Absorption and Bioavailability of orally applied proteolytic enzymes

The human intestinal epithelium has traditionally been thought to be impermeable to proteins, but it is only part of truth. There exists evidence by studies that large molecules like gamma globulins can be absorbed from the gastrointestinal tract in an intact form without degradation and without losing their functional activity (e.g. babies receive their defense against infections via the Immune globulins from mother’s milk; oral vaccination of e.g. poliomyelitis, cholera, rotavirus). Botulism is caused by ingestion of food containing the progenitor toxin (300 – 900 kDa) of Clostridium botulinum. This toxin is absorbed in the small intestine, reaches the lymphatic system and may lead to severe illness. Reactions like itching skin can occur after ingestion of proteins causing individual intolerance.
These examples from nature reveal a basic phenomenon that large molecules can be absorbed in an intact form.

Are Enzymes from animals, plants and microorganism absorbed after oral intake?

No, the low pH level in the stomach destroys enzymes (e.g. Bromelain, Lumbrokinase, Nattokinase, Pancreatin, Papain, Serrapeptase and Sfericase) and therefore practically no active enzyme would reach the blood if it were taken orally.

The great idea of Max Wolf and Karl Ransberger (the great pioneers of Enzyme-Therapy) in the 1950′s was to cover the enzyme tablets. This cover dissolves in the small intestine, so the enzymes are protected from hydrochloric acid and pepsin in the stomach and are released in neutral milieu of the small intestine.

Figure: intestinal migration of coated enzyme tablets

The coated tablets (“enteric coated”) are resistant to low pH and pepsin of the stomach. The cover dissolves at pH 7 only, which is found in the small intestine and enzymes are liberated there.

Are liberated free enzymes full-size absorbed in therapeutically significant amounts?

It has to be shown, that these enzymes reach the blood and/or lymph

1. in full-size,
2. in physiological active form and
3. in therapeutic relevant amounts.

1964 Miller found in blood samples an increased ability to digest casein after administration of coated Bromelain tablets to healthy humans.
1997 Castell used different antibodies against Bromelain to proof that these proteases are absorbed in high molecular form. In an randomized controlled double-blind study in humans he could demonstrate that after oral intake of Bromelain the full-size proteins are present in blood and that these molecules are also biological active and arrive a mean concentration of 10µg/ml in plasma were they are bound to alpha2macroglobulin. The half-life of Bromelain in men after oral application was 6 – 9 hrs in blood.

In the results from Seifert 1995 – he worked with rats – an absorption rate of 49, 6% (Trypsin), 38, 1% Chymotrypsin 26% (Papain) 36, 6% (Pancreatin) was determined. He calculated by administering 10 mg that 5 mg were absorbed and from these the half has macromolecular structure. Conclusion: 2, 5 mg of these enzymes after 10 mg oral intake reach the blood. This amount of enzymes in blood was big enough to reduce oedema in hind legs of the animals as he demonstrated in this publication.
One year later Kolac (1996) published that proteolytic enzymes (Trypsin, Chymotrypsin, Papain and Bromelain) are able to increase the permeability of the mucosal epithelium and, hence, facilitate their own absorption by a mechanism of self-enhanced paracellular diffusion (transcytosis); these investigations were done in vitro with the Caco-2 cell line, an immortalized human epithelial colorectal carcinoma cell line.
1997 Donath measured elevated hydrolytic activity in plasma after oral application of Bromelain and Trypsin in human blood by an ELISA test. Oral administration of Bromelain inhibits thrombus formation in a rat model (Mai 1996; Metzig 1999; Maurer 2001).
Results from in vitro studies by Bock 1998 showed that about 10% of the applied enzyme dose (mixture of Trypsin, Chymotrypsin, Papain and Bromelain) reached the basolateral cell surface of Caco-2 as intact, biologically active molecules. Trypsin and Bromelain were highly mucolytic active, thereby reducing the diffusion barrier based on the mucus gel layer. 77% of Trypsin auto-degrades within 2 hr, whereas auto degradation of Bromelain was negligible (Bernkop Schnurch 2000).
2001 Lauer described an elevated concentration of enzyme-activated a2macroglobulin in human blood after oral enzyme application. Binding to a2macroglobulin save partly the proteolytic activity of the enzyme and protected against immunity recognition (Wu 2002; Libicky 1996)
Serrapeptase (Moryia 1994) Nattokinase (Fujita 1995), Lumbrokinase (Fan 2001) as well as Sfericase (Yoshida 1983; Umemura 1984) are absorbed from the intestinal tract and transferred into the circulation in an enzymatic active form after oral administration, investigated in different animal models.

In blood, orally applied enzymes bind to the enzyme carrier alpha2macroglobulin (“anti-protease”) (Barrett 1973). In the complex of a2M+enzyme the enzymes are physiologically active; this may be reason for different effects in addition to the cytokine scavenger activity: e.g preparations with Nattokinase have fibrinolytic activity, Serrapeptase reduces viscosity of nasal mucus and Bromelain preparations reduce swelling and pain.
In blood the complex a2M + Enzyme binds to LRP (a2-M receptor / low-density lipoprotein receptor – related protein = CD91), which is expressed on e.g. Hepatozytes, endothelial cells, macrophages. The complex is removed from blood in short time and degraded in these cells by endocytosis.

Conclusion: Enzymes (e.g. Bromelain, Lumbrokinase, Nattokinase Papain, Serrapeptase, Sfericase) if presented “enteric coated” were absorbed in the small intestine. These enzymes reach the blood as active full-sized enzymes of about 10% of the original amount and preserve their bioavailability as proofed in many studies. Half life of enzymes after oral intake amounts between 6 and 9 hours.

References