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Active Hydrogen Adrenal Extracts Alanine Alpha-Linolenic Acid Alpha-Lipoic Acid AMP Amylase Inhibitors Arginine Bee Pollen Beta Carotene Beta-glucan Betaine Beta-Sitosterol Biotin Borage Oil Boron Bovine Cartilage Bovine Colostrum Brewer's Yeast Bromelain Calcium Capsaicin Carnitine Carnosine Chitosan Chloride Chlorophyll Chondroitin Chromium CLA Cobalt Coenzyme Q10 Copper Creatine Cysteine DHA DHEA DMAE EGCG Evening Primrose Oil 5-HTP Fiber (Insoluble) Fiber (Soluble) Fish Oil Flavonoids Fluoride Folate Fumaric Acid GABA Gamma-Linolenic Acid Glucomannan Glucosamine Glutamic Acid Glutamine Glutathione Glycine Grape Seed Extract Histidine HMB Hydroxycitric Acid Indole Inosine Inositol Iodine Ipriflavone Iron Isoleucine Lactase Lecithin Leucine Lipase Lutein Lycopene Lysine Magnesium Malic Acid Manganese Mannose Melatonin Methionine Methoxyisoflavone Molybdenum MSM N-Acetyl Cysteine NADH Naringin Niacin Octacosanol Oligosaccharides Olive Leaf Extract Ornithine Oryzanol PABA Pancreatic Enzymes Pantothenic Acid Phenylalanine Phosphatidylserine Phosphorus Phytic Acid Policosanol Potassium Pregnenolone Probiotics Propolis Psyllium Pyridoxine Pyruvate Quercetin Resveratrol Retinol Riboflavin Ribose Royal Jelly SAMe Selenium Shark Cartilage Silicon Sodium Spirulina Spleen Extracts St. John's Wort Strontium Sulforaphane Sulfur Taurine Thiamine Tocopherol Tea Tree Oil Tyrosine Usnic Acid Valine Vanadium Vinpocetine Vitamin A Vitamin B1 Vitamin B2 Vitamin B3 Vitamin B5 Vitamin B6 Vitamin B9 Vitamin B12 Vitamin C Vitamin D Vitamin H Vitamin K Whey Protein Xylitol Zinc
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Molecular and Physiologic Mechanisms of Systemic Enzyme Therapy: A Review for Clinicians

By Alex Vasquez, DC, ND

For reasons that are both political and clinical, doctors of chiropractic need to have a complete understanding (preferably molecular or genomic) of the interventions they use, whether dietary, nutritional, botanical or manual/manipulative.

This is important politically because we have a need to explain the mechanisms of our treatments to our patients, as well as to policy-makers, researchers and other clinicians;1 failure to explicate and articulate the mechanisms of their treatments makes otherwise effective and brilliant clinicians appear ignorant and unprofessional. Clinically, mechanistic and molecular understandings of our interventions helps us to fine-tune and synergize our treatments for the best possible clinical outcomes by guiding which patients will be treated and which additional therapeutics will be co-administered.

Given that the oral administration of pancreatic/proteolytic enzymes for systemic benefits (“systemic enzyme therapy”) is one of the most common nutritional/botanical treatments used by doctors of chiropractic, this article will provide a review of this treatment’s clinical benefits and molecular mechanisms, with emphasis on the latter. In this discussion, systemic enzyme therapy or the use of “oral enzymes” will be specified to mean the oral, between-meal administration of supplements containing pancreatin, bromelain, papain, amylase, lipase, trypsin and alpha-chymotrypsin; according to the research literature and clinical experience, polyenzyme preparations are more effective than the use of single enzymes.

Past and Current Use

Systemic enzyme therapy has been used clinically for more than a century, beginning with the early publications of Beard2 and Cutfield,3 who both showed the anti-cancer effects of orally administered enzymes in animals and patients, respectively. Although these and other early reports4-6 showed impressive efficacy and lack of toxicity in the treatment of cancer, they generally were ignored due to enthusiasm surrounding interventional radiation, since “X-rays” had been discovered by Roentgen just a few years earlier and radiation’s cancer-causing effects were then unknown.

Current clinical uses of pancreatic/proteolytic enzymes are varied, ranging from improved digestion (when taken with meals) to systemic benefits (when taken between meals). Briefly, systemic enzyme therapy commonly is used in the treatment of cellulitis, diabetic ulcers, sinusitis, bronchitis,7-8 injury-related disorders (including contusions, sprains, lacerations, and muscle injuries)9-10 and osteoarthritis (OA).11-12 Use of systemic enzyme therapy in the treatment of cancer is well-supported by experimental and clinical studies.13-18

Physiologic Effects

Physiologic mechanisms of systemic enzyme therapy have been discussed in several of my recent reviews19-21 and will be briefly listed here before advancing to the more detailed molecular mechanisms. Briefly, proteolytic enzymes are well-absorbed from the gastrointestinal tract into the systemic circulation22-23 to exert anti-tumor, anti-inflammatory, anti-edematous and immunostimulatory actions, which are the result of different and synergistic effects, including the following:24-27

  1. dose-dependent stimulation of reactive oxygen species production and anti-cancer cytotoxicity in human neutrophils;
  2. a pro-differentiative effect;
  3. reduction in PG-E2 production;
  4. reduction in substance P production;
  5. modulation of adhesion molecules;
  6. fibrinolytic effects; and
  7. an anti-thrombotic effect mediated at least in part by a reduction in 2-series thromboxanes.

Molecular Mechanisms: New Data

Patients with degenerative and inflammatory arthropathies (e.g., osteoarthritis and rheumatoid arthritis [RA]) have increased synovial concentrations of tissue-destroying proteases such as the matrix metalloproteinases (MMP) and cathepsin B; normally, these proteolytic enzymes are inhibited by endogenous proteinase inhibitors, such as alpha-1-antitrypsin and alpha-2-macroglobulin. Oral administration of pancreatic/proteolytic enzymes such as trypsin and chymotrypsin has been shown to increase serum levels of alpha-1-antitrypsin and alpha-2-macroglobulin, and in this way, oral administration of therapeutic proteases/proteinases stimulates the body’s production of endogenous proteinase inhibitors, which then inhibit endogenous joint-destroying proteinases. Stated more simply, systemic enzyme therapy stimulates internal defenses to protect against joint destruction.

Systemic enzyme therapy also modulates cytokine levels and thereby shifts “immune balance” away from the autoreactive cell-mediated Th-1 response and more toward a Th-2 response. Significant reductions in tumor necrosis factor-alpha, interleukin-1b, and autoreactive T-cells have been reported following the administration of oral enzymes in experimental and/or clinical settings. Importantly, systemic enzyme therapy can result in reductions in circulating immune complexes in patients with RA that are directly related to the degree of clinical improvement – the greater the enzyme-induced reduction in immune complexes, the greater the clinical response. This clearly suggests a mechanistic cause-and-effect benefit from systemic enzyme therapy in immune-complex- mediated disease.

However, we also know that RA is a prototype of dysbiosis-induced systemic inflammation28 and thus the recent article by Biziulevicius,29 proposing that the immunostimulatory action of oral enzymes may be derived from direct and indirect intra-intestinal bactericidal and antimicrobial actions, raises an alternate hypothesis that the anti-rheumatic and immune-complex-lowering benefits of systemic enzyme therapy may result not only from intravascular proteolysis of preformed immune complexes, but also primarily from a reduction in de novo immune complex formation due to antimicrobial and thus anti-dysbiotic effects. These effects of systemic enzyme therapy are summarized in Table 1.

Table 1: Molecular and Physiologic Mechanisms of Systemic Enzyme Therapy
Dose-dependent stimulation of reactive oxygen species production and anti-cancer cytotoxicity in human neutrophils
A pro-differentiative effect
Reduction in PG-E2 production
Reduction in substance P production
Fibrinolytic effect
Anti-thrombotic effect, mediated at least in part by a reduction in 2-series thromboxanes
Modulation of adhesion molecules
Modulation of cytokine balance
Induction of endogenous proteinase inhibitors (e.g., alpha-1-antitrypsin and alpha-2-macroglobulin)
Reduction in circulating immune complexes
Possible antimicrobial effect in the gastrointestinal tract, thereby alleviating dysbiosis and reducing de novo immune complex formation

The molecular and physiologic mechanisms of action by which systemic enzyme therapy exerts its various safe and significant benefits are numerous and are increasingly well-defined. Armed with this understanding, clinicians can more effectively treat their patients and more convincingly explain the mechanisms and merits of their treatments to policy-makers, researchers and other clinicians. Clinicians are wise to avail themselves of the benefits of proteolytic/pancreatic enzymes, which deserve – based on impressive safety records and diverse clinical applications – to be a routine component of patient care.


References

  1. Vasquez A. Molecular Cell Biology and Interventional Proteogenomics. Part Three: New Implications for Naturopathic Medical Education, Clinical Practice and Naturogenomics. Naturopathy Digest 2006 December.
  2. Beard J. The action of trypsin upon the living cells of Jensen's mouse-tumour. Br Med J. 1906; 4 (Jan 20): 140-1.
  3. Cutfield A. Trypsin Treatment in Malignant Disease. Br Med J. 1907; 5: 525.
  4. Wiggin FH. Case of Multiple Fibrosarcoma of the Tongue, With Remarks on the Use of Trypsin and Amylopsin in the Treatment of Malignant Disease. Journal of the American Medical Association 1906; 47: 2003-8.
  5. Goeth RA. Pancreatic treatment of cancer, with report of a cure. Journal of the American Medical Association 1907; (March 23) 48: 1030.
  6. Campbell JT. Trypsin Treatment of a Case of Malignant Disease. Journal of the American Medical Association 1907; 48: 225-226.
  7. Taussig SJ, Yokoyama MM, Chinen A, Onari K, Yamakido M. Bromelain: a proteolytic enzyme and its clinical application. A review. Hiroshima J Med Sci. 1975;24(2-3):185-93.
  8. Taub SJ. The use of bromelains in sinusitis: a double-blind clinical evaluation. Eye Ear Nose Throat Mon. 1967 Mar;46(3):361-5.
  9. Trickett P. Proteolytic enzymes in treatment of athletic injuries. Appl Ther. 1964;30:647-52.
  10. Walker JA, Cerny FJ, Cotter JR, Burton HW. Attenuation of contraction-induced skeletal muscle injury by bromelain. Med Sci Sports Exerc. 1992 Jan;24(1):20-5.
  11. 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;9:681-6.
  12. Brien S, Lewith G, Walker A, Hicks SM, Middleton D. Bromelain as a Treatment for Osteoarthritis: a Review of Clinical Studies. Evidence-based Complementary and Alternative Medicine. 2004;1(3)251–257.
  13. Saruc M, Standop S, Standop J, Nozawa F, Itami A, Pandey KK, Batra SK, Gonzalez NJ, Guesry P, Pour PM. Pancreatic enzyme extract improves survival in murine pancreatic cancer. Pancreas. 2004;28(4):401-12.
  14. Batkin S, Taussig SJ, Szekerezes J. Antimetastatic effect of bromelain with or without its proteolytic and anticoagulant activity. J Cancer Res Clin Oncol. 1988;114(5):507-8.
  15. Gonzalez NJ, Isaacs LL. Evaluation of pancreatic proteolytic enzyme treatment of adenocarcinoma of the pancreas, with nutrition and detoxification support. Nutr Cancer. 1999;33(2):117-24.
  16. Sakalova A, Bock PR, Dedik L, Hanisch J, Schiess W, Gazova S, Chabronova I, Holomanova D, Mistrik M, Hrubisko M. Retrolective cohort study of an additive therapy with an oral enzyme preparation in patients with multiple myeloma. Cancer Chemother Pharmacol. 2001 Jul;47 Suppl:S38-44.
  17. Popiela T, Kulig J, Hanisch J, Bock PR. Influence of a complementary treatment with oral enzymes on patients with colorectal cancers–an epidemiological retrolective cohort study. Cancer Chemother Pharmacol. 2001;47 Suppl:S55-63.
  18. Leipner J, Saller R. Systemic enzyme therapy in oncology: effect and mode of action. Drugs. 2000 Apr;59(4):769-80.
  19. Vasquez A. Reducing pain and inflammation naturally - Part 3: Improving overall health while safely and effectively treating musculoskeletal pain. Nutritional Perspectives 2005; 28: 34-38, 40-42. www.optimalhealthresearch.com/part3.
  20. Vasquez A. The Importance of Integrative Chiropractic Health Care in Treating Musculoskeletal Pain and Reducing the Nationwide Burden of Medical Expenses and Iatrogenic Injury and Death: A Concise Review of Current Research and Implications for Clinical Practice and Healthcare Policy. The Original Internist 2005; 12(4): 159-182.
  21. Vasquez A. Integrative Orthopedics. Second Edition. 2007. (in press) www.optimalhealthresearch.com.
  22. Gotze H, Rothman SS. Enteropancreatic circulation of digestive enzymes as a conservative mechanism. Nature 1975; 257(5527): 607-609.
  23. Liebow C, Rothman SS. Enteropancreatic Circulation of Digestive Enzymes. Science 1975; 189(4201): 472-474.
  24. 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(2):147-52.
  25. Maurer HR, Hozumi M, Honma Y, Okabe-Kado J. Bromelain induces the differentiation of leukemic cells in vitro: an explanation for its cytostatic effects? Planta Med. 1988 Oct;54(5):377-81.
  26. Gaspani L, Limiroli E, Ferrario P, Bianchi M. In vivo and in vitro effects of bromelain on PGE(2) and SP concentrations in the inflammatory exudate in rats. Pharmacology. 2002;65(2):83-6.
  27. Vellini M, Desideri D, Milanese A, Omini C, Daffonchio L, Hernandez A, Brunelli G. Possible involvement of eicosanoids in the pharmacological action of bromelain. Arzneimittelforschung. 1986;36(1):110-2.
  28. Vasquez A. Integrative Rheumatology. www.optimalhealthresearch.com.
  29. Biziulevicius GA. Where do the immunostimulatory effects of oral proteolytic enzymes (systemic enzyme therapy) come from? Microbial proteolysis as a possible starting point. Med Hypotheses. 2006;67(6):1386-8.
Dr. Alex Vasquez began his professional studies at Texas Chiropractic College and later graduated from Western States Chiropractic College in 1996. He then attended the naturopathic medicine program at Bastyr University in Seattle, Wash. A complete biography of Dr. Vasquez and a printable version of this article are available online at www.nutritionalwellness.com/columnists/vasquez.
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