Systemic Actions of Supplemental Enzymes

David Wolfson, ND, Stephen Olmstead, MD, Dennis Meiss, PhD, Janet Ralston, BS Enzymes are probably best known for their essential role in digestion of food, but they also have numerous and important metabolic functions in the body. When needed to improve digestion, supplemental enzymes should be taken with meals. When intended to increase enzyme activity throughout the body often called systemic enzyme therapy enzymes should be taken between meals to facilitate their absorption into the bloodstream. Systemic enzyme therapy has a long history of use and a demonstrated ability to favorably modulate clotting pathways, inflammatory processes, tissue healing, and immune function. reduced pain, dysphagia, and nasal obstruction compared to placebo in a group of patients suffering from acute or chronic inflammatory otorhinolaryngological conditions.7 Proteolytic enzyme combinations have also been used successfully for improved posttraumatic/postsurgical healing. One clinical trial compared a combination of proteolytic enzymes against standard postsurgical care in a group of patients who had undergone internal fracture fixation of the long bones. Patients who received the enzymes experienced significantly less postsurgical swelling and required fewer analgesics than the group receiving conventional antiinflammatory medications.8 The proposed mechanisms underlying the ability of proteolytic enzymes to mitigate inflammation and improve tissue healing include reducing inflammatory mediators like prostaglandins,2,9 plasmakinins,1,9 tumor necrosis factor- 10 and C-reactive protein,10 modulating adhesion molecules,4,11 decreasing exudate viscosity,12 and facilitating fluid drainage by enhancing fibrinolysis.9,12 One non-proteolytic enzyme with potential benefits for inflammatory conditions is catalase. Catalase is a ubiquitous, metabolic enzyme that catalyzes the breakdown of reactive hydrogen peroxide (H2O2) into oxygen and water. As an adjunct to conventional treatments, intramuscularly administered catalase significantly accelerated the rate of recovery in a group of patients with inflammatory radiculopathies.13 As hydrogen peroxide has been found to activate the proinflammatory mediator nuclear factor kappa-B,14 its clearance from damaged tissues may explain in part how catalase can help reduce healing time.

PROTEOLYTIC ENZYMES KEY TO SYSTEMIC BENEFITS

Most enzyme preparations intended for systemic use contain either one or a combination of proteolytic enzymes (proteases). Other classes of enzymes such as carbohydrases and lipases may exert systemic benefits indirectly through their digestive actions, but with few exceptions only supplemental proteases have been researched for their effects outside the gastrointestinal system. Once absorbed into the systemic circulation, proteolytic enzymes appear capable of modulating a number of biochemical pathways. Proteolytic enzymes have been tested in numerous research trials and shown to benefit persons with joint problems, musculoskeletal pain, tissue damage due to injury or surgery, infections, and ear, nose and throat conditions.

SUPPORTS INFLAMMATORY RESPONSE AND TISSUE HEALING

Perhaps the most prevalent use of systemic enzymes is to modulate inflammation and tissue healing. Combinations of various proteolytic enzymes have been used for decades to help reduce the swelling associated with injuries, arthritides and other inflammatory conditions. The proteolytic enzymes bromelain, papain, trypsin, and chymotrypsin have been widely used in Europe and their therapeutic efficacy well-documented in both preclinical and clinical research. In animal studies involving kaolin- and carrageenan-induced inflammation, oral administration of bromelain was shown to significantly reduce the presence of bradykinin, prostaglandin E2, and substance P in inflammatory exudates.1,2 These chemicals mediate inflammatory processes and the transmission of pain impulses in the body. Human studies have found that oral proteases like bromelain and trypsin significantly reduce pain and stiffness in persons with uncomplicated joint pain, osteoarthritis, and blunt injury to the musculoskeletal system.3-5 The enzyme Serratia peptidase, derived from nonpathogenic strains of the bacterial genus Serratia, has also shown considerable promise in modulating inflammatory processes. In one small trial, 10 mg of Serratia peptidase given twice daily for 6 weeks resulted in significant improvement of both electrophysiological measurements and subjective symptoms of pain, numbness, and paresthesia in a group of 20 persons with carpal tunnel syndrome.6 In another multi-center, double-blind, placebo-controlled trial, 10 mg of Serratia peptidase given 3 times daily for 7-8 days significantly

HELPS REGULATE BLOOD CLOTTING

Proteases have been used to support proper blood clotting for over 40 years. In vitro and in vivo studies show that the proteolytic enzyme bromelain inhibits platelet aggregation and reduces experimentallyinduced thrombus formation in the blood vessels of rats.15 In humans, bromelain has been shown to increase partial thromboplastin time,16 a measure of clotting time, and has successfully been used as a treatment for thrombosis of the retinal vein (also known as retinal vein occlusion or RVO).17 The mechanism by which bromelain reduces clotting is not entirely clear, but research suggests it may block activation of receptors on platelet cell surfaces and/or increase degradation of fibrin either directly or through activation of fibrinolytic factors such as plasmin.9,15

MODULATES IMMUNE SYSTEM RESPONSE

Proteolytic enzyme therapy is commonly used in Europe to enhance the immune response in a variety of clinical situations. A significant amount of research from Germany and other European countries has explored how enzymes achieve their effects. In one study, a proteolytic enzyme combination containing bromelain, trypsin, chymotrypsin, pancreatin, and papain was shown to significantly increase the capacity of neutrophils to release reactive oxygen species in vitro.18 Reactive oxygen species, a class of free radicals

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typically viewed as a detriment to health, can be of significant benefit when utilized by immune cells to kill pathogenic microbes and tumor cells. Bromelain has also been shown to significantly enhance the cytotoxicity of monocytic cells derived from immunecompromised patients with breast cancer.16 In a number of human trials, proteolytic enzyme combinations have successfully been used as adjunctive agents during cancer treatment.19,20 Another protease, papain, has been effectively used by itself and as a treatment adjunct to improve clinical outcomes in patients with lung abscesses and other infectious lesions.21,22 Proteolytic enzymes appear to exhibit immunomodulatory activity, or the ability to modify the immune response in either a positive or negative manner depending on conditions in the body. For example, bromelain has been shown to decrease production of interferon- by intestinal cells derived from patients with inflammatory bowel disease.23 Interferon- is a cytokine that stimulates macrophages to increase production of other inflammatory cytokines.24 Interferon- is also essential to immune protection against infectious organisms and growth of tumor cells.25 However, bromelain has been shown to upregulate production of interferon- by immune cells derived from severely immune-compromised mice.26 This dual ability to either enhance or suppress one or more aspects of immune function in order to bring about a benefit for the host characterizes immunomodulatory activity and may in part explain the therapeutic efficacy proteolytic enzymes have demonstrated in inflammatory and immune disorders.

SUMMARY
A significant portion of enzyme activity in the human body is devoted to digestion of dietary macronutrients such as proteins, carbohydrates, and fats into smaller molecules that can be absorbed through the intestinal mucosa into either the bloodstream or lymphatic system. Outside of the digestive system, enzymes perform numerous metabolic functions. Metabolic enzymes facilitate chemical reactions involved with energy production, growth, repair, movement, reproduction, and virtually all other aspects of human physiology. Systemic enzyme therapy involves taking an enzyme supplement, especially proteolytic enzymes, between meals so that the enzymes are absorbed into the circulation instead of being utilized for food digestion. The notion that enzymes can be absorbed through the intestinal mucosa was once controversial, but research has demonstrated that enzymes can pass intact from the digestive tract into the bloodstream.27,28 Systemic use of proteolytic enzymes has a long history of use and has demonstrated the ability to favorably modulate clotting pathways, inflammatory processes, tissue healing, and immune function.

REFERENCES
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3. Walker AF, Bundy R, Hicks SM, Middleton RW. Bromelain reduces mild acute knee pain and improves well-being in a dose-dependent fashion in an open study of otherwise healthy adults. Phytomedicine 2002;9:1-6. 4. Klein G, Kullich W. Short-term treatment of painful osteoarthritis of the knee with oral enzymes: a randomised, double-blind study versus diclofenac. Clin Drug Invest 2000;19:15-23. 5. Masson M. [Bromelain in blunt injuries of the locomotor system. A study of observed applications in general practice] Fortschr Med 1995;113:303-6. [Article in German; Abstract in English] 6. Panagariya A, Sharma AK. A preliminary trial of serratiopeptidase in patients with carpal tunnel syndrome. J Assoc Physicians India 1999;47:1170-2. 7. Mazzone A, Catalani M, Costanzo M, et al. Evaluation of Serratia peptidase in acute or chronic inflammation of otorhinolaryngology pathology: a multicentre, double-blind, randomized trial versus placebo. J Int Med Res 1990;18:379-88. 8. Kamencek V, Holn P, Frank P. [Systemic enzyme therapy in the treatment and prevention of post-traumatic and postoperative swelling] Acta Chir Orthop Traumatol Cech 2001;68:45-9. [Article in Czech; Abstract in English] 9. Maurer HR. Bromelain: biochemistry, pharmacology and medical use. Cell Mol Life Sci 2001;58:1234-45. 10. Leipner J, Iten F, Saller R. Therapy with proteolytic enzymes in rheumatic disorders. BioDrugs 2001;15:779-89. 11. Kleef R, Delohery TM, Bovbjerg DH. Selective modulation of cell adhesion molecules on lymphocytes by bromelain protease 5. Pathobiology 1996;64:339-46. 12. Mecikoglu M, Saygi B, Yildirim Y, et al. The effect of proteolytic enzyme serratiopeptidase in the treatment of experimental implant-related infection. J Bone Joint Surg Am 2006;88:1208-14. 13. Put TR. The favourable effect of adding a catalase to the treatment of syndromes due to intervertebral disc degenerations. Arzneimittelforschung 1975;25:951-6. 14. Takada Y, Mukhopadhyay A, Kundu GC, et al. Hydrogen peroxide activates NF-kappa B through tyrosine phosphorylation of I kappa B alpha and serine phosphorylation of p65: evidence for the involvement of I kappa B alpha kinase and Syk protein-tyrosine kinase. J Biol Chem 2003;278:24233-41. 15. Metzig C, Grabowska E, Eckert K, Rehse K, Maurer HR. Bromelain proteases reduce human platelet aggregation in vitro, adhesion to bovine endothelial cells and thrombus formation in rat vessels in vivo. In Vivo 1999;13:7-12. 16. Eckert K, Grabowska E, Stange R, et al. Effects of oral bromelain administration on the impaired immunocytotoxicity of mononuclear cells from mammary tumor patients. Oncol Rep 1999;6:1191-9. 17. Gray LF. Thrombosis of the central retinal vein and its treatment with ananase. South Med J 1969;62:11. 18. Zavadova E, Desser L, Mohr T. Stimulation of reactive oxygen species production and cytotoxicity in human neutrophils in vitro and after oral administration of a polyenzyme preparation. Cancer Biother 1995;10:147-52. 19. Gonzalez NJ, Isaacs LL. Evaluation of pancreatic proteolytic enzyme treatment of adenocarcinoma of the pancreas, with nutrition and detoxification support. Nutr Cancer 1999;33:117-24. 20. Sakalov A, Bock PR, Dedk L, et al. Retrolective cohort study of an additive therapy with an oral enzyme preparation in patients with multiple myeloma. Cancer Chemother Pharmacol 2001;47(Suppl):S38-44. 21. Udod VM, Trofimenko SP, Shabash EG, Storozhuk VT. [Experimento-clinical basis for using papain in purulent surgery] Vestn Khir Im I I Grek 1984;132:48-51. [Article in Russian; Abstract in English] 22. Udod VM, Kolos AI, Gritsuliak ZN. [Treatment of patients with lung abscess by local administration of papain] Vestn Khir Im I I Grek 1989;142:24-7. [Article in Russian; Abstract in English] 23. Onken JE, Greer PK, Calingaert B, Hale LP. Bromelain treatment decreases secretion of pro-inflammatory cytokines and chemokines by colon biopsies in vitro. Clin Immunol 2008;126:345-52. 24. Houri-Haddad Y, Soskolne WA, Shai E, Palmon A, Shapira L. Interferon-gamma deficiency attenuates local P. gingivalis-induced inflammation. J Dent Res 2002;81:395-8. 25. Schoenborn JR, Wilson CB. Regulation of interferon-gamma during innate and adaptive immune responses. Adv Immunol 2007;96:41-101. 26. Engwerda CR, Andrew D, Murphy M, Mynott TL. Bromelain activates murine macrophages and natural killer cells in vitro. Cell Immunol 2001;210:5-10. 27. Jackson D, Walker-Smith JA, Phillips AD. Macromolecular absorption by histologically normal and abnormal small intestinal mucosa in childhood: an in vitro study using organ culture. J Pediatr Gastroenterol Nutr 1983;2:235-47. 28. Castell JV, Friedrich G, Kuhn CS, Poppe GE. Intestinal absorption of undegraded proteins in men: presence of bromelain in plasma after oral intake. Am J Physiol 1997;273(1 Pt 1): G139-46.

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