean species rich
in IP6, is associated with reduced hypercholesterolemia. In one study,
which directly addressed the role of IP6 in hyperlipidemia, it was shown that
IP6-supplemented diet lowered total cholesterol and triglycerides levels in
serum of animals made hyperlipemic with a high cholesterol diet (reviewed by
R. J. Jariwalla, Calif. Institute for Medical Research, San Jose). The same
study demonstrated that dietary IP6 caused a lowering of the zinc/copper
ratio, a marker of hypercholesterolemia, without significantly affecting
levels of other minerals in serum. This lipid-lowering action of IP6 was seen
at dosages (upto 9% of the diet) that were free of adverse side effects in the
tested animals.

Another study reported on the hypolipidemic action of myo-inositol and
IP6 relevant to treatment of fatty liver (T. Katayama, Hiroshima Univ.). At
physiologic dosages (0.1 -0.5% of diet), these compounds inhibit rises in
hepatic total lipids andtriglycerides resulting from
administration of sucrose. The mechanism of this hypolipidemic effect in the
liver appears to be related to the inhibition of hepatic enzymes involved in
lipogenesis rather than inhibition of intestinal enzymes. Although
physiological levels of IP6 depress accumulation of lipids, they have little
effect on elevated serum lipids. Indeed, these dietary treatments (upto 2.5%
IP6) do not produce significant changes in hepatic cholesterol or serum total
lipid levels in sucrose-treated animals, consistent with findings from the
above study showing reduction of serum hyperlipidemia at higher supplementary
levels of dietary IP6.

IP6 and its derivatives also manifest other benficial effects relevant
to CVD. In separate reports, IP6 was shown to inhibit platelet
aggregation (I. Vucenik, Univ. of Maryland, Baltimore) and to enhance
inflammatory responses of neutrophils in response to microbial stimuli
(P. Eggleton, Oxford Univ.). In earlier animal studies, lower inositol
phosphates have been shown to inhibit calcification in the aorta and
lipid peroxidation in ischemic kidneys, consistent with a role for
hydrolysates of IP6 in protecting against hardening of the arteries
(reviewed by R. J. Jariwalla).

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Kidney Stones

Epidemiologic studies have shown that renal stones are more prevalent in
developed countries where populations consume diets based on refined
flour compared to those in developing nations consuming predominantly a
phytate-rich diet. IP6 is naturally present in human urine where normal
levels fluctuate between 0.5 to 5.0 mg/liter (F. Grases, Univ. of Balearic
Islands, Spain). Approximately 1-3% of oral doses are excreted in the urine
with an associated reduced risk of developing renal stones. Biochemical
studies have shown that phytate
can interfere with formation of calculi (crystals) of calcium oxalate
and phosphate (reviewed by F. Grases). This has been demonstrated in
vitro in a system that resembles calculi formation in the kidney as well as in
an animal model of nephrolithiasis where crystal/stone formation and
calcifications on renal papillary tissue are induced by ethylene glycol. In a
preliminary clinical study of 30 renal stone-formers, ingestion of 120mg/day
of IP6 was demonstrated to reduce the urinary risk of kidney stone
development.

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Role in Transmission of Chemical Messages

A portion of the symposium was devoted to the role of IP6 and inositol
in signal transduction, the pathway for transmission of external
messages to the interior of cells. Inositol phopholipids present in
plasma membranes have drawn much attention because of their role as
intermediaries in transmission of signals elicited by growth factors and
mitogens acting at the cell surface. Since inositol occurs ubiquitously in
cell membranes in conjugation with lipids as phosphatidylinositol, it plays a
critical role in this process. Additionally, IP6 is the only known dietary
source of inositol phospholipids. During cell stimulation, these molecules
are converted by special enzymes (PI kinases and phospholipase C) to inositol
triphosphate (IP3) and diacylglycerol which act as second messengers inside
cells (reviewed by G. Weber, Univ. of Indiana, Indianapolis). IP3 also plays
a role in cell-to-cell communication and can be generated from IP6 via a
salvage pathway.

In one report (by G. Weber), the activity of signal-transduction enzymes and
concentration of IP3 were reported to be elevated in several types of tumors
above those in normal cells. Anti-tumor componds such as genistein and
quercetin act by inhibiting PI kinases and lowering IP3 concentration in tumor
cells leading to cellular differentiation and death. A nuclear
inositol-lipid pathway was also described with signal-transduction components
located and acting in the nucleus (L. Cocco, Univ. of Bologna, Italy). This
signalling pathway appears to be important in switching cell programming from
a proliferative to a differentiative state. Finally, it was
reported that IP6 is the dominant inositol phosphate in
insulin-secreting cells of the pancreas where it influences secretion of the
hormone by modulating activity of a calcium channel (P.O. Berggren,Karolinska
Institute, Stockholm).

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Beneficial Effects of Other Rice Components

Much attention was devoted during the latter third of the symposium to
other components of rice that include rice germ (or bran), antioxidative
polyphenols and rice bran oil. Polyphenols from edible plants are a rich
source of antioxidative compounds with chemopreventive activity (N.Nakatani,
Osaka City Univ.).There was much discussion of ferulic acid (from rice grain)
and its esterified derivatives, gamma-oryzanol and cycloartenyl ferulate.

Ferulic acid is a ubiquitous polyphenol that is formed from metabolism
of two amino acids (phenylalanine and tyrosine), occurring primarily in
the bran fraction of plant seeds (H. Taniguchi, Industrial Technology
Center of Wakayama Prefecture). Natural ferulic acid is commercially
extracted and purified from rice bran oil for which a cost-effective
manufacturing process has been developed by Tsuno Foods. The compound
has strong antioxidant potential, protecting skin cells from light or
radiation-induced damage and preserving foods from spoilage due to lipid
peroxidation. Photoprotection of skin cells has potential utility for
dermatologic applications. The antioxidative function may also play a
protective role in inflammatory diseases and other industrial applications of
ferulic acid.

Evidence was discussed for a chemopreventive role of rice germ, ferulic
acid and its derivatives. In animal studies (presented by G. Mori, Gifu
Univ.) rice germ showed a chemopreventive effect in large bowel
carcinogenesis. Ferulic acid inhibits liver carcinogenesis and was shown to
reduce development of oral lesions induced by chemical carcinogen (G. Mori).
EGMP, a synthetic derivative of ferulic acid has a modifying effect on rat
colon carcinogenesis (H. Tsuda, National Cancer Center Research Institute,
Tokyo). Other ferulate derivatives prevented and dissolved platelet
aggregation related to thrombosis (H. Kayahara, Shinshu Univ.). An ester of
DL-alpha tocopherol (vitamin E) and ferulic acid prevented facial
hyperpigmentation by suppressing melanogenesis induced by UV light (M.
Ichihashi, Kobe Univ.).

Several papers were devoted to the benefits of rice bran oil (reviewed
by M. Sugano, Kumamoto Univ.). Known as a healthy oil, it is rich in
polyunsaturated fatty acids, lowers blood lipid levels and has a role in
preventing hardening of the arteries. In animals fed a high-fat and
cholesterol diet, rice bran oil suppressed the development of
hyper-cholesterolemia and lowered the atherogenic index. In combination with
safflower oil (7 parts to 3), it exhibits a blending effect, yielding greater
reduction of serum cholesterol than either oil alone. This effect appears to
be due to a unique balance of individual fatty acids and the presence of
non-fatty acid components.

Rice bran oil is rich in non-saponifiable matters such as steryl
ferulates which have growth-promoting vitamin like activity. They
consist of a mixture of ferulic acid esters called oryzanols, of which
gamma-oryzanol is the best characterized and studied (H. Naruse,
Kyokuto International Co., Ltd., Tokyo). It is used commercially in Japan as
a food and as a medical antioxidant in combination with alpha-tocopherol
(vitamin E). It protects rice bran oil from oxidation and inhibits
peroxidation of lipids mediated by iron or UV irradiation. Its triterpene
alcohol components, cycloartenyl and 24-methylene-cycloartenyl ferulates are
effective in the treatment of arteriosclerosis. Cycloartenol magnified the
cholesterol-lowering
effect of plant sterols and in combination with beta-sitosterol produced an
increased lowering of plasma and liver cholesterol (M. Sugano). In the
two-stage carcinogenesis model in mouse skin, cycloartenol ferulate inhibited
tumor promotion, indicating also a role in the chemoprevention of cancer
(K.Yasukawa et al., Nihon Univ.).

The future looks very promising for rice-based constituents as a source
of functional foods as new components with beneficial health functions
are isolated and identified. The impression that participants derived
after a two-day exposure to rice science was that everyone should
increase their consumption of rice or rice bran, a rich source of
phytochemicals with striking medicinal properties.

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