Medi.

cal Hypotheses 6: 99-104, 1960

@ Churchill Livingstone

THE MECHANISM OF THE PHYSIOLOGICAL ACTION OF BROMELAIN

Steven J. Taussig, Chemical Consultants International,

Inc., P. 0. Box 88041, Honolulu, Hawaii 96815, U.S.A.

SUMMARY

The pineapple protease, bromelain, selectively inhibits the

biosynthesis of proinflammatory prostaglandins, apparently by
indirect action.

The inhibition of endogenous proteases that accompanies trauma,

or prolonged exposure to excessive stress markedly elevates the
relative proportions of those prostaglandins responsible for the
symptoms of inflammation. It has been demonstrated that brome-
lain's specificity is similar to that of the endogenous protease
plasmin. Bromelain acts on fibrinogen to give products that are
similar, at least in effect, to those formed by plasmin. They
are small molecular weight active peptides, which regulate pros-
taglandin biosynthesis and create conditions existing in the
healthy organism. It has been shown that a substantial portion
of orally administered bromelain is absorbed intact into the
bloodstream, thereby elevating the proteolytic and fibrinolytic
activity of the blood for hours.

The similarity between the beneficial effects of aspirin-type

drugs and bromelain, while bromelain causes none of the unde-
sirable side effects of the others, suggests that bromelain
acts on the prostaglandin synthetic pathway at a site different
from that affected by the non-steroidal anti-inflammatory drugs.
While aspirin inhibits the cyclooxygenase and thus the biosyn-
thesis of all prostaglandins, it is postulated that bromelain
acts furtherdown the arachidonate cascade at the thromboxane
synthetase step. Circumstantial evidence suggests that brome-
lain inhibits the synthesis of the "proinflammatory" prosta-
glandins without affecting that of the "anti-inflammatory" ones.
Bromelain therefore tends to reestablish the balance of the two
types of prostaglandins that characterizes the state of the
healthy organism.

INTRODUCTION

Bromelain as a commercial product has been available only since

the mid 1950's. During the ensuing 20 years, several hundred
papers have been published describing its use in inflammations,
digestive disorders, potentiation of antibiotics, and in cardio-
vascular, circulatory, and many other diseases. Although

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evidence of its effectiveness in a variety of conditions con-
tinued to accumulate, interest in bromelain decreased somewhat
in the 1970's, possibly because the mechanism of its action
remained obscure.

Commercial bromelain used in the manufacture of pharmaceuticals

is not a chemically homogenous substance. Its main ingredient
is a proteolytic enzyme (a glycoprotein) but it also contains
small amounts of an acid phosphatase, a peroxidase, several
protease inhibitors, and organically bound calcium. If the
commercial enzyme is highly purified, it loses its stability
and most of its physiological activity;

Bromelain is an anti-inflammatory agent; it prevents blood plate-

lets from aggregating; it increases tissue permeability: and it
increases the proteolytic and fibrinolytic activity of the blood.
Accumulated evidence suggests that bromelain is a selective
prostaglandin inhibitor.

(In discussing the hypothesis of the physiological action of

bromelain that is.presented here, the following nomenclature is
used: prostaglandin E (PGE ) and prostacyclin (PGI ) will be
referred to as "anti-i4 flamm atory" prostaglandins, w 4.
ile PGE2
PGF and TxA2 (thromboxane A ) will be called "proinflammator~"
pro & aglandins, indicating t3e generally opposite effects these
two groups of structurally related substances exhibit in physio-
logical concentrations. The two groups might also be termed,
respectively, "healing" and "alarm" prostaglandins, but will be
referred to in the following as the anti- and proinflammatory
prostaglandins (PGs).)

THE HYPOTHESIS

In the healthy organism, the endogenous serum protease plasmin

acts on fibrinogen to form several low molecular weight, active
peptides that stimulate the biosynthesis of anti-inflammatory
PGs. Plasmin thus plays a role in maintenance of normal prosta-
glandin balance.

In the case of trauma, or prolonged exposure to excessive stress,

plasmin is inhibited and the inflammatory PGs consequently
increase many fold above their normal levels. Concurrently,
thrombin is activated and reacts with. fibrinogen forming fibrin;
this condition also stimulates synthesis of proinflammatory PGs.

If bromelain is administered orally under such circumstances, it

substitutes for the inhibited plasmin and acts on fibrinogen to
stimulate the snythesis of anti-inflammatory prostaglandins, as
shown by Livio et al. (2). Pirotta et al. (8) have shown that
after oral administration of bromelain, both anti-inflammatory
and serum fibrinolytic activities increase substantially. These
processes are schematically represented in Figure 1.

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 fibrInolysis
i
Stimulationof
I
Stimulation of
antiinflammatory proinflammatory bret kddovm of
prostaglandins prostaglandins fibrin

RESULTING EFPECTS:
I+
1
increased -c- C-AMP - decreased
reduced Inflammation increased
inhibited Platelet aggregation stimulated
relaxed Smmth muscle contracted
increased Vascular permeability decreased

Fig. 1 Functions of endogenous proteases in the healthy

organism 1, and during trauma 2, and suggested
actions of bromelain 3 and 4.

In the healthy organism plasmin acts on fibrinogen (pathway 1)

and the active peptides formed stimulate the biosynthesis of
anti-inflammatory PGs. The resulting effects are: inhibition
of platelet aggregation, prevention of inflammation, relaxation
of smooth muscle, increase of vascular permeability and increase
in the concentration of c-AMP at the cellular level. In the
case of an injury, plasmin is inhibited and the processes shown
in pathway 1 are either strongly inhibited or abolished, while
thrombin is activated (pathway 2) and converts fibrinogen to
fibrin. Proinflammatory PGs also increase several fold, causing
all the symptoms of inflammation, platelet aggregation, smooth
muscle contraction, decreased vascular permeability, and de-
creased concentration of c-AMP in the cell. Orally administered
bromelain takes over the role of plasmin (pathway 3) and, be-
cause of its fibrinolytic activity, dissolves the fibrin clot
(pathway 4). Bromelain thus reverses the inflammatory reaction,
reestablishing the conditions of the healthy organism and accel-
erates healing.

Vane (10) found that bromelain inhibits the biosynthesis of PGE2.

This is not a total inhibition (as in the case of aspirin) but
is partial and dose-dependent. Because of inhibition of the
PGE2-type prostaglandins, the absolute amount of proinflammatory

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PGs is substantially decreased and the ratio between the pro-
inflammatory and anti-inflammatory PGs is changed in favor of
the latter. Since both types of PGs compete for the same
receptor sites, as shown by McDonald et al. (3) inhibition of
the proinflammatory PGs permits the anti-inflammatory PGs to
compete more favorably for the receptor sites on the cell
membrane. The anti-inflammatory PGs stimulate adenylate
cyclase and increase the concentration of --AMP at the cellular
level. The implications of this are far reaching and explain
why bromelain affects so many seemingly unrelated diseases.

The physiological activity of bromelain resides in its protease

fraction. Morita et al. (6) fractionated the commercial enzyme
on carboxymethyl Sephadex, obtaining three major components by
NaCl-gradient chromatography. Two of these fractions had both
proteolytic and physiological activities, as measured by inhibi-
tion of ADP-stimulated human platelet aggregation. The impor-
tant observation that bromelain does not inhibit aggregation of
washed platelets indicated that bromelain's effect might be an
indirect one: that it acts on fibrinogen to yield peptides that
affect the arachidonate cascase (7). This was confirmed experi-
mentally by Livio et al. (2).

Another important question to be answered is: Can bromelain

(mol. wt. about 30,000) pass intact into the bloodstream from
the gastro-intestinal tract? Miller et al. (4) and Miyatani
et al. (5) showed that blood serum exhibits increased proteo-
lytic activity after oral administration of bromelain. Seifert
et al. (9) have recently provided unequivocal proof that brome-
lain does in fact pass into the bloodstream intact: duodenally
administered, radioactive bromelain passed into the blood and
lymph, up to 40% of the bromelain being absorbed in its original
high molecular weight form. The enzyme was positively identified
by use of anti-bromelain serum. The absorption of intact brome-
lain from the gastro-intestinal tract readily explains the
increased level of serum proteolytic activity following oral
administration of the enzyme.

HOW DOES BROMELAIN AFFECT THE PROSTAGLANDIN SYNTHETIC PATHWAY?

Bromelain displays all the positive effects of the nonsteroidal

anti-inflammatory (aspirin-type) drugs, but none of their unde-
sirable side effects. This suggests that the two types of sub-
stances affect the prostaglandin biosynthetic pathway at differ-
ent Sites. Figure 2 shows the arachidonate cascade in a simpli-
fied form. Aspirin inhibits the cyclooxygenase and blocks the
synthesis of all proinflammatory, as well as anti-inflammatory,
prostaglandins. This accounts not only for the side effects of
nonsteroidal anti-inflammatory drugs, but also for the lack of
otherwise expected results from administration of aspirin to
prevent heart attacks and other problems connected with blood

102
clot formation. Kelton et al. (1) reported that high doses of
aspirin produce a thrombogenic effect in rabbits via inhibi-
tion of PGI2 biosynthesis.

Phospholipase A2 Phospholipids

t
Arachidonic acid
I
Cyclooxygenase

Complete inhibition of cyclooxygenase

t t
Increase of c-AMP Decrease of c-AMP

Fig. 2 Simplified representation of the arachidonate cascade,

site of action of aspirin-type drugs, and postulated
site of action of bromelain.

Figure 2 also shows the different sites of action of aspirin and

bromelain. Because bromelain does not have the undesirable side
effects of aspirin-type drugs, it is postulated that it inhibits
only thromboxane synthetase. Since, as has been demonstrated by
Vane (lo), an incomplete, partial inhibition takes place suffi-
cient proinflammatory PGs remain in the system to control gastric
juice secretion, excessive gastric juice secretion, one of the
undesirable side effects of aspirin, is due to complete inhibi-
tion of the PGE2 -type prostaglandins.

CONCLUSIONS

Based on recent research results and circumstantial evidence, a

hypothesis is presented explaining the mechanism of the pharma-
cological action of bromelain, and the site where it affects the
prostaglandin biosynthetic pathway.

Since the main obstacle in developing bromelain-based pharmaceu-

ticals was rather the lack of knowledge of its mechanism of
action than of evidence for its performance, it is hoped that
the information presented will open up new important fields of
application for bromelain.

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 Acknowledgement. The invaluable suggestions of Dr. Y. Hokama
and Dr. D. Howton, Professors at the John A. Burns School of
Medicine, University of Hawaii in Honolulu are hereby grate-
fully acknowledged.

REFERENCES

1. Kelton JG, Hirsch J, Carter JC, Buchanan MR. Thrombogenic

effect of high dose of aspirin in rabbits. Relationship
to inhibition of vessel wall synthesis of prostaglandin
12-like activity. J. Clin. Invest. 62 (41, 892-895, 1978.
2. Livio M, Bertoni MP, deGaetano G, Donati MB. Effect of
bromelain on fibrinogen level, prothrombin complex fac-
tors and platelet aggregation in the rat. Drugs. Exptl.
Clin. Res. 4 (11, 49-53, 1978.
3. McDonald JW, Stuart RK. Interaction of prostaglandins El
and E on regulation of c-AMP and aggregation in human
plate ?ets: evidence for a common prostaglandin receptor.
J. Lab. Clin. Med. 84: 111-112, 1974.
4. Miller JM, Opher AW. The increased proteolytic activity of
human blood serum after oral administration of bromelain.
Exptl. Med. Surg. 22 (4), 277-280, 1964.
5. Miyatani K, Takehata J, Fukui I. Effect of bromelain on
fibrinolytic and antifibrinolytic enzyme systems. Rinsho
Byori (Jap.) 23 (31, 201-204, 1975.
6. Morita AH, Uchida DA, Taussig SJ, Chou SC, Hokama Y. Chroma-
tographic fractionation and characterization of the active
platelet aggregation inhibitory factor from bromelain.
Arch. Int. Pharmacodyn. Ther. (in print), 1979.
7. Morita AH, Hokama Y. Personal communication, 1978.
8. Pirotta F, DeGiuli-Morghen. Bromelain - A deeper pharmaco-
logical study. I. Anti-inflammatory and serum fibrinolytic
activity after oral administration of bromelain in the rat.
Drugs. Exptl. Clin. Res. 4 (11, l-20, 1978.
9. Seifert J, Ganser R, Brendel W. , Absorption of a proteolytic
enzyme of plant origin from the gastrointestinal tract into
the blood and lymph of adult rats. Z. Gastroenterol. 17(l)
1-18, 1979.
10. Vane JR. Personal communication, 1974.

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