ChefX

Ok you asked!!!
(this is from Dr. Sears materials... I was going to edit the parts where he lied about history but thought it would be fine this way. As many of you know my base in medicine comes from this research which, my specialty being dietary manipulation of these microhormones. cheers)


Eicosanoids
Strange, mysterious, and almost mystical, eicosanoids are the key to our health because they control the flow of information in our Biological Internet. Why are eicosanoids so important? They were the first hormones developed by living organisms more than 550 million years ago. As such they can be considered "super-hormones" because they control the hormonal actions of other hormones. Furthermore, you don't have an eicosanoid gland since every one of your 60 trillion cells can make eicosanoids.

Even though they are earliest hormones (dating from 550 million years ago), eicosanoids only were identified in the 20th century starting with the discovery of essential fatty acids in 1929. It was found that if fat in the diet was totally removed, rats would soon die. Adding back certain essential fats (then called Vitamin F) was found to enable fat-deprived rats to live. Eventually as technologies advanced, researchers realized that essential fats were composed of both Omega-6 and Omega-3 fatty acids that both needed to be obtained in the diet because the body could not synthesize them. The word eicosanoids is derived from the Greek word for 20 which is eicosa, since all of these hormones are synthesized from essential fatty acids that are 20 carbon atoms in length.

The first actual eicosanoids were discovered in 1935 by Ulf von Euler. These first eicosanoids were isolated from the prostate gland (an exceptionally rich source of eicosanoids), and were called prostaglandins (a small subset of the much larger family of eicosanoids). Since it was thought at that time that all hormones had to originate from a discrete gland, it made perfect sense to name this new hormone a prostaglandin. With time it became clear that every living cell in the body could make eicosanoids, and that there was no discrete organ or gland that was the center of eicosanoid synthesis.

To date biochemists have identified more than 100 eicosanoids and are finding more each year. The breakthrough in eicosanoids research occurred in 1971 when John Vane finally discovered how aspirin (the wonder drug of the 20th century) actually worked: It changed the levels of eicosanoids. The 1982 Nobel Prize in Medicine was awarded to Vane and his colleagues Bengt Samuelsson and Sune Bergelson for their discovery of how eicosanoids play a role in human disease.

This is where the journey with eicosanoids first started twenty years ago. It was apparent that if certain "bad" eicosanoids were associated with chronic disease conditions (like heart disease, cancer, arthritis, and so on), then the key to wellness would be to induce the body to make more "good" eicosanoids and fewer "bad" eicosanoids. Rather than using drugs to achieve that goal, It was reasoned they could use food as if it were a drug. All we needed to do was figure out the right balance of protein, carbohydrate, and fat that would turn food into this beneficial drug. After more than 20 years, we got the zone based diets (isocaloric, zone, diatia ect ect)

Of course, our colleagues in academic medicine didn't quite share the initial enthusiasm. Almost overnight, we went from being a respected research scientists with numerous patents in the area of intravenous drug delivery systems for cancer drugs, to being called a snake-oil salesmen because of our constant refrain that the appropriate diet could change the balance of eicosanoids throughout the body. Part of the problem was that very few of them even knew what an eicosanoid was.
I believe that the foundation of 21st century medicine will be the manipulation of eicosanoids. Yet ask most physicians and medical researchers what an eicosanoid is, and you will usually get a blank stare. I guess they're not familiar with the Nobel Prize winning research. As unknown as they are to the medical community, eicosanoids are the hormones that maintain the information fidelity of your Biological Internet, which means they become the key to health and longevity.

Why are eicosanoids so unknown if they are so important? First, they are made, act, and self-destruct within seconds making them very difficult to study. Second, they don't circulate in the blood stream making it extremely difficult to sample them. Finally, they work at vanishingly low concentrations making it almost impossible to detect them. Despite these barriers, more than 87,000 articles on eicosanoids have been published in peer-reviewed journals. So, the basic research community is interested in eicosanoids even if your doctor never learned about them in medical school.

Eicosanoids encompass a wide array of hormones, many of which endocrinologists have never heard of. They are derived from a unique group of polyunsaturated essential fatty acids containing 20 carbon atoms. The different classes of eicosanoids are shown below

Subgroups of Eicosanoids

Prostaglandins
Thromboxanes
Leukotrienes
Lipoxins
Hydroxylated fatty acids
Aspirin-triggered Epi-lipoxins
Isoprostanoids
Epoxyeicosatrienoic acids
Endocannabinoids

Now if you mention the word prostaglandins to physicians, they are likely to have heard of those particular hormones. However, prostaglandins are only a small subgroup of the eicosanoid family. Some of the other subgroups have been discovered only recently. As an example, aspirin-triggered epi-lipoxins are the ones that give rise to the powerful anti-inflammatory properties described in the chapter on heart disease were discovered only a few years ago.

The glory days of eicosanoid research lie ahead with new eicosanoids continually being discovered and a growing realization of the vast role these hormones play in controlling other hormonal systems. This fact has not been lost upon pharmaceutical companies, which have already spent billions of dollars trying to develop eicosanoid-based drugs. Eicosanoids as drugs, however, have a very limited role in the world of pharmaceuticals. They are not only too difficult to work with, but they are also too powerful to be used as a drug. (but food as a drug that controls them isn't)

There does remains one way to directly manipulate eicosanoids: your diet. The reason why your diet can be successful where the largest drug companies have been unsuccessful is based on evolution. Eicosanoids were the first hormonal control system that living organisms developed. You can't have organized life unless you have cell membranes separating the internal workings of the cell from its environment. Since all cell membranes contain fatty acids (including the building blocks of eicosanoids, which are known as essential fatty acids), the cell's own membrane became the ideal reservoir for eicosanoid synthesis since you could always be certain that the raw materials for making these hormones were close by.

As autocrine hormones, eicosanoids' mission is to be secreted by the cell to test the external environment and then report back to the cell what was just outside by interacting with its receptor on the cell surface. Based on that information, the cell could then make the appropriate biological action (via the appropriate second messenger) to respond to any change in its environment.

In biotechnology, one of the hot research areas today is the field of biological response modifiers. Eicosanoids represent the first (and probably the most powerful) biological response modifiers developed by living organisms. In fact, many of the eicosanoids that we make in our bodies today are identical to ones made by sponges beginning hundreds of millions of years ago.

The reason why eicosanoids play such a central role in our physiology is due to the second messengers that certain eicosanoids generate. There are a variety of eicosanoid receptors on the surface of the cell, and depending on which eicosanoid interacts with the receptor, a specific second messenger is then synthesized by the cell. Sometimes a second messenger, such as cyclic AMP is generated, and sometimes a totally different second messenger, such as the DAG and IP3 system, is generated. If one second messenger goes up, then the other goes down. In essence, the complexity of your Biological Internet is reduced to a digital system consisting of green and red lights.

Those eicosanoids that generate increased production of cyclic AMP are your key to maintaining wellness. Why? Cyclic AMP is the same second messenger used by a number of endocrine hormones in the body to translate their biological information to the appropriate target cell. By maintaining adequate cellular levels of those eicosanoids that increase cyclic AMP levels, you are guaranteed that a certain baseline level of cyclic AMP is always present in a cell. Thus, it's far more likely that the overall cyclic AMP level in the cell will be high enough to ensure that an appropriate biological response (i.e. better hormonal communications) is generated.

How can you tell a "good" eicosanoid from a "bad" eicosanoid?

An eicosanoid's effect on second messengers becomes the definition of a "good" or "bad" eicosanoid. A "good" eicosanoid will increase the levels of cyclic AMP in a cell, whereas a "bad" eicosanoid will decrease the levels of cyclic AMP through the elevation of the levels of the IP3/DAG second messengers. The table below shows a listing of the types of "good" and "bad" eicosanoids and their receptors they interact with.

Receptors for "Good" and "Bad" Eicosanoids

Receptor Effect on cyclic AMP
"Good" Eicosanoids
PGE1 EP2, EP4 increase
PGI2 IP increase
PGD2 DP increase

"Bad" Eicosanoids
TXA2 TP decrease
PGE2 EP1, EP3 decrease
PGF2a FP decrease
LTB4 BLT decrease
LTC4, Cys-LTI decrease
LTD4, LTE4 Cys-LT2 decrease
Once an eicosanoid interacts with its unique receptor, a second messenger is then synthesized inside in the target cell. If a "good" eicosanoid interacts with the right receptor, then cyclic AMP is the second messenger that is formed. On the other hand, if a "bad" eicosanoid interacts with its receptor then cyclic AMP levels are decreased. Adding further to this complexity is that some eicosanoids such as PGA and PGJ are cyclopentenone eicosanoids. These eicosanoids don't have cell receptors on the surface as they can directly enter into the cell where they can interact with the cell's nucleus to effect cellular growth and differentiation. Since there is no discrete eicosanoid "gland", there is no central site that turns "on" or "off" eicosanoid action. Nature solved this problem by developing different types of eicosanoids that have diametrically opposed physiological actions. It is the balance of these opposing actions of different eicosanoids to remain an equilibrium of biological activity. These differences in biological actions are the foundation for the eicosanoid "axis".
This eicosanoid "axis" is composed of "good" eicosanoids on one side and "bad" eicosanoids on the other. In the absence of the evolutionary development of more advanced hormonal systems (like corticosteroids) to control this eicosanoid activity, this balance of "good" and "bad" eicosanoids was the best solution that could be done at the time. Obviously, there is no such thing as an absolutely "good" eicosanoid nor an absolutely "bad" eicosanoid, anymore than there is a moral attachment to "good" and "bad" cholesterol.

Most chronic diseases are a consequence of an imbalance of "good" and "bad" eicosanoids. I have already discussed in this book the role of eicosanoids in heart disease, cancer, diabetes, arthritis, and depression among others. The 1982 Nobel Prize in Medicine provided me an insight into the molecular nature of chronic disease since it could be seen as an imbalance in eicosanoid levels. It became apparent to me at the same time that the appropriate balance of eicosanoids could be used to provide a molecular definition of wellness. In essence, the more the balance of eicosanoids is tilted toward "bad" eicosanoids, the more likely you are to develop chronic disease. Conversely, the more the balance is tilted toward "good" eicosanoids, the greater the chance that you'll achieve wellness and longevity. The AA/EPA ratio will indicate where you stand in terms of such a balance.

If you are skeptical about the statement that eicosanoids play such a fundamental role in a such number of diverse disease conditions, then ask any physician what happens when they give a high dose of corticosteroids to a patient for more than 30 days. The answer will be physiological devastation, if not death. This occurs because corticosteroids have only one mode of action, they knock out all eicosanoid production -- "good" and "bad" by inhibiting the release of essential fatty acids from cell membrane. This chokes off all supply of precursors to make any type of eicosanoid. Without eicosanoids, you can't survive.

How Eicosanoids are Synthesized
Since eicosanoids are produced in every cell-not one specific gland-- it's as you have 60 trillion separate eicosanoid glands capable of making these exceptionally powerful hormones. Unlike the endocrine hormones, which are under control of the hypothalamus, there is no such central control on eicosanoids. Rather than responding to some master signal, each cell responds to changes in its immediate environment. The first step in generating a cellular response is the actual release of an essential fatty acid from the phospholipids in the cell membrane. The enzyme responsible for the release of the essential fatty acid is called phospholipase A2.

Since there is no feedback loop to stop the production of eicosanoids, the only way to inhibit their release from the membrane is by the production of corticosteroids (such as cortisol) from the adrenal gland, which causes the synthesis of a protein (lipocortin) that inhibits the action of phospholipase A2. By inhibiting this enzyme, which releases essential fatty acids from the cell membranes, you choke off the supply of a substrate required for all eicosanoid synthesis. Obviously, if you are overproducing corticosteroids (or taking corticosteroid drugs), you will bring all eicosanoid synthesis to a crashing halt, which can cause the shut down of your immune system.

The most powerful eicosanoid modulating drugs are corticosteroids. As I mentioned above, they inhibit the release any essential fatty acid so that no eicosanoids can be synthesized. Obviously, if you have intense pain or inflammation, this may be your only course of action on a short-term basis. Over the long term, corticosteroid therapy lowers the response of your immune system, decreases cognitive function, increases fat stores, thins the skin, and accelerates osteoporosis. In fact, if you give a single injection of corticosteroids to healthy individuals, their lymphocytes will be very similar to those in AIDS patients within 24 hours.

Enzymes that Make Eicosanoids
There are three primary pathways an essential fatty acid (composed of a string of 20 carbon atoms), once released from the cell membrane, can follow. The first is via the cyclo-oxygenase system (i.e. COX) that make prostaglandins and thromboxanes. In this pathway the highly contorted essential fatty acid is closed upon itself to form a prostanoid ring. The second is through the 5-lipo-oxygenase (5-LIPO) pathway that makes leukotrienes. There is a third pathway in which the 20-carbon essential fatty acid is simply modified via either the 12 or 15-lipoxygenase (12 or 15-LIPO) enzymes as in the case of hydroxylated essential fatty acids. It is via this third pathway that many of the newly discovered eicosanoids are made. These pathways are shown below.


Types of Eicosanoid Synthesizing Enzymes

Long-chain Essential Fatty Acids

COX 5-LOX 12 and 15 LOX

Prostaglandins Leukotrienes Lipoxins and
and Thromboxanes Hydroxylated Fatty Acids


Certain drugs can inhibit the cyclo-oxygenase pathway of this eicosanoid formation. The most well known is aspirin which literally destroys a cyclo-oxygenase enzyme on a one-on-one basis. This is what is known as a suicide inhibitor. When you are suffering from a headache or arthritic pain, you are overproducing "bad" eicosanoids, but in particular "bad" prostaglandins. The aspirin temporally shuts down all prostaglandin formation (but not leukotriene formation), until the cell can make more of the cyclo-oxygenase enzyme to replace the ones destroyed by the aspirin. However, you can't be using these suicidal soldiers forever, as aspirin also shuts down the synthesis of "good" prostaglandins, especially those that protect the stomach from dissolving itself. When that happens, you get internal bleeding. This is why there are more than 10,000 deaths per year associated with the over-use of aspirin. Other drugs known as non-steroidal anti-inflammatory drugs (NSAID's) also inhibit the cyclo-oxygenase enzyme but not the lipo-oxygenase enzyme that makes leukotrienes. The common names for these NSAID's are Motrin, Advil, Aleve, and others. Continued use of these NSAID's generates the same problems as does long-term aspirin use.

COX Enzymes
The most common types of anti-inflammatory drugs are those that can only affect those eicosanoids that are synthesized via the cyclo-oxygenase enzyme or COX. It was recently discovered there are two forms of this enzyme known as COX-1 and COX-2. COX-1 enzymes are a constant fixture of the vascular cells that line the bloodstream or in stomach cells that secrete bicarbonate to neutralize stomach acid. COX-2 appears to be an enzyme that is synthesized only in response to inflammation. Standard drugs like aspirin and NSAID's (like Advil) don't discriminate between these specific forms of the COX enzyme, which is why they have side-effects associated with their long-term use.

For example, it appears that the anti-cancer benefits of aspirin may stem from its inhibition of COX-2, whereas the side-effects (like an increased risk of internal bleeding) come from its simultaneous inhibition of COX-1. However, this same inhibition of the COX-1 enzyme appears to convey the cardiovascular benefits associated with aspirin. This may explain why long-term use of COX-2 inhibitors may not work to decrease heart attack rates: They don't target the COX-1 enzyme. Weighing the risks against the benefits presents a dilemma associated with all drugs that affect eicosanoid synthesis.

LOX Enzymes
Unlike inhibitors of the COX enzymes, there are very few inhibitors of the LOX enzymes. Since leukotrienes (particular LTB4) represent a primary mediator of pain, then the only way to affect their production is to use corticosteroids with all of their associated side effects. However, the leukotrienes synthesized from EPA are physiologically neuter compared to those derived from arachidonic acid. This is why the AA/EPA ratio is a very good indicator of the body's potential to prevent the over-production of leukotrienes without using resorting to the use of corticosteroids.
Drug companies are racing to develop new patentable drugs--ones that affect the downstream enzymes that control eicosanoid production from arachidonic acid. Overlooked in this frenzy by the drug companies seeking new and more expensive drugs to go downstream to modify eicosanoid synthesis, is that there is an existing "drug" that can achieve all of these benefits without any side effects. This is because it goes upstream to modify eicosanoid production by reducing arachidonic acid levels. That "drug" is high-dose fish oil since the elevated levels of EPA will reduce the production of "bad" eicosanoids (such as PGE2 and LTB4) derived from arachidonic acid.

Synthesis of Essential Fatty Acids
To understand the importance of diet in controlling these eicosanoids and re-establishing an appropriate eicosanoid balance, we have to understand how the actual precursors of eicosanoids are made. To begin with, all eicosanoids ultimately are produced from essential fatty acids that the body cannot make, and therefore must be part of the diet. These essential fatty acids are classified as either Omega-3 or Omega-6 depending upon the position of the double bonds within them. However, typical essential fatty acids are only 18 carbons in length and must be further elongated to 20-carbon fatty acids by the body before eicosanoids can be made. Remember, all eicosanoids come from essential fatty acids that are 20 carbon atoms in length. It is just not the number of carbon atoms that count, but also their configuration. Eicosanoid precursors must have a certain spatial configuration with at least three conjugated double bonds in order to be converted into an eicosanoid. How your diet controls the formation of dietary essential fatty acids into the actual 20-carbon atom precursors of eicosanoids is a complex story.

The discovery of essential fatty acids was first reported in 1929. At that time essential fatty acids were called Vitamin F. But Vitamin F was useless unless transformed into an eicosanoid. Thus began a continuing 70-year journey to understand how your diet does three things: controls eicosanoid formation; alters eicosanoid balance in the body; and determines how eicosanoids become a central players in your health.
The differences between the two classes of essential fatty acids, Omega-6 and Omega-3, are based on the position of the double bonds within the fatty acid molecule. This is important since it is the positioning of these double bonds that dictates their three-dimensional structure in space that ultimately determines how they interact with their appropriate receptors. Although the synthesis of essential fatty acids use the same enzymes, their metabolic pathways are quite different. The metabolism of long-chain Omega-3 fatty acids are more complex, so let's start with the simpler pathway to make Omega-6 fatty acids.

Omega-6 Fatty Acids
There are two key steps in this process that determine the amount of eicosanoid building blocks that will be made. These are known in biochemistry as "rate-limiting steps". The first rate-limiting step is controlled by the enzyme delta-6-desaturase. This enzyme inserts a necessary third double bond in the essential fatty acid in just the right position to begin bending inward and forms gamma linolenic acid (GLA) from linoleic acid as shown in the figure below.


Synthesis of Omega-6 essential fatty acids into eicosanoid precursors
Linoleic Acid (C18:2)

Delta-6 desaturase

Gamma Linolenic Acid (GLA) (C18:3)

Elongase

Dihomo Gamma Linolenic Acid (DGLA) (C20:3)
Delta 5-desaturase

Arachidonic Acid (AA) (C20:4)

"Good" Eicosanoids "Bad" Eicosanoids

(The number after the C tells how many carbon atoms the essential fatty acid contains, and the number after the colon tells how many double bonds there are in the essential fatty acid)

I define an activated essential fatty acid as any essential fatty acid that has this new double bond inserted by the delta-6-desaturase enzyme. This is because this new double bond starts bending the essential fatty acid to get the appropriate spatial configuration required to make an eicosanoid. Once this new double bond has been inserted into a short-chain essential fatty acid, then very small amounts of these activated essential fatty acids can profoundly affect eicosanoid balance in your body.
However, there are many factors that can decrease the activity of delta-6-desaturase enzyme. The most important factor is age itself. There are two times in your life during which this enzyme is relatively inactive. The first is at birth. For the first six months of life, the activity of this key enzyme in the newborn is relatively low. But this is also the time at which maximum amounts of long-chain essential fatty acids are required by the child since the brain is growing at the fastest possible rate, and these long-chain essential fatty acids are the key structural building blocks for the brain. Nature has developed a unique solution to this problem: mother's breast milk. Breast milk is very rich in GLA and other long-chain essential fatty acids such as the EPA and DHA. By supplying these activated essential fatty acids through the diet, this early inactivity of the delta-6-desaturase enzyme is overcome.