Molecular and Physiologic Mechanisms of Systemic Enzyme Therapy: A Review for Clinicians

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.

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 reports^4-6 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 reviews^19-21 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 circulation^22-23 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.

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.

Vasquez A. “Molecular Cell Biology and Interventional Proteogenomics. Part Three: New Implications for Naturopathic Medical Education, Clinical Practice and Naturogenomics.” Naturopathy Digest, 2006 December.
Beard J. The action of trypsin upon the living cells of Jensen’s mouse-tumour. Br Med J, 1906 (Jan 20);4:140-1.
Cutfield A. Trypsin treatment in malignant disease. Br Med J 1907;5:525.
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.
Goeth RA. Pancreatic treatment of cancer, with report of a cure. Journal of the American Medical Association 1907 (March 23);48:1030.
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Taussig SJ, Yokoyama MM, Chinen A, et al. Bromelain: a proteolytic enzyme and its clinical application. A review. Hiroshima J Med Sci 1975;24(2-3):185-93.
Taub SJ. The use of bromelains in sinusitis: a double-blind clinical evaluation. Eye Ear Nose Throat Mon, 1967 Mar;46(3):361-5.
Trickett P. Proteolytic enzymes in treatment of athletic injuries. Appl Ther 1964;30:647-52.
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.
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.
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Saruc M, Standop S, Standop J, Nozawa F, et al. Pancreatic enzyme extract improves survival in murine pancreatic cancer. Pancreas 2004;28(4):401-12.
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Sakalova A, Bock PR, Dedik L, et al. 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.
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.
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Vasquez A. Integrative Orthopedics, 2nd edition; 2007 (in press). www.optimalhealthresearch.com.
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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.
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.
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.
Vellini M, Desideri D, Milanese A, Omini C, et al. Possible involvement of eicosanoids in the pharmacological action of bromelain. Arzneimittelforschung 1986;36(1):110-2.
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Bio: 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. By the time he graduated from Bastyr in 1999, Dr. Vasquez had published numerous articles in magazines and peer-reviewed medical journals, and was a recognized authority on disorders of iron metabolism.

Dr. Vasquez was later appointed to teach rheumatology, orthopedics, and radiographic interpretation for the naturopathic program at Bastyr. During this time, he also maintained a private practice of chiropractic and naturopathic medicine in Seattle. For family reasons, Dr. Vasquez returned to his hometown of Houston in 2002 and started a new private practice of natural medicine.