Articles
As seen in NutriNews, August,
2008
Systemic Enzyme Support - An Overview
A large number of
conditions are primarily inflammatory in nature and may be
significantly complicated by the presence of secondary forms of
inflammation. Regardless of whether the cause of the problem is due
to bacterial, viral or auto-immune influences, the result may be an
ongoing situation with significant clinical and laboratory
manifestations of the inflammatory process.
Dietary supplements
designed to provide Systemic Enzyme Support (SES) can play an
important role in helping to maintain normal inflammatory processes
within the body and thereby help support and speed healing. This is
not only beneficial for the patient, but for healthcare in general
as ultimately it may help to reduce the costs associated with
maintaining health.
Most healthcare
professionals select treatments based on what they believe will be
effective over a long period of time as well as what will bring a
specific patient the fewest risks in connection with treatment. One
of the major benefits of using systemic enzyme support is the
relatively small amount of undesirable effects combined with good
tolerance and efficacy.
Systemic enzyme
support was for a long time regarded as a purely empirical treatment
method. Due to the rapid development of immunology, biochemistry and
molecular biology in the last few decades, systemic enzyme support
has undergone significant development, as it has been shown that
behind the empirically supported clinical results are a complex set
of regulatory processes, which previously were unknown. Today,
scientists have a better understanding with respect to the
mechanisms by which Systemic Enzyme Support may be exerting it’s
desired effects. Specifically, the effect of proteolytic enzymes
(proteases) on the cytokine network and their action at the level of
the cell membrane both in terms of cellular adhesion as well as
modulation of cellular receptors has been described. One of the main
pioneers in the clinical use of the systemic proteases was Professor
Max Wolf, who worked in New York in the 1930s not only as a
sought-after physician but also as a researcher at Fordham
University. At the present time, with regard to the historically
best known pharmacological and clinical effects, proteases are
placed in the international ATC classification in the M09AB group –
anti-inflammatory enzymes.
Systemic
Enzyme Support – definition
Hydrolytic enzymes
have been used widely for decades and a range of scientific
publications have recently demonstrated their importance in
supporting numerous areas of health. At the present time proteases
are indicated for parenteral application in malfunctions of blood
coagulation (urokinase), to affect fibrotic processes (hyaluronidase)
or in treatment of malignant hemotological conditions (asparaginase).
The aim of oral application of enzymes may be either substitution of
digestive enzymes in external secretory insufficiency of the
pancreas (see accompanying article: “The Importance of Good
Digestion“) or use of their systemic effects (proteases). So,
Systemic Enzyme Support can be defined as a modality which uses oral
administration of exogenous hydrolytic (mainly proteolytic) enzymes
of animal origin (trypsin, chymotrypsin) and plant origin (bromelain,
papain) in the form of enteric-coated tablets for supporting healthy
and normal inflammatory processes in the body. As a result, systemic
enzyme support can help maintain a healthy immune system, healthy
blood flow and circulation, healthy joint function, as well as help
to reduce muscles pain after exercising. Systemic enzymes can exert
a positive effect on rheological properties of blood as a result of
their fibrinolytic properties. Data have also shown that
administering systemic enzymes together with certain antibiotics is
able to improve the tissue availability of the antibiotics.
Proteases
The main component
of products designed for systemic enzyme support are proteolytic
(i.e. protein splitting) enzymes of animal or plant origin. These
are endopeptidases which hydrolyze peptide bonds in certain protein
(peptide) chain locations on the basis of a more or less specific
affinity to particular amino acid elements of these chains.
Trypsin is a
pancreatic endopeptidase, which splits peptide bonds formed by the
carboxylic group of the amino acids such as lysine or arginine. It
is obtained from the pancreas of pigs by repeated refining and
subsequent activation of the proenzyme trypsinogen.
Chymotrypsin is a
pancreatic endopeptidase, which hydro-lytically splits peptide bonds
formed by carboxylic groups of the amino acids tyrosine,
phenylalanine and tryptophan. Chymotrypsin is obtained by extraction
and chromatographic purification from the pancreas of cattle and
subsequent activation of the proenzyme chymotrypsinogen.
Bromelain is an
endopeptidase obtained from pineapples. Bromelain hydrolytically
splits peptide bonds formed by the amino acids lysine, alanine,
tyrosine and glycine. Bromelain is a family of individual
macromolecules and is not a single enzyme.
Papain is a mixture
of proteolytic enzymes separated from the fruit of the tropical
Carica papaya, which is a member of the melon family. Papain
splits polypeptides, particularly between the bonds of arginine,
phenylalanine and lysine.
These proteases are
typically combined in preparations for oral administration. The
reason for these combinations is an assumption that the effects of
individual enzymes will complement each other resulting in the
multiplication of the final therapeutic efficacy. Another reason for
these combinations is the assumption of an increase in the
resorption of individual proteases by the intestinal mucous membrane
when administered together with other proteases.
Most of the
combined systemic enzyme support preparations currently used usually
contain rutin (rutoside) in addition to two or more proteases. Rutin
belongs to the group of bioflavonoids and can help to reduce the
permeability of veins and capillaries.
Resorption of
enzymatically active macromolecules and their pharmacokinetics
The basic condition
of the systemic effect of proteases administered orally is their
absorption in an enzymatically active form. The coated tablet
ensures that the content will resist the acid gastric juices and not
break down until it has reached the mucosa of the small intestine
with a pH of about 7. After absorption, certain parts of the
proteolytic enzymes pass into the blood stream and the lymph where
their enzymatic activity allows them to bind to natural
antiproteases of which the most important are alpha-2-macroglobulin
(a-2-M) and alpha-1-antitrypsin (a-1-AT).
Many effects of SES
are based on a-2-M-protease complex. The complex formation starts
with the hydrolysis of the specific peptide
bond in
a-2-M by a protease. It causes a very deep conformational change of
the entire a-2-M molecule. The protease becomes trapped in the a-2-M
molecule in a way that prohibits many of its potential proteolytic
abilities, however, some smaller or less protected substrates can
still reach the reaction center and thus it does retain some
catalytic activity. In the complex, a-2-M masks the protease
macromolecule’s antigenic determinants, so the enzyme has no
allergenic effect on the organism. By its interaction with a
protease, a-2-M is transformed into an “active” form (so called
“fast form”) which has new properties in relation to many
physiologically active molecules, especially, to a broad spectrum of
substances which participate in the immune response.
Protease-antiprotease complexes are transported into tissues, where
the proteases can be released (from a-1-AT, but not from a-2-M) and
operate for a short time as free enzymes or have a relatively
long-term effect as entire complexes. In these complexes, the
proteases are captured by the liver and the pancreas where 90 % of
them are eliminated in bile and excreted in stools. The biological
half-life for elimination of enzymes after their resorption is
relatively long (6 hours for bromelain and 12-20 hours for trypsin).
The biological availability of enzymes in terms of systemic effects
is relatively low after oral administration, i.e. around 1% of the
total dose administered. This explains the necessity to administer
proteolytic enzymes in large doses.
Bromelain and trypsin and similarly other proteases that are administered for systemic effects are resorbed from the intestine as active molecules. Penetration by the enzyme through the wall of the intestine in an active state has also been demonstrated for other enzymes (horse-radish peroxydase, 40 kDa; botulotoxin, 150 kDa). At the present time the generally accepted opinion is that even molecules with a weight of more than 1000 kDa can also penetrate the intestinal barrier to a limited extent.
Currently a number of mechanisms for the transfer of macromolecules
through the intestine wall are described. In the upper part of the
small intestine, persorption is regarded as the main mechanism. This
is linked with continuous desquamation of dying enterocytes, which
causes the short-term increase in permeability of the intestinal
barrier. In addition, absorption by M-cells (microfold cells)
accumulated in the intestinal mucosa over the Payer’s plaques takes
part in the transfer in the ileum. Another mechanism is the
receptor-mediated endocytosis linked with internalisation and
recycling of the receptor. In addition to transcellular paths,
paracellular transfer through tight junctions also appears to be
another possibility.18
Mechanisms of
the effect of proteases after oral application
The
systemic effect of proteases is realized in the organism either by
way of direct proteolysis of physiologically important molecules of
a protein nature or indirectly by affecting the properties of
important regulatory molecules (e.g. a-2-M or proteinase-activated
receptors, PARs).
1. Direct
proteolytic effects
In blood plasma, equilibrium is established under physiological
conditions between the body’s own free proteases and those bound to
antiproteases (a-2-M, a-1-AT). After oral application of exogenous
proteases and their absorption in the intestine, there is a shift in
this equilibrium state in terms of an increase in what is termed
proteolytic activity of the blood. Proteases bound to a-2-M, which
preserve part of their proteolytic activity (“limited proteolysis”),
also take part in this.
Proteases take part in specific activation, regulation and
degradation of a whole range of factors connected with an
inflammatory response. For example, by means of revealing antigenous
epitopes, specific proteolysis of a range of cytokines, degradation
of regulatory factors of a protein nature or activation of
receptors. In addition to this, proteases degrade proteins and
peptides damaged by inflammation and thereby allow for easier
phagocytosis and removal by means of the venous and lymphatic
systems.
2. Effect on
adhesion molecules
Adhesion molecules (AM) – are structures on the surface of cells
which play an important role in intercellular communication,
particularly in the case of immune cells. The degree of their
expression is determined by the state of activation of the cell and
has an important influence on its properties. For example, increased
expression of certain AMs on endothelial cells and thrombocytes and
also leukocytes, accompanies an inflammatory response of the
organism in all phases. In vitro and in vivo experiments show that
enzymes contained in systemic enzyme support products selectively
reduce the density of certain adhesion molecules on endothelial
cells, in damaged tissues and also on cell membranes of certain
inflammatory cells. By reducing the density of these molecules,
there occurs an increase in the activation threshold of elements
which take part in an inflammatory reaction.
In
terms of immunomodulation, the ability of trypsin to increase the
activation threshold of T-lymphocytes, owing to reduction in the
number of CD4, CD44 and B7-1 adhesion molecules on their surface,
appears to be very important. Increased expression of CD4, CD44 and
B7-1 and the reduction of the activation threshold of T-lymphocytes
connected with this is regularly observed in the focus of
inflammation. This is produced by stimulation of INFy and targeted
to increasing the reaction capability of T-lymphocytes. In view of
the fact that an activated T-lymphocyte produces additional INFy,
the whole process is amplified. The action of trypsin on the above
mentioned adhesion molecules (also with increased elimination of
INFy through the binding to the complex protease – a-2-M, see below)
returns T-lymphocytes to an inactive state and thereby helps to
maintain normal inflammatory processes.
3. Effect on
cytokines operating locally and systemically
In normal inflammatory processes, a whole range
of cytokines come into play (e.g. TNF-a, TGF-β, IFNy, IL-1, IL-6).
Some of these cytokines can contribute to the development of
imbalances in the inflammatory process. Lately, attention has been
focused mainly on the autocrine cytokine TGF-β, whose excessive
formation plays a part in various immuno-pathological processes.
Cytokines in plasma are bound (like proteases) to antiproteases,
particularly to a-2-M. The bond of a cytokine to the antiprotease
itself is reversible and a cytokine may manifest its own activity
again after being liberated. However, when a cytokine is bound to
a-2-M that contains a linked protease, a stable bond is formed,
which in turn inactivates the cytokine. Consequently, the whole
complex (protease-antiprotease-cytokine) is quickly
eliminated by phagocytosis in the liver and the spleen. Therefore,
systemic proteases can help to accelerate the clearance of increased
levels of certain cytokines.
A similar elimination mechanism has also been demonstrated for
immune complexes and even for amyloid polymer which play a
part in the development of certain chronic conditions.
4. Effect by
means of protease-activated receptors
Protease-activated
receptors – PARs (e.g. PAR-2 is a trypsin-activated receptor) -
present on the surface of most of the body cells. They have a
physiological importance, for instance in regulating the exchange of
substances between the lumen of the blood vessels and the
interstitial space. Through the protease-PAR interaction, proteases
are considered as key modulators of immune and inflammatory
responses. PAR activation by systemic enzymes can contribute to
changes in hydrodynamics, and oncotic pressure and thereby can help
to maintain normal inflammatory processes and blood flow. Overall,
this can help to improve microcirculation and to remove cellular
detritus.
5. Effect on
AGEs by exogenous proteases
Advance glycation
end-products (AGEs), which are formed by non-enzymatic reaction of
sugars, ketones or aldehyde groups with a free amino group of
proteins, lipids or amino acids, induce chemical modification of
proteins and lipids, including LDL particles. This modification is
the basis for changes of the structural and functional properties of
plasma proteins and extracellular matrices. There is, for example,
cross-linking and thickening of basal membranes. The result of
AGE-induced modification of lipoproteins (apoprotein-B, LDL) is
their delayed clearance through LDL receptors. The interaction of
AGEs with their receptors (RAGEs) and/or binding proteins on the
surface of cells may induce cell activation and increased formation
of oxygen radicals with subsequent activation of the nuclear factor
kB (NF-kB) and increased synthesis of cytokines, growth factors and
adhesion molecules. Similarly, depending on what type of cell that
AGEs are interacting with, they may impact cell proliferation as
well as programmed cell death. These effects of AGEs explain the
critical role they may play in the pathogenesis of vascular
complications of certain chronic conditions. Additionally, aging in
general is also thought to be associated with increased AGEs.
The effects of AGEs
on the endothelial function have also been well characterized. In in
vitro and in vivo experiments, AGEs alter the effect of nitric
oxide, which results in changes in vasodilatation. Transendothelial
chemotaxis of monocytes and PDGF (platelet derived growth factor)
secretion are increased, as is the expression of certain adhesion
molecules, such as VCAM-1 (vascular cell adhesion molecule-1) and
ICAM-1 (intercellular adhesion molecule-1). When extracellular
matrix glycation and inflammatory stimuli are combined, the
intensity of the endothelial adhesion can be amplified.
Proteases (trypsin
and bromelain) significantly reduce the concentration of AGEs and
lipid oxidation products, both in vitro and and in vivo. After
application of proteases, reduction in the number of over-expressed
RAGEs on the surface of cells accompanied by an increase of their
concentration in the intercellular area was observed. This both
reduces the probability of interaction of AGEs with their receptors
and also enables “inactivation” of AGEs through AGE-soluble RAGE
complexes. In connection with a reduction of AGE level, a reduction
in the concentration of TGF-β and a lower occurrence of DNA “damage”
has also been observed.
These findings also
corroborate the idea that AGEs-induced genotoxicity is mediated via
the binding of receptors and that trypsin and bromelain may
inactivate the extracellular domain of this receptor.
6. Immunomodulation by means of intestinal bacteria
The
effect of systemic enzymes on immune function may also be mediated
at the level of the intestine. While only a hypothesis, the thought
that systemic effects may in part be related to local actions at the
level of the gut arises from the observation that certain proteases
(e.g. trypsin) can strengthen the bacteriocidal effect of
intraluminal intestinal enzymes (e.g. lysozyme). This may result in
the induction of immunocompetent cells occurring directly or in
immediate contact with the intestinal epithelium.1
Pharmacodynamic effects of SES
The
effects of proteases administered orally are highly interconnected
and can be derived from the mechanisms stated above.
The
ability of systemic enzymes to support normal inflammatory processes
is a crucial and a highly complex one. The action of proteases on
normal inflammatory processes works in a number of ways,46
which helps to explain the wide spectrum of potential health issues
for which systemic enzymes can help to support.
In
instances involving occurrences such trauma, burns, haematoma, etc.,
a combination of proteolytic enzymes works mainly by improving blood
rheology and by breakdown of tissue detritus. Specifically, deposits
of proteins escaped from the arterial or venous lumen are cleaved
and degraded by proteolytic enzymes. Small thrombi created in the
periphery of the “vascular bed” can be reduced which promotes the
supply of immunocompetent cells and oxygen necessary to rebalance
normal inflammatory processes.
In
addition to the aforementioned, in situations of ongoing imbalances
of the inflammatory system, proteases can help to eliminate
immunocomplexes, alter the expression of adhesion molecules, and
normalize the cytokine network, and overall haemostasis.
The
extent of interaction of proteolytic enzymes with key inflammation
reaction mechanisms ranges from supporting the bodies normal
inflammatory reaction to helping decrease on overactive system. In
contrast to conventional medical products, proteases therefore
optimize the physiological course of inflammation and help maintain
a balanced process.
The
effect on rheological blood and lymph properties, which leads to
their decreased viscosity and improved fluidity, is caused by
interactions with the fibrinogen/fibrin system and the ability to
activate plasminogen into plasmin and increase the levels of anti-thrombine
III. Restriction of aggregation and adhesion of thrombocytes and
reduction in aggregation and improvement of the flexibility of
erythrocytes has also been described.
Improvement of microcirculation by affecting the rheological
properties of body fluids is also regarded as one of the factors
contributing to the beneficial effects of systemic enzymes. Other
important factors which play a part in this effect are all the
mechanisms which lead to normalizing an immune response reaction and
minimizing secondary damage.
The
immunomodulatory effect of systemic enzymes is mediated through
affecting the expression of adhesion molecules, interventions in the
cytokine network and impact on protease-activated receptors. The
effect on various cellular components of the immune system
(macrophages, granulocytes, NK cells, T lymphocytes) and the impact
on production and elimination of immunocomplexes have also been
demonstrated.
It has been shown
that some individual proteases and also combined preparations
increase the concentration of antibiotics, chemotherapeutic drugs
and certain other medical products in the blood and tissues.
Certain relatively
recent papers refer to the ability of proteases to reduce the level
of LDL–cholesterol. The mechanism underlying the increased
elimination of LDL-cholesterol may be the ability of a-2-M-protease
complexes to activate common receptors specific for LDL and a-2-M on
the membranes of phagocytic cells, in particular the phagocyte
system of the liver and the spleen.
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About the Authors:
Martin Wald, M.D.
Dr. Wald is a
1981 graduate of the Medical School at Charles University in Prague.
In 1991, he accepted a position of house surgeon at the Department
of Surgery, 2nd Medical School at Charles University in Prague-Motol.
The following year, he became a postgraduate fellow at the same
department. Since 1990 Dr. Wald’s interests, beyond surgery, have
included the systemic effects of proteases on organisms, both in
humans and animals. His research, lecture and publication activities
primarily involve this field from the point of view of theoretical
aspects, experimental works and clinical application of proteases in
surgery. For many years he has also been engaged in breast health,
related to both diagnostic and surgical therapy. His work has been
published in Czech and international journals as well as being
presented at congresses in the Czech Republic and abroad.
Zinovij Masinovský, Ph.D.
Dr. Masinovský
was a member of the faculty with the Department of Biophysics at
Moscow State University and received his Ph.D. at the Institute of
Microbiology, Czechoslovak Academy of Sciences. His work includes
work at the Department of Evolutionary Biology at the Institute of
Microbiology as and the Laboratory of Evolutionary Biology (LEB) of
the Czechoslovak Academy of Sciences as a researcher in the field of
biochemistry and biophysics focused on early evolution and enzymes
and photobiological mechanisms. Dr. Masinovský is a former councilor
at the International Society for the Study of the Origin of Life,
author of 65 scientific articles and a member of the J.E.Purkyne
Czech Medical Association.