Nattokinase

Scientific Name(s): Nattokinase , Subtilisin natto

Common Name(s): Natto , cardiokinase , fermented soybeans , thua nao (Thailand), shiokara (Japan), chungkook-jang (Korea), douchi (Chinese), Natto-K , NattoMax , Flite Tabs , Vein Caps

Uses

Nattokinase is promoted for use as a fibrinolytic agent; however, clinical trials are currently lacking to support this use. The enzyme may also have potential as a pharmacological vitreolytic.

Dosing

Clinical studies are lacking to guide safe and effective dosing. Dosages ranging from nattokinase 100 to 300 mg daily have been used in some studies. Nattokinase, in combination with pycnogenol, has been used for the prevention of deep vein thrombosis (DVT) in long airline flights.

Contraindications

Avoid nattokinase in patients with ischemic stroke, peptic ulcer, and coagulation disorders, as well as with concomitant anticoagulant therapy, and pre- and postsurgery.

Pregnancy/Lactation

Information regarding safety and efficacy in pregnancy and lactation is lacking.

Interactions

None well documented.

Adverse Reactions

Trials evaluating the effect of nattokinase report no adverse reactions. A theoretical risk of bleeding exists based on a case report of acute cerebellar hemorrhage in a patient with a history of ischemic stroke.

Toxicology

No information is available.

The enzyme nattokinase is produced when the bacterium Bacillus subtilis (also called Bacillus natto or Bacillus subitilis natto ) is added to boiled soybeans and allowed to ferment. Similarly, other fibrinolytic enzymes have been extracted from bacteria, such as streptokinase from streptococci and staphylokinase from Staphylococcus aureus . The enzyme has been isolated and made commercially available as a powder or capsules, or in combination with other ingredients in tablet form. Experiments with soybeans fermented with alternate bacterium ( Rhizopus and Fusarium sp.) have also been conducted. 1 , 2 , 3 , 4 , 5

History

The fermentation of soybeans is common in traditional Asian and African culinary practice. Natto is a traditional Japanese food consumed for at least a thousand years as breakfast with rice, on toast, or as sushi, and is also available as an ice cream flavor. It has been used traditionally for heart conditions, to relieve fatigue, and as an anti-beriberi agent. In the 1980s, researchers investigating food substances for thrombolytic properties isolated the enzyme nattokinase from natto. 1 , 2 , 6

Chemistry

Natto has a characteristic smell (possibly because of its pyrazine content), a strong distinct flavor, and has been described as a vegetable cheese because of its consistency. Natto is also reported to contain Vitamin K2 (menaquinone). Nattokinase is an alkaline serine protease with an amino acid sequence similar to subtilisin, which is used in laundry detergents. The enzyme catalyses the cleavage of protein to polypeptides. It can withstand temperatures of up to 50°C and repeated freezing and thawing, but is inactive in acidic conditions. Tablets containing nattokinase are therefore enteric-coated. Methods have been described to optimize the production of the enzyme. 1 , 2 , 3 , 4 , 7 , 8

Uses and Pharmacology

Fibrinolysis

The fibrinolytic action of nattokinase has been studied in vitro. Unlike streptokinase, nattokinase does not act directly on plasminogen. The enzyme appears to cleave to plasminogen activator inhibitor, thereby increasing the activity of tissue plasminogen activator and promoting the conversion of plasminogen to plasmin, with a resultant increase in clot lysis. Nattokinase is also reported to act directly on thrombi by proteolysis. The fibrinolytic action of nattokinase is reportedly 4 times that of plasmin. Using human whole blood exposed to nattokinase, dose-dependent decreases in red blood cell aggregation and low-shear viscosity have also been demonstrated. The enzyme has also been reported to degrade amyloid fibrils. 1 , 2 , 9 , 10 , 11

Animal data

Nattokinase was absorbed across rat intestine. Limited animal experiments have been conducted, and include induced thrombi and endothelial injury in the femoral arteries and common carotid artery in rats. Dietary supplementation with nattokinase suppressed intimal thickening, modulated the lysis of mural thrombi, and improved arterial blood flow more effectively than plasmin and elastase. In dogs, oral administration of nattokinase completely dissolved induced clots from major leg veins within 5 hours of administration, whereas the clots in dogs receiving placebo showed no thrombolysis up to 18 hours. 9 , 12 , 13 , 14

Clinical data

Limited clinical trials have not produced definitive results regarding the efficacy of nattokinase as a fibrinolytic. 2 , 15 One trial evaluated the effect of nattokinase daily intake on the hematological indices of 12 healthy Japanese volunteers and found enhanced fibrinolytic activity. A gradual increase in euglobulin fibrinolytic activity, increase in fibrin degradation products, and an increase in tissue plasminogen activator were recorded. Data for all subjects were not published. 2 , 9 An open-label trial evaluated the effect of nattokinase over 2 months among healthy volunteers, as well as those with cardiovascular risk factors and in patients on dialysis. Decreases in plasma fibrinogen and coagulation factors VII and VIII were observed over time within each group; however, no group effect was established. The sample size (N = 45) was too small to draw firm conclusions from the study. 16 Another trial evaluated the preventive action of nattokinase in subjects at risk of deep vein thrombosis (DVT) during a long flight. Nattokinase, in combination with pycnogenol, taken 2 hours before and 6 hours into the flight was reported to reduce thrombotic events as determined by ultrasound of the venous system. Edema scores were also reduced, possibly due to the diuretic effect of pycnogenol. However, conclusions regarding the fibrinolytic action of nattokinase cannot be drawn from this study. 2 , 17

Other effects
Dyslipidemia

A double-blind, randomized clinical trial designed to evaluate the effect of nattokinase in hyperlipidemia found changes in triglycerides and high-density lipoprotein (HDL) from baseline; however, no differences versus placebo could be demonstrated. 18 No effect on lipid profile was found in a study evaluating the fibrinolytic effect of nattokinase. 16

Hypertension

A double-blind, randomized clinical trial designed to evaluate the hypotensive effect of nattokinase (N = 86) found decreases in systolic and diastolic blood pressure at 8 weeks, but not at 4 weeks, of daily nattokinase in mildly hypertensive patients. Conflicting results were obtained for plasma renin values. 19 No hypotensive effect was found in a study evaluating the fibrinolytic effect of nattokinase, 16 or in another study evaluating the effect on lipid profile. 18

Vitreolysis

In an experiment conducted in rabbits, intravitreal nattokinase induced posterior vitreous detachment via hydrolysis of collagen fibers; however, studies are lacking for clinical applications in humans as an alternative to surgery. 20

Dosage

Clinical studies are lacking to guide safe and effective dosage. Nattokinase 100 mg (equivalent to 2,000 fibrinolytic units) taken up to 3 times a day, has been used in some studies. 9 , 16 , 19 Nattokinase in combination with pycnogenol have been used for the prevention of DVT in long flights. 17

Pregnancy/Lactation

Information regarding safety and efficacy in pregnancy and lactation is lacking.

Interactions

None well documented. Case reports are lacking; however, potentiation of anticoagulant therapy is theoretically possible.

Adverse Reactions

Trials evaluating the effect of nattokinase report no adverse reactions. 9 , 16 , 17 , 19 A case report exists of acute cerebellar hemorrhage in a 52-year-old woman with a history of ischemic stroke. The patient was taking daily aspirin and commenced nattokinase at 400 mg daily, but cause and effect of nattokinase cannot be established because of her history. 21 However, a theoretical risk of bleeding does exist, so nattokinase should not be taken by patients with ischemic stroke, peptic ulcer, or coagulation disorders, or with concomitant anticoagulant therapy, or pre- and postsurgery.

Toxicology

No information is available.

Bibliography

1. 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;43(10):1110-1111.
2. Tai MW, Sweet BV. Nattokinase for prevention of thrombosis. Am J Health Syst Pharm . 2006;63(12):1121-1123.
3. Ku TW, Tsai RL, Pan TM. A simple and cost-saving approach to optimize the production of subtilisin NAT by submerged cultivation of Bacillus subtilis natto . J Agric Food Chem . 2009;57(1):292-296.
4. Wang C, Du M, Zheng D, et al. Purification and Characterization of nattokinase from Bacillus subtilis Natto B-12. [published online ahead of print Sep 29, 2009]. J Agric FoodChem . doi:10.1021/jf901861v.
5. Sugimoto S, Fujii T, Morimiya T, Johdo O, Nakamura T. The fibrinolytic activity of a novel protease derived from a tempeh producing fungus, Fusarium sp.BLB. Biosci Biotechnol Biochem . 2007;71(9):2184-2189.
6. Inatsu Y, Nakamura N, Yuriko Y, Fushimi T, Watanasiritum L, Kawamoto S. Characterization of Bacillus subtilis strains in Thua nao, a traditional fermented soybean food in northern Thailand. Lett Appl Microbiol . 2006;43(3):237-242.
7. Fujita M, Nomura K, Hong K, Ito Y, Asada A, Nishimuro S. Purification and characterization of a strong fibrinolytic enzyme (nattokinase) in the vegetable cheese natto, a popular soybean fermented food in Japan. Biochem Biophys Res Commun . 1993;197(3):1340-1347.
8. Weng M, Zheng Z, Bao W, Cai Y, Yin Y, Zou G. Enhancement of oxidative stability of the subtilisin nattokinase by site-directed mutagenesis expressed in Escherichia coli . Biochim Biophys Acta . 2009;1794(11):1566-1572.
9. Peng Y, Yang X, Zhang Y. Microbial fibrinolytic enzymes: an overview of source, production, properties, and thrombolytic activity in vivo. Appl Microbiol Biotechnol . 2005;69(2):126-132.
10. Hsu RL, Lee KT, Wang JH, Lee LY, Chen RP. Amyloid-degrading ability of nattokinase from Bacillus subtilis natto. J Agric Food Chem . 2009;57(2):503-508.
11. Pais E, Alexy T, Holsworth RE Jr, Meiselman HJ. Effects of nattokinase, a pro-fibrinolytic enzyme, on red blood cell aggregation and whole blood viscosity. Clin Hemorheol Microcirc . 2006;35(1-2):139-142.
12. Suzuki Y, Kondo K, Matsumoto Y, et al. Dietary supplementation of fermented soybean, natto, suppresses intimal thickening and modulates the lysis of mural thrombi after endothelial injury in rat femoral artery. Life Sci . 2003;73(10):1289-1298.
13. Suzuki Y, Kondo K, Ichise H, Tsukamoto Y, Urano T, Umemura K. Dietary supplementation with fermented soybeans suppresses intimal thickening. Nutrition . 2003;19(3):261-264.
14. Fujita M, Hong K, Ito Y, Fujii R, Kariya K, Nishimuro S. Thrombolytic effect of nattokinase on a chemically induced thrombosis model in rat. Biol Pharm Bull . 1995;18(10):1387-1391.
15. Lee T. Ask the doctor. I would like to find a safer, easier alternative to warfarin, which I have been taking for a couple of years. I have been hearing about nattokinase—can I take it in place of warfarin? Harv Heart Lett . 2006;17(2):7.
16. Hsia CH, Shen MC, Lin JS, et al. Nattokinase decreases plasma levels of fibrinogen, factor VII, and factor VIII in human subjects. Nutr Res . 2009;29(3):190-196.
17. Cesarone MR, Belcaro G, Nicolaides AN, et al. Prevention of venous thrombosis in long-haul flights with Flite Tabs : the LONFLIT-FLITE randomized, controlled trial. Angiology . 2003;54(5):531-539.
18. Yang NC, Chou CW, Chen CY, Hwang KL, Yang YC. Combined nattokinase with red yeast rice but not nattokinase alone has potent effects on blood lipids in human subjects with hyperlipidemia. Asia Pac J Clin Nutr . 2009;18(3):310-317.
19. Kim JY, Gum SN, Paik JK, et al. Effects of nattokinase on blood pressure: a randomized, controlled trial. Hypertens Res . 2008;31(8):1583-1588.
20. Takano A, Hirata A, Ogasawara K, et al. Posterior vitreous detachment induced by nattokinase (subtilisin NAT): a novel enzyme for pharmacologic vitreolysis. Invest Ophthalmol Vis Sci. 2006;47(5):2075-2079.
21. Chang YY, Liu JS, Lai SL, Wu HS, Lan MY. Cerebellar hemorrhage provoked by combined use of nattokinase and aspirin in a patient with cerebral microbleeds. Intern Med . 2008;47(5):467-469.

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