Prostaglandins (PGs), Thromboxanes (TXs) and Leukotrienes (LTs) part 1

Eicosanoids

Prostaglandins (PGs), Thromboxanes (TXs) and Leukotrienes (LTs)
- Eicosanoids are oxygenation products of polyunsaturated long-chain (20 Catom) fatty acids. - There are considered "local hormones" They have specific effects and they are multiple subfamilies   of eicosanoids, e.g. Prostaglandins (PGs), Thromboxanes (TXs) and Leukotrienes (LTs). - The PGs and TXs are collectively identified as Prostanoids. - Prostaglandins were originally shown to be synthesized in the prostate gland, thromboxanes from   platelets (thrombocytes) and leukotrienes from leukocytes, hence the derivation of their names. - The eicosanoids produce a wide range of biological effects on inflammatory responses, on the   intensity and duration of pain and fever, and on reproductive function. They also play important   roles in inhibiting gastric acid secretion, regulating blood pressure through vasodilation or   constriction, and inhibiting or activating platelet aggregation and thrombosis.
Bio Synthesis	- Eicosanoids are not stored within cells, but are synthesized as required. - Two main pathways are involved in the biosynthesis of eicosanoids. - The prostaglandins and thromboxanes are synthesized by the cyclic pathway, the   leukotrienes by the linear pathway. - Eicosanoids biosynthesis steps; 1) 20-carbon atoms fatty acid (arachidonic acid; AA) formation: - Eicosanoid biosynthesis begins when a cell is activated by mechanical trauma,   cytokines, growth factors or other stimuli. - This triggersà release of a phospholipase at the cell membrane. - The phospholipase catalyzes ester hydrolysis of phospholipid (by phospholipase A2;    PLA) - This frees a 20-carbon fatty acid (arachidonic acid; AA). 2) Prostanoids formation (cyclooxygenase pathway): - The cyclic pathway is initiated through the action of prostaglandin  G/H  synthase (also called prostaglandin-endoperoxide synthase). - This enzyme possesses two activities, cyclooxygenase (COX) and peroxidase. - There are two forms of COX activity in humans, COX-1 and COX-2. - COX-1 (prostaglandin synthase-1; PGS-1) is expressed constitutively in gastric mucosa, kidney, platelets, and vascular endothelial cells. - COX-2 (prostaglandin synthase-2; PGS-2) is inducible and is expressed in macrophages and monocytes in response inflammation. - Both COX-1 and COX-2 catalyse the 2-step conversion of arachidonic acid to prostanoids, including prostaglandins (PGs), prostacyclin (PGI2) and thromboxane (TXA2) 3) Leukotrienes formation (Leukotriene pathway): - The linear pathway is initiated through the action of lipoxygenase (LOX) enzymes of   which there are three forms, 5-LOX, 12-LOX and 15-LOX. - The most actively investigated leukotrienes are those produced by the 5-LOX. The   leukotrienes are synthesized by several different cell types including white blood   cells (leukocytes), mast cells, lung, spleen, brain and heart. - The enzyme 5-lipoxygenase (5-LOX) uses 5-lipoxygenase activating convert   arachidonic acid into protein hydroperoxyeicosatetraenoic acid (5-HPETE), which   spontaneously reduces to 5-hydroxyeicosatetraenoic acid (5-HETE). - The enzyme LTA synthase acts on 5-HPETE to convert it into leukotriene A4 (LTA4), which may be converted into LTB4 by the enzyme leukotriene A4 epoxide hydrolase. - Leukotriene C4 synthase to conjugate glutathione with LTA4 to make LTC4, which is   transported outside the cell, where a glutamic acid (FLAP) moiety is removed from   it to make LTD4. The leukotriene LTD4 is then cleaved by dipeptidases to make   LTE4. The leukotrienes LTC4, LTD4 and LTE4 all contain cysteine and are collectively   known as the cysteinyl leukotrienes.
Inhibition Of Eicosanoid Synthesis	- Corticosteroids block all the known pathways of eicosanoid synthesis. - Non-steroidal anti-inflammatory drugs (NSAIDS) e.g. Aspirin, Indomethacin, block   both prostaglandin and thromboxane formation by reversibly inhibiting COX   activity. - Aspirin is an irreversible non-selective COX inhibitor. - NSAIDS are not selective for COX-1 or COX-2. - Selective COX-2 inhibitors (e.g. Celecoxib), which were developed more recently. - 5-LOX inhibitor (e.g. Zileuton) and selective antagonists of the CysLT1 receptor for leukotrienes (LTC4, LTD4 and LTE4) (Zafirlukast, Montelukast and Pranlukast, are used clinically in mild to moderate asthma.

 

 

 

 

 

 

Eicosanoid Receptors

- Each of the eicosanoids functions via interactions with cell-surface receptors that are members of   the G-protein coupled receptor (GPCR) family. - There are at least ten characterized prostaglandin receptors. Receptors that bind the prostaglandin   D family of lipids are called the DP receptors, those that bind E family prostaglandins are called the   EP receptors, those that bind F family prostaglandins are called the FP receptors, those that bind   prostacyclin (PGI:) are called the IP receptors, and those that bind the thromboxanes are called the   TP receptors. - There are at least four leukotriene receptors. Two receptors have been characterized that bind LTB4 called BLT1 and BLT2 and two receptors that bind the peptidoleukotrienes (cysteinyl leukotrienes) called CysLT1 and CysLT2.

 

 

 

 

 

Eicosanoid	Major Site of Synthesis	Major Biological Activities
PGI2 (Prostacyclin)	Heart and vascular endothelial cells	- Inhibit platelet aggregation. - Induce vasodilation. - decrease T-cell proliferation and lymphocyte migration.
PGE1		- Induce vasodilation. - Inhibit platelet aggregation.
PGE2	Kidney, spleen and heart	- Induce vasodilation - Induce platelet aggregation. - Induce uterine contractions. - Maintaining the open passageway of the fetal ductus   arteriosus.
PGD2	Mast cells, eosinophils and brain	- It is a major prostaglandin produced by mast cells. - Induce inflammatory response. - Induces vasodilation. - Induce bronchoconstriction. - Involved in androgenetic alopecia, inhibitors of PGD2 being   studied to treat male pattern baldness.
PGF2α	Kidney, spleen and heart	- Induce vasoconstriction. - Induce bronchoconstriction. - Induce smooth muscle contraction.
TXA2	Platelets	- Induce platelet aggregation. - Induce vasoconstriction. - Induce bronchoconstriction.
LTB4	Monocytes, basophils, eosinophils, mast cells epithelial cells	- Powerful inducer of leukocyte chemotaxis and TXA2 Platelets LTB4 aggregation, vascular permeability, T-cell proliferation and secretion of INF-y (Interferon gamma), IL-1 and IL-2 (Interleukin 1 and 2).
LTC4  LTD4		- Component of slow-reactive substance of anaphylaxis and   (SRS-A). - Induce vasoconstriction. - Induce bronchoconstriction. - Secretion of INF-y.
LTE4	Mast cells and basophils

N.B: SRS-A; is a mixture of the leukotrienes LTC4, LTD4 and LTE4. Mast cells secrete it during the anaphylactic reaction, inducing inflammation.

 

 

 

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