Abstract

In the course of research into the biochemistry and physiology of the endpoints of essential fatty acid metabolism known as eicosanoids, the mechanism by which aspirin exerts its analgesic effect was revealed. It is now known that aspirin does not prevent the COX enzyme from converting arachidonic acid to pain-producing proinflammatory eicosanoids as had long been assumed, but rather it modifies the COX enzyme by acetylating it thereby making it convert arachidonic acid to antiinflammatory eicosanoids. During these same research activities, hitherto unknown classes of naturally occurring, anti-inflammatory, pro-healing eicosanoids known as lipoxins, resolvins, protectins, neuroprotectins, and maresins were discovered. Aspirin was found to multiply many times the healing power of these natural lipid mediators by creating aspirin-triggered counterparts to all.

Introduction

The Nobel Prize in Physiology and Medicine was awarded to Sune Bergstrom, Bengt Samuelsson, and Sir John Vane in 1982 for “their discoveries concerning prostaglandins and related biologically active substances” (1). The Nobel Laureates at that time explained that the analgesic effect of aspirin was due to its ability to prevent conversion of arachidonic acid, a 20-carbon, 4-double bond, omega-6 essential fatty acid, to inflammatory prostaglandins by cyclooxygenase, the enzyme that has now come to be known by the general public as the COX enzyme.

Because the biochemistry of the COX enzyme had not yet been fully elucidated in 1982, it was assumed that aspirin’s effect was due to inhibition of COX’s active site. Thus, the Nobel Prize Laureates’ findings stimulated a massive research program to create a new class of drugs that would inhibit the COX enzyme and offer competitors for the nonpatentable aspirin. These new COX inhibitors were labeled Non-Steroidal Anti-Inflammatory Drugs or NSAIDS for short. Now, several decades later many different NSAIDS have been produced. Some were rejected because they were ineffective or unsafe. Others were restricted to prescription use only, and a few turned out to be reasonably effective and safe for over-the-counter sale. Interestingly, to date, no NSAID has been shown to have a better safety record than aspirin or to be more effective for first aid treatment of cardiac events. Regular users of aspirin also have lower rates of chronic inflammatory diseases such as Alzheimer’s disease than do users of NSAIDS (2).

Aspirin is an Age-Old Remedy

The story of aspirin had beginnings with the methyl ester of salicylic acid, the principle ingredient of oil of wintergreen obtained from natural sources such as willow bark. Oil of wintergreen is a centuries-old liniment used for the aches and pains of rheumatism. However, because of its considerable toxicity, oil of wintergreen could not be taken internally. Throughout the decades, many derivatives of salicylic acid were synthesized in an effort to find a less toxic painkiller that would be acceptable for internal use. Some, including salicylic acid itself, were used internally and found to be very effective in relieving pain, but they were difficult to tolerate because of unpleasant side effects (2). In the mid-nineteenth century, the acetic acid derivative of salicylic acid was synthesized by a chemist at the German chemical company now known as Bayer. Bayer patented the process for making acetylsalicylic acid and the name they gave it (Aspirin) in 1899. In the 100+ years since aspirin was introduced to the public, it has become the most widely used medication in the world with a yearly production of 50,000 tons and consumption by Americans of about 80 million tablets per day (2). And the daily use of a “baby” aspirin was universally accepted several decades ago as a preventive remedy for cardiovascular diseases (2).

The Cyclooxygenase Enzyme

During NSAID development, it was discovered that the COX enzyme had two forms: COX-1 and COX-2, and that each form contained two active sites. Each form catalyzes the same two reactions. COX-1 and COX-2 are different in that they carry out two different functional roles (3). COX-1 is a constitutive form of the enzyme, namely a form that is always present in cells and tissues. It has been described as an enzyme that carries out routine housekeeping functions to maintain homeostasis. COX-2 is an inducible form, which means it is synthesized only when a need for it arises, such as trauma, increased levels of arachidonic acid, or inflammatory stimuli, such as cytokines (4). In normal good health when all is oing well internally, COX-2 cannot be found in tissues. COX-2 is called into action by a sudden injury or illness that requires immediate induction of pain and acute inflammation (4).

Important exceptions are that COX-2 is constitutive in brain and kidney (3) and in flowing blood (4). The motion of flowing blood induces synthesis of the COX-2 enzyme. Therefore, COX-2 is always present in arterial blood and can properly be considered constitutive in this medium.

Mechanism of Aspirin’s Effect

When acetylated by aspirin, both sites on COX-1 and one site COX-2 are blocked. The remaining site in COX-2 converts arachidonic acid to an intermediate metabolite called 15 HETE that is further metabolized to antiinflammatory, pro-healing eicosanoids termed aspirin-triggered lipoxins (4). It is important to note that the arachidonic acid that is converted to aspirin triggered lipoxins is no longer available as a substrate for inflammatory eicosanoids. This is an important difference between aspirin and NSAIDS in their interaction with the COX-2 enzyme.

NSAIDS do not eliminate arachidonic acid but merely prevent it from being metabolized by the COX enzymes to inflammatory, pain producing eicosanoids. This has positive, immediate pain-relieving effects; however, the unused arachidonic acid is diverted to the 5-lipoxygenase enzyme where it is converted to inflammatory leukotrienes that do damage elsewhere in the body. NSAIDs have the potential for adverse effects not seen with aspirin.

Arachidonic Acid

Arachidonic acid has become a center of interest in recent years because it has been found to be the major biochemical substrate for eicosanoids that are responsible for low-level, chronic inflammation. This chronic inflammation is widely accepted as the underlying cause of the growing numbers of non-infectious diseases that now plague this country (4). These diseases include cardiovascular diseases, asthma, cancer, arthritis, periodontal disease, and Alzheimer’s disease. Although arachidonic acid is an essential fatty acid found in reasonable amounts in meats, the current source of high systemic levels of arachidonic acid is dietary linoleic acid, an omega-6, 18-carbon essential fatty acid that is biochemically converted in the body to arachidonic acid. This arachidonic acid is biochemically transformed by COX-1, COX-2, and lipoxygenase-5 (LOX-5) to inflammatory eicosanoids. The source of this excess linoleic acid is the very high consumption of fats and oils derived from vegetable seeds (5).

A Constitutive COX-2 and the Human Heart

The fact that COX-2 is constitutive (always at hand) in flowing blood explains why a daily low-dose aspirin protects the heart. In the presence of aspirin COX-1 is completely blocked so that it can no longer convert arachidonic acid to thromboxane and other inflammatory eicosanoids that cause atherosclerosis. The site that remains active in the COX-2 enzyme produces protective antiinflammatory aspirin-trigged lipoxins instead of inflammatory eicosanoids (4). To quote Serhan:

This is important in vascular endothelial cells that are numerous in all blood vessels in vivo; under physiological flow conditions, COX-2 is constitutively expressed, which can release substantial amounts of 15 HETE when aspirin is given to healthy volunteers (4).

More Good News

As important as aspirin is in its fundamental role in modifying the COX enzymes, perhaps of even greater consequence for the health and well being of present and future generations are the more recent discoveries of the hitherto unsuspected role of aspirin in resolution (the healing process) and the unanticipated existence of whole new classes of aspirin-triggered anti-inflammatory eicosanoids that have been revealed as a result of the research into the biochemistry of aspirin and its mechanism of action (6).

Beginning in 2005, Charles Serhan and colleagues published a series of research reports that opened a door to a family of eicosanoids, termed lipid mediators that managed the healing processes (4). They stopped inflammation, swelling and pain, removed debris, initiated healing, and returned the affected area to homeostasis. Serhan and colleagues showed that this healing process was managed and carried out by pro-resolving biochemicals termed lipoxins, resolvins, protectins, neuroprotectins, and maresins that are naturally biosynthesized in the body. The body, given a healthful diet is fully capable of healing itself. Aspirin plays a major role in these healing processes by creating aspirin-triggered counterparts to all of hese pro-resolving, pro-healing natural lipid mediators. Aspirin is unique in that it significantly multiplies the power of the body’s natural healing processes (7; 8). Past studies have shown that regular use of aspirin reduces the risk of Alzheimer’s disease, heart disease, stroke, and gastric, colorectal, and breast cancers. A recently completed study found that Aspirin reduced the risk of melanoma, a deadly form of skin cancer., by up to 50%. In the same study, NSAIDs (Ibuprofen, etc) and acetaminophen (Tylenol) failed to reduce melanoma risk (9).

Editorial Commentary

The following is an editorial comment on the above melanoma study. It appeared in the same edition of the journal, Cancer, to warn readers of the dangers and ineffectiveness of aspirin. Aspirin is not recommended to prevent cancer. Despite this study and others like it, there are several reasons why aspirin is not the best defense against melanoma or other cancer, and may be harmful for some people.

Eric Jacobs, PhD, American Cancer Society strategic director of pharmacoepidemiology, said,

It is important to remember that aspirin is a real drug with real side effects, including sometimes causing serious, even occasionally fatal, stomach bleeding, even at low doses. Aspirin use is for heart disease prevention for most people who have had a heart attack, and has some benefits for cancer as well. However, at this point the American Cancer Society does not recommend that people use aspirin specifically to prevent cancer. People who are wondering if they should be using aspirin should talk to their health care provider who knows their personal medical history and can help weigh their individual risks and benefits.

According to Jacobs, the overall evidence that aspirin helps lower risk of melanoma is mixed. Jacobs said,

While some previous studies have suggested that aspirin might be linked to lower risk of melanoma, other studies, similar in size and design to this one, have not found any link.

Prevention and early detection of melanoma

The best way to lower your risk of melanoma is to protect yourself from ultraviolet (UV) radiation emitted by the sun and indoor tanning booths, lamps, and sunbeds. It’s also important to know your skin, and tell your doctor about any skin changes or growths that are new or look different. Jacobs said,

Results of this study definitely does not mean that you can safely use a tanning booth or throw away your sunscreen if you are using aspirin. Whether or not you use aspirin, you can lower your risk of developing melanoma by limiting your time in direct sun, and using protective clothing and sunscreen.

References

1. Serhan CN. The Allergy Archives: The discovery and characterization of the leucotrienes. Journal of Allergy and Clinical Immunology. October 2006: 972-976.
2. Metcalf E. Aspirin: The Miracle Drug. New York, NY: Avery: a member of the Penguin Group, 2005.
3. Eicosanoids and Related Compounds – An Introduction. Eicosanoid Structures and Key Enzymes. The Lipid Library. aocs.org/ Updated November 23, 2011. Accessed January 4, 2012
4. Serhan CN. Lipoxins and aspirin-triggered 15-epilipoxins are the first lipid mediators of endogenous anti-inflammation and resolution. Prostaglandins, Leukotrienes, and Essential Fatty Acids (2005) 141-162.
5. Hibbeln JR, et al. Healthy intakes of n-3 and n-6 fatty acids: estimations considering worldwide diversity. American Journal of Clinical Nutrition. 2006; 83(suppl): 1483S-94S.
6. Serhan CN et al. Resolution of inflammation: State of the art, definitions and terms. The FASEB Journal. 2007; 21 (2): 325-332.
7. Bannenberg GL, Therapeutic applicability of anti-inflammatory and pro-resolving polyunsaturated fatty acid-derived lipid mediators. The Scientific World Journal (2010) 10, 676-712.
8. Serhan CN, et al. Maresins: Novel macrophage mediators with potent antiinflammatory and Proresolving actions. The Journal of Experimental Medicine. 2009; 206(1): 15-23.
9. Christina A. Gamba, et al. Aspirin is associated with lower melanoma risk among postmenopausal Caucasian women. Published online March 11, 2013 in CANCER, a peer-reviewed journal of the American Cancer Society.