Arachidonic acid (AA) is an omega-6 polyunsaturated fatty acid. In humans, it is one of the essential fatty acids that must be acquired from the diet.
AA is converted by cyclooxygenase (COX) to prostaglandin H2 , which is the precursor for a group of biologically important molecules called prostanoids.
Currently, three slightly different forms of COX are known:
- COX-1 is ubiquitous, being present in most mammalian cells.
- COX-2 is an enzyme that is produced by cells at sites of inflammation.
- COX-3 is sufficiently similar to COX-1 that some scientists refer to it as COX-1b. (Chandrasekharan N, et al. COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: Cloning, structure, and expression. Proc Natl Acad Sci U S A. 2002 October 15; 99[21]: 13926–13931)
All COX enzymes are capable of catalyzing the process that funnels arachidonic acid into the prostanoid pathway.
Many of the prostanoids arising from the activity of COX enzymes — particularly those that result from the conversion of AA — are inflammatory in nature. Although inflammation is a necessary immunologic process, it can cause pain and tissue damage when it continues unabated.
Thus, various pharmaceutical agents have been designed in an attempt to inhibit the activity of COX and reduce the effects of inflammatory processes.
Roles of Prostaglandins and Related Molecules
Aside from their well-documented role in inflammation, prostanoid molecules exert their effects in a myriad of physiologic processes:
- Modulate vascular, bronchial, or gastrointestinal contractility by regulating smooth muscle tone
- Control gastric acid and mucous production
- Initiate uterine contractility during labor
- Regulate intraocular pressure (important for persons with glaucoma)
- Stimulate or inhibit aggregation of platelets (part of the blood clotting mechanism)
- Control activity of hormones
- Regulate fat metabolism
- Mediate cellular growth
- Regulate movement of ions (e.g., calcium) across cell membranes
- Enhance neuronal pain response
- Play a role in fever generation.
The COX Paradox, or Why a Little Cyclooxygenase is a Good Thing
Unfortunately, prostaglandins and their relatives serve so many roles in the body that it is difficult to design a COX-inhibiting drug — even a “selective” one — that does not unintentionally interfere with the production of other vital molecules.
In addition to controlling the production of inflammatory prostanoids, both COX-1 and COX-2 help to convert essential fatty acids to other prostanoids that actually reduce inflammation or serve other regulatory functions.
For example, most people are familiar with the health benefits of eicosapentaenoic acid (EPA), a constituent of fish oil. Oxygenated EPA (a product of COX activity) competes with arachidonic acid for metabolism in the COX pathway, thus limiting the number of AA molecules that eventually get converted to inflammatory molecules.
Understanding this competitive interaction not only helps one to comprehend how COX enzymes do their work; it is a fundamental concept of all enzyme pathways.
The Control-Gate Concept of Enzymatic Activity
Enzymes act as catalysts that enable critical chemical reactions within cells. Conversion of one molecule to another biologically active (or less toxic) molecule is often a multi-step process, with enzymes present at each step along the way. Without enzymes, these chemical reactions might not occur at the necessary times.
But enzymes also act as controlling or rate-limiting checkpoints that keep the chemical reactions from occurring too quickly or at inappropriate times. Just like a dam or control gate channels water in a river, enzymes regulate the rate at which molecules can pass from one step in the process to the next.
If an enzyme is inhibited by a drug or removed from the pathway — as in the case of a genetic defect where a specific enzyme is not manufactured — all of the molecules flowing toward that enzyme’s place in the river will back up and flow in different directions. Some of these molecules may have already been converted “upstream” by other enzymes; they may already have the ability to perform other biological tasks, or they may be toxic to the cells where they were produced.
When a drug is used to inhibit COX activity, arachidonic acid cannot proceed through the cyclooxygenase gateway. It gets shunted into other enzymatic pathways, one of which leads to the production of chemicals called leukotrienes, which are hormone-like molecules that trigger and sustain allergic responses.
Overproduction of thromboxanes, a class of molecules derived from another alternate enzymatic pathway, may be behind the increased incidence of clotting, vasoconstriction and subsequent heart attacks in people who take COX-2 inhibitors (e.g., celecoxib, rofecoxib, etc.).
The role of cyclooxygenase is evidenced by the protean manifestations of its “offspring,” the prostanoid molecules. Learning to selectively inhibit COX’s pro-inflammatory activities without evoking undesirable side effects is a topic of energetic research.
 |
