Enzyme Extract of Traditional Japanese Food
Landmark Development for
What Is Nattokinase?
Nattokinase is a potent fibrinolytic enzyme extracted
and highly purified from a traditional Japanese food called Natto. Natto is a
fermented cheese-like food that has been used in Japan for over 1000 years for
its popular taste and as a folk remedy for heart and vascular diseases. Natto
is produced by a fermentation process by adding Bacillus natto, a benefical
bacteria, to boiled soybeans. The resulting nattokinase enzyme, is produced
when Bacillus natto acts on the soybeans. While other soy foods contain
enzymes, it is only the natto preparation that contains the specific
The Discovery of Nattokinase
Doctor Hiroyuki Sumi had long researched thrombolytic
enzymes searching for a natural agent that could successfully dissolve thrombus
associated with cardiac and cerebral infarction (blood clots associated with
heart attacks and stroke). Sumi discovered nattokinase in 1980 while working as
a researcher and majoring in physiological chemistry at Chicago University
Medical School. After testing over 173 natural foods as potential thrombolytic
agents, Sumi found what he was looking for when Natto was dropped onto
artificial thrombus (fibrin) in a Petri dish and allowed it to stand at 37 C
(approximately body temperature). The thrombus around the natto dissolved
gradually and had completely dissolved within 18 hours. Sumi named the
newly discovered enzyme "nattokinase", which means "enzyme in natto". Sumi
commented that nattokinase showed "a potency matched by no other
Potent Thrombolytic Activity
The human body produces several types of enzymes for
making thrombus, but only one main enzyme for breaking it down and dissolving
it - plasmin. The properties of nattokinase closely resemble plasmin. According
to Dr. Martin Milner, from the Center for Natural Medicine in Portland, Oregon,
what makes nattokinase a particularly potent treatment, is that it enhances the
body's natural ability to fight blood clots in several different ways; Because
it so closely resembles plasmin, it dissolves fibrin directly. In addition, it
also enhances the body's production of both plasmin and other clot-dissolving
agents, including urokinase (endogenous). "In some ways, Milner says,
nattokinase is actually superior to conventional clot-dissolving drugs. T-PAs
(tissue plasminogen activators) like urokinase (the drug), are only effective
when taken intravenously and often fail simply because a stroke or heart attack
victim's arteries have hardened beyond the point where they can be treated by
any other clot-dissolving agent. Nattokinase, however, can help prevent that
hardening with an oral dose of as little as 100 mg a day." 1,7
The Prolonged Action of Nattokinase
Nattokinase produces a prolonged action (unlike
antithrombin drugs that wear off shortly after IV treatment is discontinued) in
two ways: it prevents coagulation of blood and it dissolves existing thrombus.
Both the efficacy and the prolonged action of NK can be determined by measuring
levels of EFA (euglobulin fibrinolytic activity) and FDP (fibrin degradation
products), which both become elevated as fibrin is being dissolved. By
measuring EFA & FDP levels, activity of NK has been determined to last from
8 to 12 hours. An additional parameter for confirming the action of NK
following oral administration is a rise in blood levels of TPA antigen (tissue
plasminogen activator), which indicates a release of TPA from the endothelial
cells and/or the liver.6,7
The Mechanism Behind Thrombus
Blood clots (or thrombi) form when strands of protein
called fibrin accumulate in a blood vessel. In the heart, blood clots cause
blockage of blood flow to muscle tissue. If blood flow is blocked, the oxygen
supply to that tissue is cut off and it eventually dies. This can result in
angina and heart attacks. Clots in chambers of the heart can mobilize to the
brain. In the brain, blood clots also block blood and oxygen from reaching
necessary areas, which can result in senility and/or stroke.1
Thrombolytic enzymes are normally generated in the
endothelial cells of the blood vessels. As the body ages, production of these
enzymes begins to decline, making blood more prone to coagulation. This
mechanism can lead to cardiac or cerebral infarction, as well as other
conditions. Since endothelial cells exist throughout the body, such as in the
arteries, veins and lymphatic system, poor production of thrombolytic enzymes
can lead to the development of thrombotic conditions virtually anywhere in the
It has recently been revealed that thrombotic clogging
of the cerebral blood vessels may be a cause of dementia. It has been estimated
that sixty percent of senile dementia patients in Japan is caused by thrombus.
Thrombotic diseases typically include cerebral hemorrhage, cerebral infarction,
cardiac infarction and angina pectoris, and also include diseases caused by
blood vessels with lowered flexibility, including senile dementia and diabetes
(caused by pancreatic dysfunction). Hemorrhoids are considered a local
thrombotic condition. If chronic diseases of the capillaries are also
considered, then the number of thrombus related conditions may be much higher.
Cardiac infarction patients may have an inherent imbalance in that their
thrombolytic enzymes are weaker than their coagulant enzymes. Nattokinase holds
great promise to support patients with such inherent weaknesses in a convenient
and consistent manner, without side effects.1,6,7 Nattokinase is
capable of directly and potently decomposing fibrin as well as activating
Research In The United States
Dr. Martin Milner of the Center for Natural Medicine
in Portland, Oregon and Dr. Kouhei Makise of the Imadeqawa Makise Clinica in
Kyoto, Japan were able to launch a joint research project on nattokinase and
write an extensive paper on their findings. "In all my years of research
as a professor of cardiovascular and pulmonary medicine, natto and nattokinase
represents the most exciting new development in the prevention and treatment of
cardiovascular related diseases," Dr. Milner said. "We have
finally found a potent natural agent that can thin and dissolve clots
effectively, with relative safety and without side effects." 1
Animal & Human Studies
Nattokinase has been the subject of 17 studies,
including two small human trials. Dr. Sumi and his colleagues induced blood
clots in male dogs, then orally administered either four capsules of
nattokinase (250 mg per capsule) or four placebo capsules to each dog.
Angiograms (X-rays of blood vessels) revealed that the dogs who received
nattokinase regained normal blood circulation (free of the clot) within five
hours of treatment. Blood clots in the dogs who received only placebo
showed no sign of dissolving in the 18 hours following
Researchers from Biotechnology Research Laboratories
and JCR Pharmaceuticals Co. of Kobe, Japan, tested nattokinase's ability to
dissolve a thrombus in the carotid arteries of rats. Animals treated with
nattokinase regained 62 percent of blood flow, whereas those treated with
plasmin regained just 15.8 percent of blood flow.1
Researchers from JCR Pharmaceuticals, Oklahoma State
University, and Miyazaki Medical College tested nattokinase on 12 healthy
Japanese volunteers (6 men and 6 women, between the ages of 21 and 55). They
gave the volunteers 200 grams of natto (the food) before breakfast, then
tracked fibrinolytic activity through a series of blood plasma tests. The tests
indicated that the natto generated a heightened ability to dissolve blood
clots: On average, the volunteers' ELT (a measure of how long it takes to
dissolve a blood clot) dropped by 48 percent within two hours of
treatment, and volunteers retained an enhanced ability to dissolve blood
clots for 2 to 8 hours. As a control, researchers later fed the same amount of
boiled soybeans to the same volunteers and tracked their fibrinolytic activity.
The tests showed no significant change.1,3,6
The Benefits of Nattokinase on Blood
Traditionaly in Japan, Natto has been consumed not
only for cardiovascular support, but also to lower blood pressure. In recent
years, this traditional belief has been confirmed by several clinical trials.
In 1995, researchers from Miyazaki Medical College and Kurashiki University of
Science and Arts in Japan studied the effects of nattokinase on blood pressure
in both animal and human subjects (see below). In addition, the researchers
confirmed the presence of inhibitors of angiotensin converting enzyme (ACE),
which converts angiotensin I to its active form angiotensin II within the test
extract, which consisted of 80% ethanol extract of lyophilized viscous
materials of natto. ACE causes blood vessels to narrow and blood pressure to
rise - by inhibiting ACE, nattokinase has a lowering effect on blood
After a single intraperitoneal administration of
400-450 grams of the test extract (equivalent to 25 mg of natto food) into male
Wister rats, systolic blood pressure (SBP) significantly decreased from 166 +
mmHg to 145 + 24 mmHg in just two hours (p<0.05), and decreased further to
144 + 27 mmHg in 3 hours (p<0.05). On average, this data represents a 12.7
percent drop in SBP within two hours.1,2
The same natto extract was then tested on human
volunteers with high blood pressure. Blood pressure levels were measured after
30 grams of lyophilized extract (equivalent to 200 grams of natto food) was
administered orally for 4 consecutive days. In 4 out of 5 volunteers, the
systolic blood pressure (SBP) decreased on average from 173.8 + 20.5 mmHg to
154.8 + 12.6 mmHg. Diastolic blood pressure (DBP) decreased on average from
101.0 + 11.4 mmHg to 91.2 + 6.6 mmHg. On average, this data represents a 10.9
percent drop in SBP and a 9.7 percent drop in DBP.1,2,6
The traditional Japanese food Natto has been used
safely for over 1000 years. The potent fibrinolytic enzyme nattokinase appears
to be safe based upon the long-term traditional use of this food. Nattokinase
has many benefits including convenience of oral administration, confirmed
efficacy, prolonged effects, cost effectiveness, and can be used
preventatively. It is a naturally occurring, food based dietary supplement that
has demonstrated stability in the gastrointestinal tract, as well as to changes
in pH and temperature.
Glossary of Terms:
Cardiac Infarction: Heart attack.
Cerebral Infarction: Stroke.
Fibrin: A whitish, filamentous protein formed
by the action of thrombin on fibrinogen and makes up part of coagulum or blood
Fibrinolytic: Pertaining to or causing the
breaking up of blood clots.
Infarction: Cardiac or cerebral tissue death
due to failure of blood supply to the area usually caused by a blood clot.
Plasmin: An endogenously produced fibrinolytic
Plasminogen: A precursor to plasmin. A protein
found in many tissues and body fluids.
Thrombus: A blood clot that obstructs a blood
vessel or a cavity of the heart.
Thrombolytic: Pertaining to or causing the
breaking up of a thrombus.
TPA: Tissue plasminogen activator.
t-PAs: The most commonly used thrombolytic
drugs including activase, urokinase, and streptokinase.
Urokinase: An endogenously produced
thrombolytic enzyme & also a commonly used thrombolytic drug given
intravenously to cardiac and cerbral infarction patients.
1. Prevent Heart Attack and Stroke
with Potent Enzyme that Dissolves Deadly Blood Clots in Hours. Health Sciences
Institute, March 2002.
2. Maruyama M, Sumi H. Effect of Natto
Diet on Blood Pressure. JTTAS, 1995.
3. Sumi H, Hamada H, Nakanishi K,
Hiratani H. Enhancement of the fibrinolytic activity in plasma by oral
administration of nattokinase. Acta Haematol 1990;84(3):139-43.
4. Sumi H, Hamada H, Mihara H. A novel
strong fibrinolytic enzyme (nattokinase) in the vegetable cheese "natto."
5. Journal of Fibronolysis and
Thrombolysis. Abstracts of the ninth international congress on fibrinolysis,
Amsterdam, 1988, Vol.2, Sup.1:67. 5. Sumi H, Hamada H, Tsushima H, Mihara H,
Muraki H. A novel fibrinolytic enzyme (nattokinase) in the vegetable cheese
Natto; a typical and popular soybean food in the Japanese diet. Experientia
1987, Oct 15;43(10):1110-1.
6. Sumi H. Healthy Microbe "Bacillus
natto". Japan Bio Science Laboratory Co. Ltd.
7. Sumi H. Interview With Doctor of
Medicine Hiroyuki Sumi. Japan Bio Science Laboratory Co. Ltd. 8. Sumi H.
Structure and Fibronolytic Properties of Nattokinase.
Potent fibrinolytic enzyme from a mutant of
Bacillus subtilis IMR-NK1.
Chang CT, Fan MH, Kuo FC, Sung HY. J Agric Food Chem
2000 Aug;48(8):3210-6 Department of Food and Nutrition, Providence University,
Shalu, Taiwan, Republic of China.
A mutant of Bacillus subtilis IMR-NK1, which is used
for the production of domestic "natto" in Taiwan, produced high fibrinolytic
enzyme activity by solid-state fermentation using wheat bran as medium.
Purification and characterization of a fibrinolytic
enzyme produced from Bacillus sp. strain CK 11-4 screened from
Kim W, Choi K, Kim Y, Park H, Choi J, Lee Y, Oh H,
Kwon I, Lee S. Appl Environ Microbiol 1996 Jul;62(7):2482-8 Department of
Biotechnology, Institute of R & D, Yangpyung-Dong, Youngdeungpo-Gu, Seoul,
(South) Korea. firstname.lastname@example.org
Bacillus sp. strain CK 11-4, which produces a strongly
fibrinolytic enzyme, was screened from Chungkook-Jang, a traditional Korean
fermented-soybean sauce. The fibrinolytic enzyme (CK) was purified from
supernatant of Bacillus sp. strain CK 11-4 culture broth and showed
thermophilic, hydrophilic, and strong fibrinolytic activity.
Thrombolytic effect of nattokinase on a chemically
induced thrombosis model in rat.
Fujita M, Hong K, Ito Y, Fujii R, Kariya K, Nishimuro
S. Biol Pharm Bull 1995 Oct;18(10):1387-91 Biotechnology Research Laboratories,
JCR Pharmaceuticals Co., Ltd., Kobe, Japan.
Nattokinase is a new fibrinolytic enzyme which cleaves
directly cross-linked fibrin in vitro. In this study, we investigated the
thrombolytic effect of nattokinase on a thrombus in the common carotid artery
of rat in which the endothelial cells of the vessel wall were injured by acetic
acid. When a section of occluded vessel was stained for CD61 antigen by
immunofluorescence utilizing a monoclonal antibody, the antigen was localized
around the surface of the occluded blood vessels. This result suggests that the
occlusive thrombosis was caused by platelet aggregation. In addition,
thrombolysis with urokinase (UK; 50000 IU/kg, i.v.) or tissue plasminogen
activator (tPA; 13300 IU/kg, i.v.) in our model was observed to restore the
blood flow over a 60 min monitoring period. The results indicate that our
chemically induced model is useful for screening and evaluating a thrombolytic
agent. We evaluated the thrombolytic activity of nattokinase using this model
and compared it with fibrino(geno)lytic enzyme, plasmin or elastase. On a molar
basis, the recovery of the arterial blood flow with nattokinase, plasmin and
elastase were 62.0 +/- 5.3%, 15.8 +/- 0.7% and 0%, respectively. The results
indicate that the thrombolytic activity of nattokinase is stronger than that of
plasmin or elastase in vivo.
Transport of nattokinase across the rat intestinal
Fujita M, Hong K, Ito Y, Misawa S, Takeuchi N, Kariya
K, Nishimuro S. Biol Pharm Bull 1995 Sep;18(9):1194-6 Biotechnology Research
Laboratories, JCR Pharmaceuticals Co., Ltd., Kobe, Japan.
Intraduodenal administration of nattokinase (NK) at a
dose of 80 mg/kg, resulted in the degradation of fibrinogen in plasma
suggesting transport of NK across the intestinal tract in normal rats. The
action of NK on the cleavage of fibrinogen in the plasma from blood samples
drawn at intervals after intraduodenal administration of the enzyme was
investigated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis
(SDS-PAGE) and Western blotting analysis with an anti-fibrinogen gamma chain
antibody. In parallel with the degradation process, plasma recalcification
times were remarkably prolonged NK was also detected in the plasma from blood
samples drawn 3 and 5 h after administration of the enzyme by SDS-PAGE and
Western blotting analysis with an anti-NK antibody. The results indicate that
NK is absorbed from the rat intestinal tract and that NK cleaves fibrinogen in
plasma after intraduodenal administration of the enzyme.
Purification and characterization of a strong
fibrinolytic enzyme (nattokinase) in the vegetable cheese natto, a popular
soybean fermented food in Japan.
Fujita M, Nomura K, Hong K, Ito Y, Asada A, Nishimuro
S. Biochem Biophys Res Commun 1993 Dec 30;197(3):1340-7 Biotechnology Research
Laboratories, JCR Pharmaceuticals Co., Ltd., Kobe, Japan.
A strong fibrinolytic enzyme (nattokinase) was
purified from the vegetable cheese natto. Nattokinase was extracted from natto
with saline and isolated by sequential use of hydrophobic chromatography. The
isolated protein gave a single sharp band on SDS-PAGE either before or after
reduction. The sequence, as determined by automated Edman degradation of the
uncleaved molecule and its enzymatically derived peptide, consisted of a total
275 amino acid residues (M.W = 27,728) and exhibited a high homology with the
Enhancement of the fibrinolytic activity in plasma
by oral administration of nattokinase.
Sumi H, Hamada H, Nakanishi K, Hiratani H. Acta
Haematol 1990;84(3):139-43 Department of Physiology, Miyazaki Medical College,
The existence of a potent fibrinolytic enzyme
(nattokinase, NK) in the traditional fermented food called 'natto', was
reported by us previously. It was confirmed that oral administration of NK (or
natto) produced a mild and frequent enhancement of the fibrinolytic activity in
the plasma, as indicated by the fibrinolytic parameters, and the production of
tissue plasminogen activator. NK capsules were also administered orally to dogs
with experimentally induced thrombosis, and lysis of the thrombi was observed
by angiography. The results obtained suggest that NK represents a possible
compound for use not only in the treatment of embolism but also in the
prevention of the disease, since NK has a proven safety and can be
A novel fibrinolytic enzyme (nattokinase) in the
vegetable cheese Natto; a typical and popular soybean food in the Japanese
Sumi H, Hamada H, Tsushima H, Mihara H, Muraki H.
Experientia 1987 Oct 15;43(10):1110-1 Department of Physiology, Miyazaki
Medical College, Japan.
A strong fibrinolytic activity was demonstrated in the
vegetable cheese Natto, which is a typical soybean food eaten in Japan. The
average activity was calculated at about 40 CU (plasmin units)/g wet weight.
This novel fibrinolytic enzyme, named nattokinase, was easily extracted with
saline. Nattokinase not only digested fibrin but also the plasmin substrate
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