Eicosanoids

 

Metabolism of the Eicosanoids

The eicosanoids consist of the 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.

Structures of Representive Clinically Relevant Eicosanoids
	PGE2
	TXA2
	LTA4

The eicosanoids produce a wide range of biological effects on inflammatory responses (predominantly those of the joints, skin and eyes), on the intensity and duration of pain and fever, and on reproductive function (including the induction of labor). 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.

The principal eicosanoids of biological significance to humans are a group of molecules derived from the C₂₀ fatty acid, arachidonic acid. Minor eicosanoids are derived from eicosopentaenoic acid which is itself derived from a-linolenic acid obtained in the diet. The major source of arachidonic acid is through its release from cellular stores. Within the cell, it resides predominantly at the C-2 position of membrane phospholipids and is released from there upon the activation of phospholipase A₂ (see diagram above). The immediate dietary precursor of arachidonate is linoleic acid. Linoleic acid is converted to arachidonic acid through the steps outlined in the figure below. Linoleic acid (arachidonate precursor) and a-linolenic acid (eicosapentaenoate precursor) are essential fatty acids, therefore, their absence from the diet would seriously threaten the body's ability to synthesize eicosanoids.

Pathway from linoleic acid to arachidonic acid. Numbers in parentheses refer to the fatty acid length and the number and positions of unsaturations.

All mammalian cells except erythrocytes synthesize eicosanoids. These molecules are extremely potent, able to cause profound physiological effects at very dilute concentrations. All eicosanoids function locally at the site of synthesis, through receptor-mediated G-protein linked signaling pathways leading to an increase in cAMP levels.

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.

Synthesis of the clinically relevant prostaglandins and thromboxanes from arachidonic acid. Numerous stimuli (e.g. epinephrine, thrombin and bradykinin) activate phospholipase A2 which hydrolyzes arachidonic acid from membrane phospholipids. The prostaglandins are identified as PG and the thromboxanes as TX. Prostaglandin PGI2 is also known as prostacyclin. The subscript 2 in each molecule refers to the number of -C=C- present.

Synthesis of the clinically relevant leukotrienes from arachidonic acid. Numerous stimuli (e.g. epinephrine, thrombin and bradykinin) activate phospholipase A2 which hydrolyzes arachidonic acid from membrane phospholipids. The leukotrienes are identified as LT. The leukotrienes, LTC4, LTD4, LTE4 and LTF4 are known as the peptidoleukotrienes because of the presence of amino acids. The peptidoleukotrienes, LTC4, LTD4 and LTE4 are components of slow-reacting substance of anaphylaxis The subscript 4 in each molecule refers to the number of -C=C- present.

The linear pathway is initiated through the action of lipoxygenases. It is the enzyme, 5-lipoxygenase that gives rise to the leukotrienes.

The cyclic pathway is initiated through the action of prostaglandin G/H synthase, PGS (also called prostaglandin endoperoxide synthetase). This enzyme possesses two activities, cyclooxygenase (COX) and peroxidase. There are 3 forms of the COX activity. COX-1 (PGS-1) is expressed constitutively in gastric mucosa, kidney, platelets, and vascular endothelial cells. COX-2 (PGS-2) is inducible and is expressed in macrophages and monocytes in response to inflammation. The primary trigger for COX-2 induction in monocytes and macrophages is platelet-activating factor, PAF and interleukin-1, IL-1. Both COX-1 and COX-2 catalyze the 2-step conversion of arachidonic acid to PGG₂ and then to PGH₂. Most recently a splice variant of COX-1 mRNA has been found in many tissues such as heart, kidney and several neuronal tissues. This variant mRNA retains intron 1 from the COX-1 gene and the encoded protein has been termed COX-3. In vitro evidence indicates that the canine COX-3 enzyme is inhibited by acetominophen. However, data also shows that in humans the consequence of inclusion of intron 1 sequences leads to synthesis of a truncated protein with no significant homology to COX-1 or COX-2 and that this protein appears unresponsive to acetominophen action.

A widely used class of drugs, the non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, indomethacin, naproxen, phenylbutazone and aspirin, all act upon the cyclooxygenase activity, inhibiting both COX-1 and COX-2. Because inhibition of COX-1 activity in the gut is associated with NSAID-induced ulcerations, pharmaceutical companies have developed drugs targeted exclusively against the inducible COX-2 activity [e.g. Celebrex (celecoxib), Prexige (lumiracoxib) and the recently removed Vioxx (rofecoxib) and Bextra (valdecoxib)].

Another class, the corticosteroidal drugs, act to inhibit phospholipase A₂, thereby inhibiting the release of arachidonate from membrane phospholipids and the subsequent synthesis of eicosinoids.

 

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Properties of Significant Eicosanoids

Eicosanoid	Major site(s) of synthesis	Major biological activities
PGD2	mast cells	inhibits platelet and leukocyte aggregation, decreases T-cell proliferation and lymphocyte migration and secretion of IL-1a and IL-2; induces vasodilation and production of cAMP
PGE2	kidney, spleen, heart	increases vasodilation and cAMP production, enhancement of the effects of bradykinin and histamine, induction of uterine contractions and of platelet aggregation, maintaining the open passageway of the fetal ductus arteriosus; decreases T-cell proliferation and lymphocyte migration and secretion of IL-1a and IL-2
PGF2a	kidney, spleen, heart	increases vasoconstriction, bronchoconstriction and smooth muscle contraction
PGH2		precursor to thromboxanes A2 and B2, induction of platelet aggregation and vasoconstriction
PGI2	heart, vascular endothelial cells	inhibits platelet and leukocyte aggregation, decreases T-cell proliferation and lymphocyte migration and secretion of IL-1a and IL-2; induces vasodilation and production of cAMP
TXA2	platelets	induces platelet aggregation, vasoconstriction, lymphocyte proliferation and bronchoconstriction
TXB2	platelets	induces vasoconstriction
LTB4	monocytes, basophils, neutrophils, eosinophils, mast cells, epithelial cells	induces leukocyte chemotaxis and aggregation, vascular permeability, T-cell proliferation and secretion of INF-g, IL-1 and IL-2
LTC4	monocytes and alveolar macrophages, basophils, eosinophils, mast cells, epithelial cells	component of SRS-A, microvascular vasoconstrictor, vascular permeability and bronchoconstriction and secretion of INF-g
LTD4	monocytes and alveolar macrophages, eosinophils, mast cells, epithelial cells	predominant component of SRS-A, microvascular vasoconstrictor, vascular permeability and bronchoconstriction and secretion of INF-g
LTE4	mast cells and basophils	component of SRS-A, microvascular vasoconstrictor and bronchoconstriction

**SRS-A = slow-reactive substance of anaphylaxis