Prostaglandins and Leukotrienes

Prostaglandins and Leukotrienes

What do prostaglandins and leukotrienes have to do with lipids?

A group of compounds derived from fatty acids has a wide range of physiological activities; they are called prostaglandins because they were first detected in seminal fluid, which is produced by the prostate gland. It has since been shown that they are widely distributed in a variety of tissues. The metabolic precursor of all prostaglandins is arachidonic acid, a fatty acid that contains 20 carbon atoms and four double bonds. The double bonds are not conjugated. The production of the prostaglandins from arachidonic acid takes place in several steps, which are catalyzed by enzymes. The prostaglandins themselves each have a five-membered ring; they differ from one another in the numbers and positions of double bonds and oxygen-containing functional groups (Figure 8.34).

The structures of prostaglandins and their laboratory syntheses have been topics of great interest to organic chemists, largely because of the many physi-ological effects of these compounds and their possible usefulness in the phar-maceutical industry. Some of the functions of prostaglandins are control of blood pressure, stimulation of smooth-muscle contraction, and induction of inflammation. Aspirin inhibits the synthesis of prostaglandins, particularly in blood platelets, a property that accounts for its anti-inflammatory and fever-reducing properties. Cortisone and other steroids also have anti-inflammatory effects because of their inhibition of prostaglandin synthesis.

Prostaglandins are known to inhibit the aggregation of platelets. They may thus be of therapeutic value by preventing the formation of blood clots, which can cut off the blood supply to the brain or the heart and cause certain types of strokes and heart attacks. Even if this behavior were the only useful property of prostaglandins, it would justify considerable research effort. Heart attacks and strokes are two of the leading causes of death in industrialized countries. More recently, the study of prostaglandins has been a topic of great interest because of their possible antitumor and antiviral activity.

Leukotrienes are compounds that, like prostaglandins, are derived fromarachidonic acid. They are found in leukocytes (white blood cells) and have three conjugated double bonds; these two facts account for the name. (Fatty acids and their derivatives do not normally contain conjugated double bonds.) Leukotriene C (Figure 8.35) is a typical member of this group; note the 20 carbon atoms in the carboxylic acid backbone, a feature that relates this compound structurally to arachidonic acid. (The 20-carbon prostaglandins and leukotrienes are also called eicosinoids.)  

An important property of leukotri-enes is their constriction of smooth muscle, especially in the lungs. Asthma attacks may result from this constricting action because the synthesis of leu-kotriene C appears to be facilitated by allergic reactions, such as a reaction to pollen. Drugs that inhibit the synthesis of leukotriene C are now being used in the treatment of asthma, as are other drugs designed to block leukotriene receptors. In the United States, the incidence of asthma has increased drasti-cally since 1980, providing considerable incentive to find new treatments. The Centers for Disease Control (CDC) have made information available on the Internet at http:/ www.cdc.gov/asthma.) Leukotrienes may also have inflam-matory properties and may be involved in rheumatoid arthritis.

Thromboxanes are a third class of derivatives of arachidonic acid. They con-tain cyclic ethers as part of their structures. The most widely studied member of the group, thromboxane A₂ (TxA₂) (Figure 8.36), is known to induce platelet aggregation and smooth-muscle contraction.

Summary

Prostaglandins are compounds of related structures derived from long-chain fatty acids. They have a number of physiological roles, including control of smooth muscle contraction, development of inflammation, and inhibition of platelet aggregation. The last of these three roles makes them objects of research on ways to prevent heart disease.

Leukotrienes are also derived from fatty acids. They play a role in smooth muscle contraction in the lungs. Drugs that block the binding of leuko-trienes to their receptors in lung tissue are under study for the treatment of asthma.