prostaglandins and their related compounds- I prostacyclins (PGl), thromboxanes (TXA), leukotrienes (LT) and lipoxins are collectively known as eicosaniods, since they all contain 20 carbons (Creek : eikosi-twenty). Eicosanoids are considered as locally acting hormones with a wide range of biochemical functions. History : Prostaglandins (PCs) were first discovered in human semen by Ulf von Euler (of Sweden) in 1930. These compounds were found to stimulate uterine contraction and reduce blood pressure. von Euler presumed that they were synthesized by prostate gland and hence named them as prostaglandins. lt was later realized that PCs and other eicosanoids are synthesized in almost all the tissues (exception- erythrocytes). By then, however, the name prostaglandins was accepted worldwide, and hence continued. The prostaglandins E and F were first isolated from the biological fluids. They were so named due to their solubility in ether (PCE) and phosphate buffer (PCF, F for fosfat, in Swedish). All other prostaglandins discovered later were denoted by a letter-PCA, PCH etc. Structure o{ prostaglandins Prostaglandins are derivatives of a hypothetical 2O-carbon fatty acid namely prostanoic acid hence known as prostanoids. This has a cyclopentane ring (formed by carbon atoms 8 to 12) and two side chains, with carboxyl group on one side. Prostaglandins differ in their structure due to substituent group and double bond on cyclopentane ring. The different prostaglandins are given in Fig.32.l. The structures of the most important prostaglandins (PGF2 and PGF2o), prostacyclins (PCl2), thromboxanes (TXA2) and leukotrienes (LTA+) along with arachidonic acid are depicted in Fi9.32.2. A subscript numeral indicates the number of double bonds in the two side chains. A subscript c-denotes that the hydroxyl group at Ce of the ring and the carboxyl group are on thesame side of the ring.Synthesis of prostaglandins Arachidonic acid (5,8,1 1,1 4-eicosatetraenoic acid) is the precursor for most of the prostaglandins inhumans. The biosynthesis of PCs was described by scene Bergstrom and Bengt Samuelsson (1960). lt occurs in the endoplasmic reticulum in the following stages, as depicted in Fi9,32.3. 1. Release of arachidonic acid from membrane bound phospholipids by phospho- lipase A2-this reaction occurs due to a specific stimuli by hormones such as epinephrine or bradykinin. 2. Oxidation and cyclization of arachidonic acid to PGG2 which is then converted to PCH2 by a reduced glutathione dependent peroxidase. 3. PGH2 serves as the immediate precursor for the synthesis of a number of prostaglandins, including prostacyclins and thromboxanes. The above pathway is known as cyclic pathway of arachidonic acid. ln the linear pathway of arachidonic acid, leukotrienes and lipoxins are synthesized (details given later). Cyclooxygenase-a suicide enzyme : lt is interesting to note that prostaglandin synthesis can be partly controlled by suicidal activity ofthe enzyme cyclooxygenase. This enzyme is capable of undergoing self-catalysedestruction to switch off PG synthesis. lnhibition of PG synthesis : A number of structurally unrelated compounds can inhibit prostaglandin synthesis. Corticosteroids (e.g. cortisol) prevent the formation of arachidonic acid by inhibiting the enzyme phospholipase 42. Many non-steroidal anti-inflammatory drugs inhibit the synthesis of prostaglandins, prostacyclins and thromboxanes. They do so by blocking the action of the enzyme cyclo' oxygenase. Aspirin inhibits PG synthesis :Aspirin (acetyl salicylic acid) has been used since nineteenth century as an antipyretic (fever-reducing) and analgesic (pain relieving). The mechanism of action of aspirin however, was not known for a Iong period. lt was only in 1971, John Vane discovered that aspirin inhibits the synthesis of PC from arachidonic acid. Aspirin irreversibly inhibits the enzyme cyclooxygenase.