Eicosanoids

Prostaglandins, and the related compounds thromboxanes and leukotrienes, are collectively known as EICOSANOIDS to reflect their origin from polyunsaturated fatty acids with 20 carbons. They are extremely potent compounds that elicit a wide range of responses, both physiologic (inflammatory response) and pathologic (hyper-sensitivity). They ensure gastric integrity and renal function, regulate smooth muscle contraction (intestine and uterus are key sites) and blood vessel diameter, and maintain platelet homeostasis

Although they have been compared to hormones in terms of their actions, eicosanoids differ from the true hormones in that they are produced in very small amounts in almost all tissues rather than in specialized glands. They also act locally rather than after transport in the blood to distant sites, as occurs with true hormones such as insulin. Eicosanoids are not stored, and they have an extremely short half-life, being rapidly metabolized to inactive products

METABOLISM OF UNSATURATED FATTY ACIDS AND EICOSANOIDS   Humans have limited ability in desaturating fatty acids.   Dietary intake of certain polyunsaturated fatty acids derived from a plant source is necessary.  These essential fatty acids give rise to eicosanoic (C20) fatty acids, from which are derived families of compounds known as eicosanoids.  Eicosanoids include prostaglandins, prostacyclins, thromboxanes, leukotrienes, and lipoxins. 

Deficiency symptoms in the absence of essential fatty acids from the diet: Nonlipid diet plus vitamins A and D Rat –––––––––––––––––––––––––––––––– Reduced growth rate and reproductive deficiency Deficiency syndrome was cured by the addition of linoleic, a-linolenic, and arachidonic acids to the diet. Essential fatty acids are found in structural lipids of the cell and are concerned with structural integrity of mitochondrial membrane. Arachidonic acid is present in membranes and accounts for 5-15% of the fatty acids in phospholipids.

SOME MAJOR POLYUNSATURATED FATTY ACIDS Name Structure Type Significance Linoleic 18:2(9,12) ω-6 Essential FA Linolenic 18:3(9,12,15) ω-3 Arachidonic 20:4(5,8,11,14) Prostaglandin precursor

Linoleic (18:2) (ω-6) arachidonic (AA) (20:4) (ω-6) METABOLISM OF LINOLEIC VERSUS LINOLENIC INTO POLYUNSATURATED FATTY ACIDS (PUFAS): Linoleic (18:2) (ω-6) arachidonic (AA) (20:4) (ω-6) Linolenic (18:3)(ω-3) eicosapentanoic acid (EPA) (20:5) (ω-3) and docosahexanoic acid (DHA) (22:6) (ω-3) Dietary linoleic acid is the precursor. It is elongated and further desaturated to 20-carbon, 3, 4, or 5 double bond FAs

Omega-3 fatty acids EPA & DHA are precursors for different eicosanoids than arachidonic acid Fish oils have high content of ω-3 FA

Biological actions of eicosanoids Biologic actions of eicosanoids are diverse in various organs: vasodilation, constriction, platelet aggregation, contraction of smooth muscle, chemotaxis of leukocytes, release of lysosomal enzymes

Also, they have roles in: Biological actions of eicosanoids ……. 2 Also, they have roles in: regulation of blood pressure, blood clotting and immune system modulation Excess production symptoms: pain, inflammation, fever, nausea, vomiting

Arachidonic acid, 20:4 (5, 8, 11, 14), is the precursor of many eicosanoids Arachidonic acid is normally part of membrane phospholipids (especially phosphatidylinositol).

arachidonic acid is often esterified to OH on C2 of glycerophospho-lipids, especially phosphatidyl inositol. Arachidonic acid is released from phospholipids by hydrolysis catalyzed by Phospholipase A2. This enzyme hydrolyzes the ester linkage between a fatty acid and the OH at C2 of the glycerol backbone, releasing the fatty acid & a lysophospholipid as products.

Phosphatidyl inositol signal cascades may lead to release of arachidonic acid. After PI is phosphorylated to PIP2, cleavage via Phospholipase C yields diacylglycerol (and IP3).

Prostaglandins all have a cyclopentane ring. A letter code is based on ring modifications (e.g., hydroxyl or keto groups). A subscript refers to the number of double bonds in the two side-chains. Thromboxanes are similar but have instead a 6-member ring.

Thromboxanes are similar but have instead a 6-member ring. CLINICAL ASPECTS: Thromboxanes are similar but have instead a 6-member ring. Thromboxanes are synthesized in platelets and upon release cause vasoconstriction and platelet aggregation. Their synthesis is inhibited by low-dose aspirin.

Prostaglandin H2 Synthase catalyzes the committed step in the “cyclic pathway” that leads to production of prostaglandins, prostacyclins, & thromboxanes. Different cell types convert PGH2 to different compounds. Mast cells attracts immune cells

Corticosteroids are anti-inflammatory because they prevent inducible Phospholipase A2 expression, reducing arachidonic acid release. There are multiple Phospholipase A2 enzymes, subject to activation via different signal cascades. The inflammatory signal platelet activating factor is involved in activating some Phospholipase A2 variants. arachidonic acid may give rise to inflammatory or anti-inflammatory eicosanoids in different tissues.

Non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin and derivatives of ibuprofen, inhibit cyclooxygenase activity of PGH2 Synthase. They inhibit formation of prostaglandins involved in fever, pain, & inflammation. They inhibit blood clotting by blocking thromboxane formation in blood platelets. Ibuprofen and related compounds block the hydrophobic channel by which arachidonic acid enters the cyclooxygenase active site.

There are at least two isozymes of PGH2 Synthase (COX-1 and COX-2) COX-1 is constitutively expressed at low levels in many cell types Specifically, COX-1 is known to be essential for maintaining the integrity of the gastrointestinal epithelium.

COX-2 expression is stimulated by growth factors, cytokines, and endotoxin COX-2 levels increase in inflammatory disease states such as arthritis and cancer Up-regulation of COX-2 is responsible for the increased formation of prostaglandins associated with inflammation

Next generation NSAIDs Older NSAIDs inhibit both COX-1 & COX-2: acetylsalicylate (Aspirin®, Disprin®, etc.) ibuprofen ( Brufen®, etc.) Newer generation drugs are specific COX-2 inhibitors: Nise® Nims®

Thromboxane A2 stimulates blood platelet aggregation, essential to the role of platelets in blood clotting. Many people take a daily aspirin for its anti-clotting effect, attributed to inhibition of thromboxane formation in blood platelets. This effect of aspirin is long-lived because platelets lack a nucleus and do not make new enzyme.

LIPOXYGENASE PATHWAY: –Produces leukotrienes from eicosanoic acids in leukocytes, mast cells, platelets, and macrophages in response to both immunologic and nonimuunologic stimuli.

SYNTHESIS OF LEUKOTRIENES FROM ARACHIDONIC ACID Leukotrienes are produced from arachidonic acid via a different enzyme: lipoxygenase HPETE Hydroxyperoxytetraenoic

LEUKOTRIENES HAVE ROLES IN INFLAMMATION. They are produced in areas of inflammation in blood vessel walls as part of the pathology of atherosclerosis. Leukotrienes are also implicated in asthmatic constriction of the bronchioles.

inhibitors of 5-Lipoxygenase, e.g., Zyflo (zileuton) ANTI-ASTHMA MEDICATIONS INCLUDE: inhibitors of 5-Lipoxygenase, e.g., Zyflo (zileuton) drugs that block leukotriene-receptor interactions e.g., Singulair (montelukast) & Accolate (zafirlukast) block binding of leukotrienes to their receptors on the plasma membranes of airway smooth muscle cells.