27.4 Prostaglandins and Other Eicosanoids

Prostaglandins and eicosanoids are lipid molecules that act as local hormones in our bodies. They're involved in many processes, from inflammation to blood clotting, and are made from a fatty acid called arachidonic acid.

These compounds are produced by two main pathways: cyclooxygenase (COX) and lipoxygenase (LOX). Understanding how they're made and work helps us grasp their role in health and disease, as well as how certain medications affect our bodies.

Prostaglandins and Other Eicosanoids

Structure and effects of prostaglandins

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• Prostaglandins are a class of eicosanoids derived from arachidonic acid
  • Contain a cyclopentane ring and two side chains
  • Designated by the letters A through I, depending on the structure of the cyclopentane ring (PGE2, PGF2α)
• Prostaglandins act as local hormones, regulating various physiological processes
  • Inflammatory response
    • Some prostaglandins promote inflammation (PGE2, PGF2α)
    • Others have anti-inflammatory effects (PGE1)
  • Smooth muscle contraction and relaxation
    • PGE2 and PGI2 cause vasodilation and bronchodilation
    • PGF2α causes vasoconstriction and bronchoconstriction
  • Platelet aggregation
    • TXA2 promotes platelet aggregation
    • PGI2 inhibits platelet aggregation
  • Gastrointestinal protection
    • PGE2 and PGI2 protect the stomach lining from acid and ulcers
  • Renal function
    • PGE2 and PGI2 regulate renal blood flow and electrolyte balance
  • Reproductive processes
    • PGE2 and PGF2α are involved in ovulation, menstruation, and labor induction

Biosynthesis of eicosanoids

• Arachidonic acid is released from cell membrane phospholipids by phospholipase A2
  • Arachidonic acid is derived from omega-6 fatty acids in the diet
• Cyclooxygenase (COX) pathway
  1. Arachidonic acid is converted to prostaglandin H2 (PGH2) by COX enzymes
     • Two isoforms: COX-1 (constitutive) and COX-2 (inducible)
  2. PGH2 is further metabolized by specific synthases to form various prostaglandins and thromboxanes
     • Prostaglandin E2 (PGE2) by PGE synthase
     • Prostaglandin F2α (PGF2α) by PGF synthase
     • Prostaglandin I2 (PGI2 or prostacyclin) by prostacyclin synthase
     • Thromboxane A2 (TXA2) by thromboxane synthase
• Lipoxygenase (LOX) pathway
  1. Arachidonic acid is converted to hydroperoxyeicosatetraenoic acids (HPETEs) by LOX enzymes
     • 5-LOX, 12-LOX, and 15-LOX
  2. HPETEs are further metabolized to form leukotrienes and lipoxins
     • Leukotriene A4 (LTA4) is converted to LTB4, LTC4, LTD4, and LTE4
     • Lipoxins (LXA4 and LXB4) are formed from 15-HPETE

COX-1 vs COX-2 in prostaglandin production

• COX-1 (cyclooxygenase-1)
  • Constitutively expressed in most tissues
  • Involved in the production of prostaglandins for homeostatic functions
    • Gastrointestinal protection
    • Platelet aggregation
    • Renal function
• COX-2 (cyclooxygenase-2)
  • Inducible enzyme, expressed in response to inflammatory stimuli
  • Primarily involved in the production of prostaglandins during inflammation
    • Mediates pain, fever, and swelling
• Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit COX enzymes
  • Non-selective NSAIDs (aspirin, ibuprofen) inhibit both COX-1 and COX-2
    • Effective in reducing inflammation but may cause gastrointestinal side effects due to COX-1 inhibition
  • Selective COX-2 inhibitors (celecoxib) specifically target COX-2
    • Reduce inflammation with fewer gastrointestinal side effects
    • May increase the risk of cardiovascular events

Eicosanoids as Lipid Mediators in Cell Signaling

• Eicosanoids function as lipid mediators in various cellular processes
• They play crucial roles in cell signaling pathways related to inflammation and immune responses
• Eicosanoids act through specific G protein-coupled receptors to initiate intracellular signaling cascades
• The biosynthesis and release of eicosanoids are tightly regulated to maintain physiological balance
• Dysregulation of eicosanoid signaling can contribute to various pathological conditions