Synthesis and metabolism of prostaglandins, prostacyclin, and thromboxanes: The arachidonic acid cascade

This review of prostaglandins (PG) and related compounds discusses in considerable detail their chemical terminology, synthesis, degradation and clinical significance. PGs and related metabolites are easily synthesized by most tissues; at least one-third of all drugs seem to interact at some level of the PG-generating system. Most of the PGs are derived from a 20-carbon, straight chain, fatty acid, arachidonic acid. This acid is obtained directly from the diet or by anabolic transformation from linolenic acid. Indomethacin or a deficiency of essential fatty acids in the diet will ultimately cause PG deficiency. Arachidonic acid is transported free in the plasma bound electrostatically and hydrophobically to albumin. The majority of arachidonic acid is covalently bound and present in the esterified form in phospholipids or bound to cholesterol. The release of free arachidonic acid from its ester seems to be the rate-limiting step in the cascade which leads to the formation of the various PGs. PGs are not stored. The acyl hydroxylase (a lipase) necessary for deesterification of arachidonic acid has been found in many tissues and can be activated by many stimuli including burns, toxins, mechanical stretching and probably also catecholamines, bradykinin and angiotensin II. Arachidonic acid release is inhibited, as far as is known, by only antiinflammatory corticosteroids and anesthetic agents. The arachidonic acid chain is converted to a PG by three routes. The most studied route involves a cyclooxygenase which adds molecular oxygen at C15 followed by the bridging of the gap between C8 and C12 to form a 5 carbon ring (cyclopentane). At the same time, a second molecule of oxygen is added across C9 and C11. This endoperoxide, or PGG, can then be converted to a hydroendoperoxide known as PGH. The subscript numbers found in PG terminology refer to the number of double bonds remaining in the chain after the above-mentioned conversions and depend on the precursor acid; most compounds of clinical importance are derived from arachidonic acid and have a subscript of 2. The cyclic endoperoxides, PGG and PGH, are unstable but give rise to the clinically important PGDs, PGEs, PGIs (or prostacyclins) and the thromboxines (TX). TXs are not considered PGs because the cyclopentane ring has been split open. Clinically, PGE and PGF have found some use in obstetrics as uterine constrictors (although PGE is a potent vasodepressor). Both arachidonic acid and PGF2α will help to maintain patency of the ductus arteriosus in newborns. The inhibition of platelet aggregation by prostacyclin (PGI₂), a bicyclic PG formed in vessel walls, and the thrombotic action of the thromboxines, largely derived from platelets, seem to play a major role in blood clotting. Arachidonic acid may be converted by another pathway (5-lipo-oxygenase) to the leukotrienes. Leukotriene C is identical to slow-reacting substance of anaphylaxis and is involved in the bronchoconstriction of asthma and aspirin sensitivity of asthmatics. Catabolism of the PGs is largely by oxidation of the hydroxyl group on carbon 15, and occurs primarily in the lung and, to a lesser degree, in the kidney and liver. Prostacyclin is not inactivated in the lung and follows a different route of inactivation. (Bloodworth Jr. - Madison, Wis.)