Chemistry, Biosynthesis and Degradation

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Chapter: Essential pharmacology : Prostaglandins, Leukotrienes (Eicosanoids) and Platelet Activating Factor

Chemically, PGs may be considered to be derivatives of prostanoic acid, though prostanoic acid does not naturally occur in the body. It has a five membered ring and two side chains projecting in opposite directions at right angle to the plane of the ring. There are many series of PGs and thromboxanes (TXs) designated A, B, C....I,



Chemically, PGs may be considered to be derivatives of prostanoic acid, though prostanoic acid does not naturally occur in the body. It has a five membered ring and two side chains projecting in opposite directions at right angle to the plane of the ring. There are many series of PGs and thromboxanes (TXs) designated A, B, C....I, depending on the ring structure and the substituents on it. Each series has members with subscript 1, 2, 3 indicating the number of double bonds in the side chains.


Leukotrienes are so named because they were first obtained from leukocytes (leuko) and have 3 conjugated double bonds (triene). They have also been similarly designated A, B, C.....F and given subscripts 1, 2, 3, 4.



In the body PGs, TXs and LTs are all derived from eicosa (referring to 20 C atoms) tri/tetra/ penta enoic acids. Therefore, they can be collectively called eicosanoids. In human tissues, the fatty acid released from membrane lipids in largest quantity is 5,8,11,14 eicosa tetraenoic acid (arachidonic acid). During PG, TX and prostacyclin synthesis, 2 of the 4 double bonds of arachidonic acid get saturated in the process of cyclization, leaving 2 double bonds in the side chain. Thus, subscript 2 PGs are most important in man, e.g. PGE2, PGF2α, PGI2, TXA2. No cyclization or reduction of double bonds occurs during LT synthesis— the LTs of biological importance are LTB4, LTC4, LTD4.


Eicosanoids are the most universally distributed autacoids in the body. Practically every cell and tissue is capable of synthesizing one or more types of PGs or LTs. The pathways of biosynthesis of eicosanoids are summarized in Fig. 13.1.


There are no preformed stores of PGs and LTs. They are synthesized locally at rates governed by the release of arachidonic acid from membrane lipids in response to appropriate stimuli. These stimuli activate hydrolases, including phospholipase A, probably through increased intracellular Ca2+.


The cyclooxygenase (COX) pathway generates eicosanoids with a ring structure (PGs, TXs, prostacyclin) while lipoxygenase (LOX) produces open chain compounds (LTs). All tissues have COX—can form cyclic endoperoxides PGG2 and PGH2 which are unstable compounds. Further course in a particular tissue depends on the type of isomerases or other enzymes present in it. PGE2 and PGF2α are the primary prostaglandins (name based on the separation procedure: PGE partitioned into Ether while PGF into phosphate [Fosfat in Swedish] buffer; α in PGF2α refers to orientation of OH group on the ring). PGs A, B and C are not found in the body: they are artifacts formed during extraction procedures. Lung and spleen can synthesize the whole range of COX products. Platelets primarily synthesize TXA2 which is —chemically unstable, spontaneously changes to TXB2. Endothelium mainly generates prostacyclin (PGI2); also chemically unstable and rapidly converts to 6keto PGF1α.


Cyclooxygenase is now known to exist in two isoforms COX1 and COX2. While both isoforms catalyse the same reactions, COX1 is a constitutive enzyme in most cells—its activity is not changed once the cell is fully grown. On the other hand, COX2 normally present in insignificant amounts, is inducible by cytokines, growth factors and other stimuli during the inflammatory response. It is believed that eicosanoids produced by COX1 participate in physiological (house keeping) functions such as secretion of mucus for protection of gastric mucosa, haemostasis and maintenance of renal function, while those produced by COX2 lead to inflammatory and other pathological changes. However, certain sites in kidney and brain constitutively express COX2 which may play physiological role.


A splice variant of COX1 (designated COX3) has been found in the dog brain. This isoenzyme is inhibited by paracetamol, but its role in humans is not known.


Lipoxygenase pathway appears to operate mainly in the lung, WBC and platelets. Its most important products are the LTs, (generated by 5LOX) particularly LTB4 (potent chemotactic) and LTC4, LTD4 which together constitute the ‘slow reacting substance of anaphylaxis’ (SRSA) described in 1938 to be released during anaphylaxis. A membrane associated transfer protein called FLAP (five lipoxygenase activating protein) carrys arachidonic acid to 5LOX, and is essential for the synthesis of LTs. Platelets have only 12LOX.


HPETEs produced by LOX can also be converted to hepoxilins, trioxilins and lipoxins. A third enzymatic pathway involving cytochrome P450 can metabolize arachidonic acid into 19 and 20HETEs and epoxyeicosatrienoic acids. Free radicals can attack arachidonic acid to produce isoprostanes nonenzymatically. Brain cells couple arachidonic acid with ethanolamine to produce anandamide which has cannabinoid like action. The above named metabolites of arachidonic acid have a variety of vascular, inflammatory and other actions, but their pathophysiological role is not clear.


Inhibition of synthesis Synthesis of COX products can be inhibited by nonsteroidal anti-inflammatory drugs (NSAIDs). Aspirin acetylates COX at a serine residue and causes irreversible inhibition while other NSAIDs are competitive and reversible inhibitors. Most NSAIDs are nonselective COX1 and COX2 inhibitors, but some newer ones like celecoxib, rofecoxib are selective for COX2.


The sensitivity of COX in different tissues to inhibition by these drugs varies; selective inhibition of formation of some products may be possible

at lower doses. NSAIDs do not inhibit the production of LTs: this may even be increased since all the arachidonic acid becomes available to the LOX pathway.


Zileuton inhibits LOX and decreases the production of LTs. It was used briefly in asthma, but has been withdrawn.


Glucocorticosteroids inhibit the release of arachidonic acid from membrane lipids (by stimulating production of proteins called annexins or lipocortins which inhibit phospholipase A2) — indirectly reduce production of all eicosanoids— PGs, TXs and LTs. Moreover, they inhibit the induction of COX2 by cytokines at the site of inflammation.


Degradation of arachidonates occurs rapidly in most tissues, but fastest in the lungs. Most PGs, TXA2 and prostacyclin have plasma t½ of a few seconds to a few minutes. First a specific carrier mediated uptake into cells occurs, the side chains are then oxidized and double bonds are reduced in a stepwise manner to yield inactive metabolites. Metabolites are excreted in urine. PGI2 is catabolized mainly in the kidney.


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