An important family of regulatory molecules is derived from arachidonic acid, which is an n-6 polyunsaturated fatty acid. These regulatory molecules collectively are often called the eicosanoids. They are synthesized by most tissues and have an incredibly wide range of actions. However, many of the most important are linked to defense against damage and pathogens. We will encounter them especially in the areas of inflammation and hemostasis.
The formation of these molecules begins with a stimulus to a cell that activates a membrane enzyme called phospholipase A2. The stimulus, for example, might be a condition that causes, or threatens to cause, tissue damage. Phospholipases act on phospholipids. In this case, the phospholipase A2 acts on a membrane phospholipid that contains arachidonic acid, which, as described earlier, is a polyunsaturated fatty acid.
The arachidonic acid released from the phospholipid is now the substrate for one of two enzymes. The first enzyme is cyclooxygenase (COX). The product of this reaction then proceeds through a further sequence of enzymatic reactions to produce a regulatory molecule that is either a prostaglandin or a thromboxane.
The second possibility is for lipoxygenase (LOX) to act on the arachidonic acid. In this pathway, the actions of further enzymes lead to regulatory molecules in the family of the leukotrienes.
All of the eicosanoid regulatory molecules tend to act locally as paracrines. This is because they are degraded too rapidly to move about the body through the circulatory system.
The familiar and widely used nonsteroidal anti-inflammatory drugs (NSAIDS), such as aspirin, ibuprofen, and naproxen, are inhibitors of cyclooxygenase.
But there are several variants of the enzyme. COX1 is found widely in the body and tends to be expressed constantly as a normal part of the functioning of the body. It is especially common in the digestive tract. Notably, in the stomach it produces prostaglandins that inhibit the secretions of stomach acid.
On the other hand, COX2 is released mainly by special, inflammatory cells, and its expression is induced by molecules such as various inflammatory paracrines. Glucocorticoids*, which are often used as powerful anti-inflammatory drugs, repress the expression of COX2.
The most common NSAIDS, such as aspirin, ibuprofen, and naproxen, inhibit both COX1 and COX2. More recent (and expensive) drugs, such as celecoxib, selectively act on COX2. These are prescribed to selectively counter inflammation without stimulating the secretion of stomach acid. But these are not without cardiovascular risk and one of these drugs, rofecoxib, was removed from the market for this reason.
Aspirin is interesting in that it covalently modifies COX, and thus new enzyme must be synthesized to replace that blocked. This is why relatively small amounts of aspirin affect platelets for more than a day. As aspirin is being absorbed, platelets moving through the intestines have their COX permanently blocked. Since platelets lack a nucleus, new COX forms only with the synthesis of new platelets.
A substance related to NSAIDs, acetaminophen, has been a puzzle because, while it supresses pain and fever, it has relatively little effect on inflammation and the secretion of stomach acid. There are various hypotheses about its mechanism of action.
*You will also see the term "corticosteroids" used in this context. Steroid hormones released from the adrenal cortex are corticosteroids. Also included in this term are drugs with similar structures and actions. Glucocorticoids are one of the three types of corticosteriods. Since glucocorticoids are the type most commonly used as drugs, you will often see "corticosteroid" and "glucocorticoid" used interchangeably. In practice there is little confusion since steroid drugs other than glucocorticoids are referred to more specifically.
Drugs are also used to modify the action of leukotrienes. Some drugs block lipoxygenase (e.g. zileuton), much like the NSAIDs block cyclooxygenase. More commonly used, however, are the leukotriene receptor antagonists (e.g. montelukast). These don't reduce the formation of leukotrienes, but reduce their action by blocking the receptor. The leukotriene modifiers are used sometimes for asthma and also atopic rhinoconjunctivities (hay fever). The NSAIDs, by contrast, don't effectively block the inflammation in these disorders.
The above introduces regulatory molecules derived from arachidonic acid. These are the best known and best understood of the paracrines derived from polyunsaturated fatty acids. We will discuss these in many contexts in physiology. However, there are also paracrines formed in a related fashion, but beginning with n-3 polyunsaturated fatty acids. These regulatory molecules are not nearly as well investigated and understood as those derived from arachidonic acid and typically have different or opposing actions. Also, the n-3 fatty acids can compete with arachidonic acid at COX or LOX.
QUESTION: What molecule is the source of arachidonic acid and where is it found?
QUESTION: Name the enzyme that, when activated, releases arachidonic acid.
QUESTION: What enyzme acts on arachidonic acid and begins the process through which leukotrienes are formed?
QUESTION: Name a specific enzyme that acts on arachidonic acid and that is induced by inflammatory paracrines.
QUESTION: Name a drug that does not tend to block COX1 in the stomach.
QUESTION: Name a drug that covalently binds to COX.
If you like, for fun, view the molecular structure of both COX1 and COX2 below in Jmole. Try to see why the catalytic sites of the two enzymes bind different inhibitors. (The COX2 has an extra pocket that will accept a special region of a COX2 inhibitor. By contract, the catalytic site of COX1 does not have a corresponding space, and hence the COX2 inhibitors cannot enter the catalytic site.)