Tripping Lightly Down the Prostaglandin Pathways
Sally Fallon, M.A. and Mary G. Enig, Ph.D.
The mysterious and complex family of prostaglandins
constitutes one of the most intriguing discoveries
in the history of modern medicine. Discovered
in 1936 by von Euler, prostaglandins derive
their name from the fact that they were first
detected in human seminal fluid. It was not
until the advent of more sophisticated instruments
40 years later that these compounds could
be studied in depth. Researchers discovered
that the original substance is just one of
a family of compounds found in every cell
of the body; in fact, prostaglandins are
found throughout the animal kingdom, even
in species as lowly as insects, shellfish
and corals.
Prostaglandins are a subset of a larger family
of substances called eicosanoids. Other subgroups
include thromboxanes, leukotrienes and lipoxins.
Eicosanoids are localized tissue hormones
that seem to be the fundamental regulating
molecules in most forms of life. They do
not travel in the blood like hormones, but
are created in the cells to serve as catalysts
for a large number of processes including
the movement of calcium and other substances
into and out of cells, dilation and contraction,
inhibition and promotion of clotting, regulation
of secretions including digestive juices
and hormones, and control of fertility, cell
division and growth. The list of biological
functions involving prostaglandins is limited
only by our ignorance of their effects. As
research continues, so will our knowledge
of these fascinating substances expand and
grow.
Prostaglandins are produced in the cells
by the action of enzymes on essential fatty
acids. There are two prostaglandin pathways,
one that begins with double-unsaturated omega-6
linoleic acid and one that begins with triple-unsaturated
omega-3 alpha-linolenic acid. Both pathways
essentially involve elongation of the 18-carbon
EFA's to the 20-carbon root used in each
of the three eicosanoid types, plus further
desaturation. (See accompanying diagram.)
On the omega-6 pathway, the Series 1 prostaglandins
are produced from a 20-carbon, triple unsaturated
fatty acid called dihomo-y-linolenic acid
(DGLA) that is found in liver and other organ
meats. The Series 2 prostaglandins are produced
from a 20-carbon quadruple unsaturated fatty
acid called arachidonic acid (AA) found in
butter, animal fats, especially pork, organ
meats, eggs and seaweed. On the omega-3 pathway,
the Series 3 prostaglandins are procuded
from a 20-carbon quintuple unsaturated fatty
acid called eicosapentaenoic acid (EPA) found
plentifully in fish liver oils and fish eggs.
Early research focused on the interplay between
the Series 1 and Series 2 prostaglandins.
In the most simple terms, the Series 2 prostaglandins
seem to be involved in swelling, inflammation,
clotting and dilation, while those of the
Series 1 group have the opposite effect.
This has led some writers, notably Barry
Sears in his popular book The Zone, to call
the Series 2 family the "bad" eicosanoids
and to warn readers against eating liver
and butter, sources of arachidonic acid,
the Series 2 precursor. Sears also asserts
that perfect balance of the various prostaglandin
series can be achieved by following a diet
in which protein, carbohydrate and fat are
maintained in certain strict proportions.
This is a highly simplistic view of the complex
interactions on the prostaglandin pathway,
one which does not take into account individual
requirements for macro and micro nutrients,
nor of imbalances that may be caused by nutritional
deficiencies, environmental stress or genetic
defects. Like all systems in the body, the
many eicosanoids work together in an array
of loops and feedback mechanisms of infinite
complexity. Furthermore, liver and eggs are
both highly nutritious foods. Liver supplies
DGLA, a precursor of the Series 1 prostaglandins,
and both liver and eggs supply DHA, an important
nutrient for the brain and nervous system.
Arachadonic acid found in butter and eggs
is also an important constituent of cell
membranes.
The Series 2 prostaglandins do indeed play
a role in swelling and inflammation at sites
of injury. This is not at all a "bad"
effect, but an important protective mechanism--the
body's way of immobilizing the affected site
to prevent further injury and facilitate
healing. Series 2 prostaglandins also seem
to play a role in inducing birth, in regulating
temperature, in lowering blood pressure,
and in the regulation of platelet aggregation
and clotting.
Later investigators have focused on the balance
between Series 2 and Series 3 prostaglandins.
The Series 2 group is involved in intense
actions, often in response to some emergency
such as injury or stress; the Series 3 group
has a modulating effect. Series 2 eicosanoids
might be likened to the "fast lane"
in that they are often associated "with
an explosive, but transient burst of synthesis.
. . if the rate of synthesis is too slow,
there will be insufficient active eicosanoids
to occupy receptors. If the rate is synthesis
is too fast, excess active eicosanoids can
cause pathophysiology." (1) The Series
3 prostaglandins are formed at a slower rate
and work to attenuate excessive Series 2
production. Their response is "less
vigorous." The omega-3 pathway might
therefore be likened to the "slow lane."
Adequate production of the Series 3 prostaglandins
seems to protect against heart attack and
stroke as well as certain inflammatory diseases
like arthritis, lupus and asthma.
Research into prostaglandins holds enormous
promise for the treatment of disease with
various drugs that selectively inhibit or
stimulate the production of specific prostaglandins.
Such drugs might be likened to police officers
used to direct traffic or called on to help
at the scene of an accident. For most of
us, however, the best way to ensure adequate
prostaglandin production along with proper
balance between the various series and their
subsets is to follow a diet that provides
precursors to eicosanoid production, and
keeps the pathways free from blocks and potholes,
a diet that provides fuel for our prostaglandin
cars and keeps the highways clear.
One of the most common blocks in the prostaglandin
chain involves delta-6 desaturase (D6D),
the first sept in the production of prostaglandins
from essential fatty acids. When action of
this enzyme is blocked, so is the entire
pathway. This vital enzyme is inhibited first
and foremost by trans fatty acids found in
margarine, shortening and hydrogenated fats.2
These should be avoided at all costs. In
addition, excess omega-6 fatty acids from
modern commercial vegetable oils inhibits
the pathway that leads to the Series 3 group.
This is because both pathways begin with
desaturation by the same delta-6 desaturase
enzymes. Too much omega-6 in the diet "uses
up" the delta-6 desaturase enzymes needed
for the omega-3 pathway.(3)
The modern diet contains large amounts of
omega-6 fatty acids compared to that of a
generation ago, because high omega-6 oils
from soy, corn, cottonseed and safflower
have been introduced into the food supply.
They are used to make hydrogenated fats and
as a replacement for traditional fats and
oils such as olive oil, butter, coconut oil,
goose fat and lard. The modern diet is also
deficient in omega-3 fatty acids compared
to that of a generation ago because modern
farming methods have the effect of increasing
the amounts of omega-6 and oleic acid in
vegetables, fruits, fish, eggs, grains and
legumes, while decreasing the amount of valuable
triple unsaturated omega-3. A good way to
put omega-3 fatty acids back into the diet
is to add a small amount of flax oil, rich
in linolenic acid, to salad dressing.
Deficiencies of biotin, vitamin E, protein,
zinc, B12 and B6 all interfere with the action
of delta-6 desaturase and other enzymes involved
in prostaglandin production.(4) B12 is found
only in animal foods. B6 is also found chiefly
in animal foods. It is highly sensitive to
heat. Best sources are raw dairy products,
raw fish and raw meat. Zinc absorption is
inhibited by phytic acid in whole grains
and legumes, particularly soy, that have
not been properly prepared. Best sources
of zinc are animal foods--red meat, organ
meats and some sea foods such as oysters.
Alcohol consumption interferes with D6D,
as does malnutrition and overeating--so moderation
is the key to tripping lightly down the prostaglandin
pathway. There is some evidence that an excess
of oleic acid (found chiefly in olive oil
and nuts) may inhibit prostaglandin production.(5)
Even consumption of essential fatty acids
should be restricted to about 4% of the diet.
Excess of EFA's, especially omega-6 EFA's,
can cause problems with both pathways. Excess
consumption of sugar also interferes with
the desaturating enzymes.
Diabetes, poor pituitary function and low
thyroid function are synonymous with altered
and inhibited D6D function.(6) These ailments
are often treated with evening primrose,
borage or black current oils, which contain
GLA, the Series 1 precursor. Dietary GLA
can be used when production is blocked by
defective D6D action. Fish oils provide EPA
and DHA, the production of which is also
blocked by poor D6D function. Supplements
of evening primrose, borage or black current
oils, and of fish liver oils are a good idea
for everyone.
Diseases caused by altered D6D function include
diabetes, alcoholism, cancer, premature aging,
high cholesterol, Crohn's disease, cirrhosis
of the liver, eczema, PMS, noncancerous breast
disease, Sjogren's syndrome, scleroderma,
ulcerative colitis and irritable bowel syndrome.
In cancerous cells, all D6D activity is lost.
GLA (from evening primrose, borage or black
current oils) inhibits the growth of cancer
cells but not of normal cells. The effectiveness
of GLA compared to most drugs in treating
not only cancer, but all of the diseases
caused by inhibited D6D function, may explain
the Food and Drug Administration's efforts
to suppress the sale of evening primrose
oil and similar products.
Some popular writers claim that saturated
fats in the diet inhibit the production of
prostaglandins. Actually the reverse is true.
Saturated fats in the diet improve the body's
utilization of essential fatty acids,(7)
and protect them from becoming rancid. Remember
that the kind of fat the body itself makes
is saturated fat, which it needs for energy
and a variety of other purposes.
Lauric acid, a 12-carbon saturated fatty
acid found chiefly in mother's milk and coconut
oil, and in smaller amounts in butter, seems
to improve the function of the omega-6 pathway.(8)
When lauric acid is present in the diet,
the long chain omega-6 fatty acids accumulate
in the tissues where they belong, even when
consumption of essential fatty acids is low.
Unfortunately, highly useful and beneficial
coconut oil has been forced out of the food
supply by adverse propaganda originating
with the fabricated food industry, which
would rather use cheap hydrogenated oils
rather than more expensive coconut oil for
shortening.
The actions of delta-5 and delta-4 desaturase
enzymes further along the pathway are less
well understood, because they have not been
as well studied. Nevertheless, it is known
that diabetes, protein deficiency and alcohol
all inhibit the action of D5D. Butter, eggs
and organ meats provide arachadonic acid,
the substrate for the Series 2 prostaglandins,
and would be extremely important to include
in the diet of diabetics and others whose
D5D function may be compromised.
The desaturase enzyme systems do not work
well in infants. This is why mammalian milk
is rich in long chain fatty acids of both
pathways--AA, EPA and DHA. DHA, the end product
of the omega-3 pathway, is essential for
the development and function of the brain.
Egg yolk will be rich in DHA if the chickens
are fed foods rich in omega-3 linolenic acid--flax
meal, fish meal or insects. DHA-rich egg
yolk fed to infants, beginning at about four
months, is an easy way to ensure proper development
of the brain, early speech, good coordination
and freedom from learning disabilities. (The
Japanese put a very high value on eggs as
a brain food.) The desaturase enzyme systems
also become less efficient in old age. Researchers
at the University of California at Berkeley
compared two groups of men in their eighties--those
suffering from senility and those with all
their mental faculties in tact. Their diets
were similar with the exception of one item--the
men with all their mental faculties intact
ate at least one egg per day!(9) Vegans are
deficient in the omega-3 fatty acids, particularly
DHA.(10)
Carnivorous animals lack both D6D and D5D
enzymes, and must obtain the longer chain
fatty acids from their food supply. This
is why carnivorous animals prefer organ meats
to muscle meats, as these supply DGLA, AA
and DHA. Some population groups that have
been largely carnivorous for generations,
such as the Eskimo and Irish seacoast peoples,
also lack these enzymes. Fish liver oils
and organ meats are a must for people with
this kind of ancestry, otherwise their prostaglandin
pathways are largely dysfunctional. Is this
why certain groups so quickly degenerate
into alcoholism and other chronic diseases
when they no longer have access to sea foods
and organ meats found traditionally in their
diets?
In the 1930's, nutrition pioneer Weston A.
Price studied primitive diets throughout
the globe. He found that organ meats, butter,
fish liver oils and fish eggs were highly
valued items in every diet he studied.(11)
(Insects, high in superunsaturated fatty
acids, are also highly valued among peoples
who have little access to other animal foods.)
He noted that all these foods were exceptionally
rich in vitamins A and D. What he did not
know was that these foods also supply long
chain fatty acids the body needs to overcome
any stumbling blocks that may lie on the
prostaglandin pathways. Dr. Price was often
called to the bedsides of dying individuals,
when last rites were being administered.
He brought with him two things--a bottle
of cod liver oil and a bottle of high vitamin
butter oil from cows eating growing grass.
He put drops of both under the tongue of
the patient--and more often that not the
patient revived. He was puzzled by the fact
that cod liver oil alone and butter oil alone
seldom revived the dying patient--but the
two together worked like magic.(12) Research
into prostaglandins may supply the answer.
High vitamin butter may be rich in AA and
possibly other factors needed for the omega-6
pathway; and cod liver oil is rich in EPA
needed for the omega-3 pathway. In addition,
the saturated fatty acids in butter help
the unsaturated fatty acids in cod liver
oil to work more efficiently.
Many delicious traditional dishes provide
the synergystic combination of LNA, EPA and
DHA of the omega-3 family with AA of the
omega-6 family and short and medium chain
fatty acids--lox and cream cheese, caviar
and sour cream, liver and bacon, salmon and
Bernaise sause, dark green vegetables with
butter, cream cheese and flax oil. In India,
milk products provide AA and shorter chain
fatty acids while insects provide the longer
chain fatty acids of the omega-3 chain. Fish,
pork and coconut oil provide all the necessary
fatty acids in the Polynesian diet; American
Indians valued fish, bear fat and oil of
the eveining primrose plant. Traditional
combinations of rich foods, therefore, need
not be avoided. They provide factors that
open both lanes of the prostaglandin pathway,
creating a wide and open highway to skip
along for renewed vitality and vibrant health.
Tips for Tripping Lightly Down the Prostaglandin
Pathways
- Avoid all hydrogenated fats
- Avoid high levels of processed omega-6 vegetable
oils, especially soy, corn, cottonseed and
safflower oils
- Use high quality butter
- Use small amounts of flax oil in salad dressings.
- Use coconut oil or whole coconut milk in
cooking
- Supplement with cod liver oil and evening
primrose, borage or black current oils
- Eat organ meats and fish eggs occasionally
- Eat good quality eggs frequently
- Eat raw meat or fish occasionally (Note:
Fish should be marinated in an acidic medium,
and meat should be frozen for at least 14
days before preparation, to avoid parasite
contamination.)
- Avoid high phytate foods that block zinc.
These include grains, legumes and nuts that
have not been properly prepared to reduce
phytate content.13 Modern soy foods have
potent zinc-blocking effects.
- Avoid refined sweeteners like sugar and high
fructose corn syrup
- Eat and drink in moderation--but don't deprive
yourself of delicious traditional foods.
Let's Get Technical ... About Prostaglandins
The omega-6 pathway begins with double-unsaturated
linoleic acid (LA) found mainly in seed oils.
It is desaturated by the action of a desaturating
enzyme, delta-6 desaturase (D6D), resulting
in an 18-carbon, triple-unsaturated fatty
acid called gamma-linolenic acid, GLA. (GLA
differs from the 18-carbon triple-unsaturated
alpha-linolenic acid in that the unsaturated
carbon double bonds are in different places
along the carbon chain.) An elongase enzyme
then adds two more carbon atoms to GLA, taking
us another step along the prostaglandin pathway
to form a 20-carbon triple-unsaturated fatty
acid called dihomo-gamma-linolenic acid (DGLA).
DGLA forms the root of the Series 1 prostaglandins
such as PGE1, PGF1a, and PGD1, and thromboxanes
such as TXA1
DGLA is then transformed into 20-carbon quadruple-unsaturated
arachidonic acid (AA), which is the root
or precursor of the Series 2 eicosanoids.
The Series 2 family includes a number of
prostaglandins such as pge2 pgf2a and pgd2
,prostacyclins such as pgI2, thromboxanes
such as TXA2, leukotrienes and lipoxins.
Series 3 prostaglandins are produced on another
pathway entirely, one that begins with triple
unsaturated alpha-linolenic acid, found in
seed oils of northern origin, like flax.
This essential fatty acid is desaturated
twice and elongated once to produce eicosapentaenoic
acid (EPA), a 20-carbon fatty acid with five
double bonds. EPA is the root substance of
the Series 3 family that includes the prostaglandins
such as PGE3, PGH3 and PGI3, thromboxanes
such as TXA3 and leukotrienes. EPA is then
further elongated and desaturated to produce
docosahexaeonic acid (DHA) a 22-carbon fatty
acid with six double bonds. DHA is found
plentifully in the brain and is in fact essential
for the development and function of the brain.
DHA also acts as a storage molecule. It can
be shortened and resaturated to produce EPA
and the Series 3 eicosanoids.
During the early years of prostaglandin study,
the eminent researcher David Horrobin described
the complex relationships between thromboxanes
and prostacyclins of Series 2 (TXA2 and PGI2)
with prostaglandins PGE1 of Series 1.14 For
example, TXA2 seems to be essential for the
release of calcium from the cells, while
PGI2 inhibits release of calcium. At low
concentrations PGE1 blocks the effects of
PGI2 and enhances those of TXA2; at higher
concentrations it imitates PGI2 and blocks
TXA2 . He notes that a variety of diseases
can be explained in terms of imbalance between
Series 1 and Series 2 prostaglandins. Over-synthesis
of Series 2 prostaglandins encourages thrombosis;
inhibition of overall prostaglandin syntheses
can elevate blood pressure, and paradoxically,
increase serum cholesterol. Kidney disease
as well as hyperthyroidism are associated
with inadequate amounts of PGE1. TXA2 synthesis
seems to be deficient in cases of ulcerative
colitis, leaving to an overproduction of
other prostaglandins. Massive overproduction
of certain prostaglandins seems to be involved
in rheumatoid arthritis. A failure of TXA2
production, with concurrent excess production
of other prostaglandins, leads to an increased
susceptibility to cell mutation and hence
to cancer. PGE1 deficiency seems to be involved
in psoriasis and schizophrenia. On the other
hand, manic behavior is associated with higher
PGE1 production rates than normal. Depression
is associated with elevation of TXA2 synthesis.
Various types of muscular dystrophy are associated
with accumulation of calcium in the cells,
due to reduced TXA2 production. Deficient
TXA2 formation may also be involved in multiple
sclerosis. Migraine headaches with accompanying
gastrointestinal disturbances can be explained
by increased prostaglandin production, particularly
PGE1.
The action of many drugs can be explained
by their ability to stimulate or interfere
with Series 1 and Series 2 prostaglandin
production. Aspirin and steroids inhibit
TXA2 activity and therefore reduce swelling;
Lithium inhibits PGE1 which seems to be elevated
in manic-depressive disorders. Melatonin,
amantadine and colchicine (used to treat
gout) activate TXA2 .
1. Lands, William E M, "Biochemistry
and physiology of n-3 fatty acids",
The FASEB Journal, Vol 6, May 1992, pp 2530-2536
2. Horrobin, David F, "The regulation
of prostaglandin biosynthesis by manipulation
of essential fatty acid metabolism",
Reviews in Pure and Applied Pharmacological
Sciences, Vol 4, pp 339-383, Freund Publishing
House, 1983
3. Ibid
4. Ibid
5. Horrobin, David F, Prostaglandins: Physiology,
Pharmacology and Clinical Significance The
Book Press, Brattleboro, Vermont, 1978, p
20, 35
6. Horrobin, "The regulation of prostaglandin
biosynthesis by manipulation of essential
fatty acid metabolism", op cit
7. Garg, M L et al, FASEB Journal 1988 2:4:A852
8. Horrobin, "The regulation of prostaglandin
biosynthesis by manipulation of essential
fatty acid metabolism", op cit
9. Personal communication, Marion Diamond,
Ph.D., University of California at Berkeley,
1994
10. Sanders, T B A, et al, "Studies
of vegans: the fatty acid composition of
plasma choline phosphoglycerides, erythrocytes,
adipose tissue and breast milk, and some
indicators of susceptibility to ischemic
heart disease in vegans and omnivore controls",
The American Journal of Clinical Nutrition,
Vol 31, May 1978, pp 805-813
11. Price, Weston A, DDS, Nutrition and Physical
Degeneration, 1945, Price-Pottenger Nutrition
Foundation, Inc., San Diego, CA (619) 574-7763
12. Personal communication, Pat Connolly,
Executive Director, Price-Pottenger Nutrition
Foundation
13. For proper grain and legume preparation
methods, see Sally Fallon, Nourishing Traditions:
The cookbook that Challenge Politically Correct
Nutrition and the Diet Dictocrats, (with
Pat Connolly and Mary G. Enig, Ph.D.), ProMotion
Publishing, 1996 Available from Price-Pottenger
Nutrition Foundation (619) 574-7763
14. Horrobin, Prostaglandins, op cit, p 273
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