Arachidonic acid

Arachidonic Acid Overview

  • Definition: Arachidonic acid is a 20-carbon polyunsaturated fatty acid (PUFA) denoted as (20:4ω-6).

  • Structure: Usually assumes a hairpin configuration.

  • Synthesis: Can be synthesized in the liver from linoleic acid.

  • Dietary Sources: Found in significant amounts in meat, eggs, and fish.

Biological Significance

  • Cell Membrane Component: Arachidonic acid is a vital constituent of biological cell membranes found ubiquitously in organisms.

  • Eicosanoid Hormones: A precursor for eicosanoid hormones, which are paracrine signals acting locally at their sites of synthesis.

Membrane Phospholipids

  • Structure:

    • Composed of a polar head (hydrophilic) and non-polar fatty acid tail (hydrophobic).

    • Form a phospholipid bilayer essential for cell membrane structure.

  • Constituent: Arachidonic acid is integrated within membrane phospholipids which also include:

    • A phosphate group (hydrophilic)

    • A glycerol backbone

Arachidonic Acid Cascade

  • Eicosanoid Derivatives: Produced from arachidonic acid when needed and function as paracrine hormones- secreted into interstitial fluid and act locally to regulate a variety of physiological processes, including inflammation, immune responses, and blood pressure.

  • Prostaglandins: Involved in the inflammatory response and modulate pain and fever.

  • Thromboxanes: Play a role in platelet aggregation and blood clotting.

  • Leukotrienes: Important in mediating allergic reactions and asthma.

  • Types of Eicosanoids:

    • Leukotrienes:

      • Initially found in leukocytes, produced by WBCs (eosinophils, neutrophils), mast cells, and macrophages.

    • Prostaglandins:

      • First isolated from the prostate gland, produced by almost all nucleated cells.

    • Thromboxanes: Primarily produced by platelets.

Leukotriene Functions

  • Importance:

    • Leukotriene B4 (LTB4): Attracts neutrophils and other leukocytes to sites of inflammation and infection.

    • Cysteinyl leukotrienes (LTC4 and its metabolites - LTD4, LTE4):

      • Cause bronchoconstriction, vasoconstriction, and increased vascular permeability.

  • Role in Health: Involved in conditions such as asthma and allergies (allergic rhinitis, allergic dermatitis, anaphylaxis).

Lipoxins

  • Function: Produced by lipoxygenases, lipoxins have anti-inflammatory effects and are produced by 3 major lipooxegenases

Cyclooxygenase Pathway

  • Overview:

    • Cyclooxygenase (COX) is responsible for the conversion of arachidonic acid into prostaglandins and thromboxanes.

  • COX Activities:

    • Cyclooxygenase Activity: Converts arachidonic acid to PGH2.

    • Peroxidase Activity: Essential for thromboxane and prostaglandin synthesis.

  • Key Enzymes:

    • Thromboxane synthase converts PGH2 to TXA2 (thromboxane A2).

    • Prostacyclin synthase converts PGH2 to PGI2 (prostacyclin).

Prostaglandin Actions

  • Thromboxanes:

    • TXA2 is the biologically active compound with significant roles in physiology.

    • TXB2 is a metabolite of TXA2, often used as a biomarker in laboratory tests for thromboxane production.

COX Isoenzymes

  • COX-1:

    • Constitutively expressed in most tissues, involved in regulating normal physiological functions, such as gastric mucosal protection and vascular homeostasis through the synthesis of prostaglandins and thromboxanes.

  • COX-2:

    • Induced by stimuli such as inflammation and injury, involved in the production of inflammatory prostaglandins that mediate pain and fever.

    • Inflammatory response

    COX-1 highly expressed in platelets → TXA2

    COX-2 highly expressed in endothelial cells → PGI2

  • COX-3:

    • A splice variant of COX-1- in which intron 1 is retained, its role is uncertain but selectively inhibited by paracetamol.

Eicosanoids Functions

  • Drugs Targeting Arachidonic Acid Pathways:

    • Corticosteroids: Indirectly inhibit phospholipase A2- PLA2, providing anti-inflammatory effects; examples include prednisone and dexamethasone.

    • Anti-leukotriene drugs: Include 5-Lipoxygenase Inhibitors and Leukotriene Receptor Antagonists.

  • NSAIDs (Non-Steroidal Anti-Inflammatory Drugs):

    • Inhibit COX enzymes, leading to reduced prostaglandin synthesis, examples include ibuprofen and naproxen.

    • COX-1 & COX-2: ibuprofen, naproxen, diclofenac…

    • COX-2: celecoxib, rofecoxib…

    COX-mediated effects of NSAIDs

    Effects:

    1. Antipyretic

    2. Analgesic

    3. Anti-inflammatory

Side Effects of NSAIDs

  • Risk of gastric/duodenal ulcers due to loss of mucosal protection, bleeding from altered platelet function, among others.

Aspirin (Acetylsalicylic Acid)

  • A non-selective COX inhibitor with irreversible effects on both COX-1 and COX-2, leads to prolonged TXA2 suppression in platelets.

Selective COX-2 Inhibitors (Coxibs)

  • Designed to block inflammatory prostaglandin synthesis while preserving gastric mucosal protection, but increasing cardiovascular risk due to imbalance between PGI2 (COX-2) and TXA2 (COX-1).

Summary

  • The metabolism of arachidonic acid is pivotal in producing various eicosanoids that mediate inflammation and homeostasis, impacting health significantly.