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Subject: phytate
ROLE OF PHYTIC ACID IN CANCER AND DISEASE PREVENTION
by D. R. RAO and L. U. Thompson*
Food Science Program, Department of Life Science, Alabama A&M
University, Normal, AL 35762; *Department of Nutritional Science,
University of Toronto, M5S1A8
Animal model and cell culture studies provide convincing evidence for
the anticarcinogenic properties of phytic acid (inositol
hexaphosphate; InsP6). In several studies, dietary InsP6 has been
shown to suppress colon, mammary, lung, liver and skin tumorigenesis
and the growth of transplanted fibrosarcoma in rat or mouse models
with at least one study showing a clear dose-response of colon tumors.
InsP6 appears to be effective at both pre- and post-initiation stages
of carcinogenesis. InsP6 also showed striking anticancer potential in
several cell lines in vitro (erythroleukemia K562, HT-29, MCF 7, MDAMB
231, PC-3, Fibroblasts and JB-6). Interestingly, InsP6 can
dedifferentiate transformed cell lines and reverse the growth of
tumors. Therefore, InsP6 has been suggested to possess both
chemopreventive and chemotherapeutic activities against cancer. While
the mechanism of anticarcinogenic action of InsP6 is unclear, recent
studies point out to control mechanisms existing at cell division
level. For example, InsP6 has been shown to: 1) inhibit the activation
of activator protein 1 (a crucial tumor promotion step) by targeting
phosphatidyl inositol-3' kinase in signal transduction path ways, and
2) up-regulate the tumor suppressor gene P53 expression in HT-29 human
colon carcinoma cells. Free radical sequestering activity of and
induction of phase-2 enzymes by InsP6 may be equally important,
especially when one considers the evidence from pre-initiation
experiments. Direct epidemiological data on the antitumorigenic
properties of InsP6, however, are lacking. Meta-analysis of existing
data on antitumorigenic effect of dietary fiber with InsP6 as a
covariable may yield some meaningful results.
Animal studies have shown that dietary InsP6 supplementation results
in significant reduction in serum cholesterol and triglycerides. The
purported benefits of dietary InsP6 in preventing heart disease, and
preventing formation of renal calculi also need further investigation.
Subject: Ip6/phytic acid
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Antitumor Activity of Physic Acid (Inositol Hexaphosphate) in Murine
Transplanted and Metastatic Fibrosarcoma, a Pilot Study
Authors: Vucenik I, Tomazic VJ, Fabian D, Shamsuddin AM
Source: Cancer Letters. 1992; 65:9-13.
_________________________________________________________________
Comparison of Pure Inositol Hexaphosphate and High-Bran Diet in the
Prevention of DMBA-Induced Rat Mammary Carcinogenesis
Authors: Vucenik I, Yang G, Shamsuddin AM
Source: Nutrition and Cancer. 1997; 28(1):7-13.
_________________________________________________________________
Dose-dependent Inhibition of Large Intestinal Cancer by Inositol
Hexaphosphate in F344 Rats
Authors: Ullah A, Shamsuddin AM
Source: Carcinogenesis. 1990; 2(12):2219-2222.
_________________________________________________________________
Effects of Inositol Hexaphosphate on Growth and Differentiation in
K-562 Erythroleukemia Cell Line
Authors: Shamsuddin AM, Baten A, Lalwani ND
Source: Cancer Letters. 1992; 64:195-202.
_________________________________________________________________
Growth Inhibition and Differentiation of HT-29 Cells in vitro by
Inositol Hexaphosphate (Phytic Acid)
Authors: Sakamoto K, Venkatraman G, Shamsuddin AM
Source: Carcinogenesis. 1993; l4(9):l815-1819.
_________________________________________________________________
IP6-Induced Growth Inhibition and Differentiation of HT-29 Human Colon
Cancer Cells: Involvement of Intracellular Inositol Phosphates
Authors: Yang G, Shamsuddin AM
Source: Anticancer Research. 1995; 15:2479-2488.
_________________________________________________________________
IP6: A Novel Anti-Cancer Agent
Authors: Shamsuddin AM, Vucenik I, Cole KE
Source: Life Sciences. 1997; 61(4):343-354.
_________________________________________________________________
Inhibition of Rat Mammary Carcinogenesis by Inositol Hexaphosphate
(Phytic Acid). A Pilot Study.
Authors: Vucenik I, Sakamoto K, Bansal M, Shamsuddin AM
Source: Cancer Letters.1993; 75:95-102.
_________________________________________________________________
Inositol Hexaphosphate Inhibits Cell Transformation and Activator
Protein 1 Activation by Targeting Phosphatidylinositol-3'
Kinase
Authors: Huang C, Ma W, Hecht SS, Dong Z
Source: Cancer Research. 1997; 57:2873-2878.
_________________________________________________________________
Inositol Hexaphosphate Inhibits Growth and Induces Differentiation of
PC-3 Human Prostate Cancer Cells
Authors: Shamsuddin AM, Yang G
Source: Carcinogenesis. 1995; 16(8):1975-1979.
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Inositol Hexaphosphate Inhibits Large Intestinal Cancer in F344 Rats 5
Months After Induction by Azoxymethane
Authors: Shamsuddin AM, Wah A
Source: Carcinogenesis. 1989; l0(3):625-626.
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Inositol Hexaphosphate and Inositol Inhibit DMBA-induced Rat Mammary
Cancer
Authors: Vucenik I, Yang G, Shamsuddin AM
Source: Carcinogenesis. 1995; l6(5):l055-1058.
_________________________________________________________________
Inositol Phosphates Have Novel Anticancer Function
Authors: Shamsuddin AM
Source: J. Nutr. 1995; 125:725S-732S.
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Inositol and Inositol Hexaphosphate Suppress Cell Proliferation and
Tumor Formation in CD-1 Mice
Authors: Shamsuddin AM, Ullah A, Chakravarthy AK
Source: Carcinogenesis. 1989; 10(8):1461-1463.
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Inositol-phosphate-induced Enhancement of Natural Killer Cell Activity
Correlates with Tumor Suppression
Authors: Baten A, Ullah A, Tomazic VJ, Shamsuddin AM
Source: Carcinogenesis. 1989; 10(9):1595-1598.
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Novel Anti-Cancer Functions of IP6: Growth Inhibition and
Differentiation of Human Mammary Cancer Cell Lines in Vitro
Authors: Shamsuddin AM, Yang GY, Vucenik I
Source: Anticancer Research. 1996; 16:3287-3292.
_________________________________________________________________
Novel Anticancer Function of Inositol Hexaphosphate: Inhibition of
Human Rhabdomyosarcoma in Vitro and in Vivo
Authors: Vucenik I, Kalebic T, Tantivejkul K, Shamsuddin AM
Source: Anticancer Research. 1998; 18:1377-1384.
_________________________________________________________________
Suppression of Large Intestinal Cancer in F344 Rats by Inositol
Hexaphosphate
Authors: Shamsuddin AM, Elsayed AM, Ullah A
Source: Carcinogenesis. 1988; 9(4):577-580.
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Up-regulation of the Tumor Suppressor Gene p53 and WAF1 gene
expression by IP6 in HT-29 Human Colon Carcinoma Cell Line
Authors: Saied IT, Shamsuddin AM
Source: Anticancer Res. 1998; 18(3A):1479-1484.
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[3H]Inositol Hexaphosphate (Phytic Acid) Is Rapidly Absorbed and
Metabolized by Murine and Human Malignant Cells In Vitro
Au thors: Vucenik I, Shamsuddin AM
Source: J. Nutr. 1994; 124:861-868.
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[3H]Phytic Acid (Inositol Hexaphosphate) Is Absorbed and Distributed
to Various Tissues in Rats
Authors: Sakamoto K, Vucenik I, Shamsuddin AM
Source: J. Nutr. 1993; 123:713-720.
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From The June 2000 Issue of Nutrition Science News
Feature
Too Much of a Good Thing
by Bill Sardi
fortified bread Recent studies reveal that blood donors exhibit lower
rates of many diseases and experience better than average health.
Additionally, the centuries-old practice of bloodletting is being
revived as a treatment for disorders such as heart disease, cancer and
Alzheimer's.1 Why would blood reduction improve health parameters? In
part, because blood removal helps to control circulating iron levels.
Iron is an essential component of hemoglobin in red blood cells, is
associated with strength, and is required for oxygen transport, DNA
synthesis and other processes. But it also has a destructive nature.
In its free form, unbound from hemoglobin or other binding proteins,
it accelerates oxidation or "rusting" of body tissues. Since
iron-induced oxidation worsens the course of virtually every disease,
iron control could be a universal approach to disease prevention and
therapy.2
Whereas poor iron intake, or impaired absorption, may lead to anemia,
too much iron--iron overload--is even more problematic.3 After full
growth is achieved, at about age 18 or so, excess iron accumulates in
the blood of all humans at the rate of 1 mg per day.2 About 80 percent
of the body's iron stores are in the blood. Women are less at risk for
iron buildup than men because of the blood they lose monthly during
menstruation. As a result, women have somewhere around half the
circulating iron levels as men. Their rates for heart disease, cancer
and diabetes are also about half those of males. Because men have no
direct outlet for iron, by age 40 their iron levels are similar to
those of a postmenopausal 70-year-old woman. This amount of iron can
lead to premature aging and diseases such as arthritis, cancer,
cataracts, diabetes, osteoporosis, and retinal, liver and brain
disorders.4 Postmenopausal women, or women who have undergone early
hysterectomy in their 20s, 30s and early 40s, may experience similar
problems.5
Recognizing the Problem
Iron overload hasn't gone completely unnoticed. There are a number of
books on the topic, but most are written for health professionals,
leaving the public largely unaware of the problem. Also, some
confusion exists regarding the role of iron in health and disease.
First, there is a mistaken idea that the majority of the people
affected by iron overload diseases have the genetic form, called
hemochromatosis, which affects only about 1 million of the estimated
275 million Americans. In fact, the potential threat of iron overload
is universal. It comes with advancing age and regardless of genetic
factors. Second, the emphasis on preventing anemia in children and
menstruating women has detracted attention from progressive iron
buildup in adult men and postmenopausal women.6
Upon closer inspection, many health-promoting practices inadvertently
control iron. For example, taking an aspirin a day to prevent heart
attacks and strokes causes blood loss via the digestive tract on the
order of about a tablespoon per day. This results in iron loss.7
Raymond Hohl, M.D., an assistant professor of internal medicine and
pharmacology at the University of Iowa in Iowa City, says even chronic
use of a baby aspirin may help to control iron and in some cases can
induce iron-deficiency anemia.8 Aspirin also appears to increase the
production of ferritin, an iron-binding protein that prevents iron
from inducing oxidation.9 By exercising, a person loses about 1 mg of
iron through sweat.10 Fasting and vegetarian diets, both of which
promote longevity in animals and humans, limit iron consumption
because red meat contains the highly absorbable heme iron. Whether or
not related to iron consumption, restricting red meat consumption has
been shown in various studies to reduce the risk of colon cancer.11
Normal Iron Regulation
In healthy individuals there is little if any unbound iron circulating
in the blood. In all disease states, however, unbound iron (also
called free iron) is released at sites of inflammation and can spark
uncontrolled oxidation.12 Fortunately, there are numerous automatic
mechanisms in the body that help to control iron, many by
chelation--compounds that bind to a toxic substance (such as iron) and
render it nontoxic or nonactive. Albumin, a simple protein found in
blood, acts as a chelator by loosely binding to iron.13 Ferritin,
produced in the liver, is another iron-binding protein.14 Transferrin
is a protein that chelates iron and totes it back to the liver, where
it is metabolized and excreted.15 The liver produces lactoferrin,
another iron chelator, when challenged by infectious agents.16 This is
important because pathogenic organisms such as viruses, bacteria and
fungi require iron for growth. Furthermore, as iron stores increase,
the gastric absorption of iron decreases. So the body employs numerous
mechanisms to control iron that are activated when threatened by
disease. However, these defensive mechanisms can be overwhelmed.
Blood tests for iron levels (i.e., hemoglobin and ferritin levels are
checked for transferrin saturation percentages) are often useful, but
the results of these tests are confounded in states of prolonged
inflammation or disease.17 A skilled hematologist is often the best
professional from whom to obtain personal information concerning blood
iron levels.
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Differentiating between anemia and iron overload can be difficult
because both conditions cause fatigue. One study at the Department of
Medicine, University of Western Ontario in Canada, found that iron
overload can produce a wide range of symptoms, such as joint pain
(particularly hip), unexplained gastric pain, frequent infections,
skin bronzing, elevated liver enzymes, cessation of menstruation, hair
loss and heart flutters (fibrillation). Yet, of 410 iron-overload
patients, 27 percent experienced no symptoms whatsoever.18 Common
symptoms of iron-deficiency anemia are lowered resistance to
infections, fainting, breath holding, mental fatigue, sleepiness, cold
hands and feet, and cravings for ice, meat or tomatoes, all which are
more likely to occur among women.19
Dietary Iron Control
Various dietary practices can help control iron levels. In a
relatively short period of time, dietary changes can result in anemia,
iron overload or an ideal state of iron control. Anemia can be induced
in about 120 days, while symptoms of iron overload can come on in just
60 days.
Humans absorb only a fraction of the iron they consume, but there are
many controlling factors.20 Iron absorption rates from food vary
widely, from less than 1 percent to nearly 100 percent.21 Cooks who
use iron or stainless steel pots increase the amount of iron they
consume.22 Generally, iron in plant foods is not as well absorbed as
iron from meat: Only 5 percent of iron in plant foods is available,
vs. 30 to 50 percent of iron from meat.23 Olive oil and spices such as
anise, caraway, cumin, licorice and mint promote iron absorption,24
while antacids, eggs and soy reduce availability.25 Since dairy
products contain lactoferrin, milk also inhibits the absorption of
iron.26 Moderate alcohol consumption is unlikely to pose a problem
with iron absorption, but excessive amounts of alcohol is associated
with iron overload, particularly in adult males.27
Vitamin C also increases iron absorption.28 However, there is no
evidence that vitamin C leads to iron overload. Thus vitamin C should
not be avoided by meat-eaters for this reason, since studies show
high-dose vitamin C supplements are associated with a decreased risk
for heart disease, cancer, cataracts and other disorders.29 A
vegetarian diet does not generally cause iron-deficiency anemia
because there is more vitamin C in plant-food diets, which enhances
absorption.30
A 1982 human study was conducted to assess the effect of various
drinks on iron absorption. A subject ate a standard meal of a
hamburger, string beans, mashed potatoes and water. When green tea was
drunk instead of water, iron absorption was reduced by 62 percent.
Coffee reduced iron absorption by 35 percent, whereas orange juice (as
a source of vitamin C) increased absorption by 85 percent. Contrary to
other studies, milk and beer had no significant effect.31
Bioflavonoids (found in berries, coffee, green tea, pine bark,
quercetin and the rind of citrus fruits, particularly blueberry,
cranberry, elderberry and grape seed) and phytic acid (a component of
whole grains and seeds such as sesame) bind to iron and other minerals
in the gastric tract and help to limit iron availability. If
bioflavonoids and phytic acid haven't bound to minerals in the
digestive tract they will get into the bloodstream, where they can
bind to free iron, acting as blood-cleansing iron chelators.
Therefore, maximum iron chelation in the blood circulation is achieved
when these iron binders are consumed apart from meals.
Phytic acid--also called inositol hexaphosphate, or IP6--is comprised
of six phosphorus molecules and one molecule of inositol. It has been
mistakenly described for decades as an "anti-nutrient" because it
impairs mineral absorption. However, in the 1980s food biochemist
Ernst Graf, Ph.D., began to tout phytic acid for its beneficial
antioxidant properties achieved through mineral chelation.32
Phytic acid in foods or bran should be distinguished from supplemental
phytic acid, which is derived from rice bran extract. In foods, phytic
acid binds to iron and other minerals in the digestive tract and may
interfere with mineral absorption. As a purified extract of rice bran,
taken between meals so it will not bind to minerals in the digestive
tract, phytic acid is readily absorbed into the bloodstream, where it
acts as a potent mineral chelator.33 Phytic acid binds to any free
iron or other minerals (even heavy metals such as mercury, lead and
cadmium) in the blood, which are then eliminated through the kidneys.
Phytic acid removes only excess or unbound minerals, not mineral ions
already attached to proteins.
Phytic acid is such a potent--but safe--iron and mineral chelator that
it may someday replace intravenous chelation therapy such as the
mineral-chelator EDTA or iron-binding drugs such as desferrioxamine
(Desferal). Because of its ability to bind to iron and block
iron-driven hydroxyl radical generation (water-based) as well as
suppress lipid peroxidation (fat-based), phytic acid has been used
successfully as an antioxidant food preservative.34
Phytic acid supplements should not be taken during pregnancy since the
developing fetus requires minerals for proper development. Because
aspirin causes a small loss of blood and consequently helps to control
iron levels, the simultaneous use of phytic acid with a daily aspirin
tablet is not advised. A three-month course of phytic acid should
achieve adequate iron chelation, and prolonged daily supplementation
may lead to iron-deficiency anemia. Anemic individuals who take phytic
acid as a food supplement are likely to feel weak shortly after
consumption, whereas iron-overloaded individuals are likely to feel
increased energy.
For those at risk for iron overload, it may be wise to avoid iron in
multivitamins and shun fortified foods that provide more than 25
percent of the recommended daily intake for iron. No doctor should
prescribe iron tablets for patients who complain of fatigue without
blood tests and a thorough health history. Iron-rich foods such as red
meat and molasses may prevent anemia and build strength during the
growing years but in adulthood may lead to iron overload among men and
postmenopausal women. Those individuals who learn how to achieve iron
balance will maintain the most desirable state of health throughout
life.
Sidebars:
Why Fortify Foods?
Bill Sardi is a health journalist and consumer advocate in Diamond
Bar, Calif. He recently published
The Iron Time Bomb (Bill Sardi, 1999).
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References
1.Bonkovsky HL, et al. Iron in liver diseases other than
hemochromatosis. Semin Liver Dis 1996;16:65-82.
2. Gutteridge JMC, Halliwell B. Antioxidants in nutrition, health and
disease. New York: Oxford University Press; 1994. p 24-39.
3. McCord JM. Iron, free radicals, and oxidative injury. Sem in Hem
1998;35:5-12.
4. Crawford RD. Proposed role for a combination of citric acid and
ascorbic acid in the production of dietary iron overload: a
fundamental cause of disease. Biochem Mol Med 1995;54:1-11.
5. Emery TF. Iron and your health. Boca Raton (FL): CRC Press; 1991. p
1-13.
6.Arthur CK, Isbister JP. Iron deficiency. Drugs 1987;33:171-82.
7. Rider JA, et al. Double-blind comparison of effects of aspirin and
namoxyrate on pH of gastric secretions, fecal blood loss, serum iron
and iron-binding capacity in normal volunteers. Curr Ther Res
1965;7:633-8.
8. Bankhead C. In assessing anemia, doctors must decipher role of iron
deficiency. Med Tribune Clin Focus 1997 Mar; 20:24.
9. Oberle S, et al. Aspirin increases ferritin synthesis in
endothelial cells: a novel antioxidant pathway. Circ Res
1998;82:1016-20.
10. Vellar OD. Studies on sweat losses of nutrients. Scand J Clin Lab
Invest 1968;21:157-67.
11. Kampman E, et al. Meat consumption, genetic susceptibility, and
colon cancer risk. Cancer Epid Biomarker Prev 1999;8:15-24.
12. Griffiths, E. Iron and infection. New York: John Wiley &
Sons;1987. p 1-25.
13. Goldwasser P, Feldman J. Association of serum albumin and
mortality risk. J Clin Epid 1997;50:693-703.
14. Aust SD. Ferritin as a source of iron and protection from
iron-induced toxicities. Toxicol Lett 1995;82:941-4.
15. Aisen P, Brown EB. The iron-binding function of transferrin in
iron metabolism. Sem Hematol 1977;14:31-46.
16. Baker EN, et al. Three-dimensional structure of lactoferrin. Adv
Exp Med Biol 1998;443:1-14.
17. Hulten L, et al. Iron absorption from the whole diet in men: how
effective is the regulation of iron absorption? Am J Clin Nut
1997;66:347-56.
18. Adams PC, et al. The relationship between iron overload, clinical
symptoms and age in 410 persons with genetic hemochromatosis.
Hepatology 1997;25:162-6.
19. Marinella MA. Tomatophagia and iron-deficiency anemia. N Eng J Med
1999;341:60-1.
20. Monsen ER. The ironies of iron. Am J Clin Nutr 1999;69:831-2.
21. Hurrell RF. Preventing iron deficiency through food fortification.
Nut Rev 1997;55:210-22.
22. Park J, Brittin HC. Increased iron content of food due to
stainless steel cookware. J Am Diet Assoc 1997;97:659-61.
23. U.S. Agricultural Research Service, USDA Bulletin. 1998 Dec 23.
24. El-Shobaki FA, et al. The effect of some beverage extracts on
intestinal iron absorption. Z Ernahrungswiss 1990;29:264-9.
25. Morris ER. An overview of current information on bioavailability
of dietary iron to humans. Fed Proc 1983;42:1716-20.
26. Davidsson L, et al. Influence of ascorbic acid on iron absorption
from an iron-fortified chocolate-flavored milk drink in Jamaican
children. Am J Clin Nut 1998:67:873-7.
27. Fletcher LM. Alcohol and iron: one glass of red or more? J Gastro
Hepatol 1996;11:1039-41.
28. Derman DP, et al. Importance of ascorbic acid in the absorption of
iron from infant foods. Scand J Haematol 1980;25: 193-201.
29. Gerster H. High-dose vitamin C: a risk for persons with high iron
stores? Int J Vitam Nutr Res 1999;69:67-82.
30. Craig WJ. Iron status of vegetarians. Am J Clin Nut 1994 May; 59(5
Suppl):12335-7.
31. Hallberg L, Rossander L. Effect of different drinks on the
absorption of non-heme iron from composite meals. Hum Nutr Appl Nutr
1982;36:116-23.
32. Graf E, et al. Phytic acid--a natural antioxidant. J Biol Chem
1987;262:11647-50.
33. [No authors listed] Phytic acid: new doors open for a chelator.
Lancet 1987 Sept 19:2;2(8560):664-6.
34. Lee BJ, Hendricks DG. Phytic acid protective effect against beef
round muscle lipid peroxidation. J Food Sci 1995;60:241-4.
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