Arachidonic Acid Pathway Lecture Notes

Overview

• Arachidonic Acid (AA): Precursor of bioactive lipid metabolites known as eicosanoids.
• Eicosanoids: Include prostaglandins, leukotrienes, and epoxyeicosatrienoic acids.
  • Pro-inflammatory, triggering oxidative stress and stimulating immune response.
• Pathway Intervention: Can be targeted to treat/manage inflammation.

Arachidonic Acid Pathway

1. Release: Arachidonic acid is released by phospholipase A2 from the membrane.
2. Pathway Options:
   • Reincorporation: Back into the phospholipid membrane.
   • Enzymatic Conversion: Into downstream bioactive metabolites via two pathways:
     • Lipoxygenase Pathway (LOX) – Left
     • Cyclooxygenase Pathway (COX) – Right

Lipoxygenase Pathway (LOX)

• Enzyme: 5-lipoxygenase converts AA into 5-HPETE.
• Conversion:
  • 5-HPETE to Leukotriene A4 (LTA4)
  • LTA4 can form:
    • Leukotriene C4, D4, E4: Increase bronchial tone.
    • Leukotriene B4: Involved in neutrophil chemotaxis.

Cyclooxygenase Pathway (COX)

• Enzymes: COX-1 and COX-2 convert AA into PGG2, then PGH2.
• PGH2 Conversion:
  • To Prostacyclin (PGI2)
  • To Prostaglandins (PGE1, PGE2, PGF2)
  • To Thromboxanes (TXA2, TXB2)

Functions of Bioactive Products

• Leukotriene B4: Neutrophil chemotaxis (mnemonic: LTB4 buses neutrophils).
• Leukotriene C4, D4, E4: Increase bronchial tone (mnemonic: CDE bronchial tone).
• Prostacyclin (PGI2): Decreases platelet aggregation, vasodilator.
• PGE1: Vasodilator.
• PGE2, PGF2: Increase uterine tone (mnemonic: EF2 uterine tone 2).
• Thromboxane A2 (TXA2): Increases platelet aggregation, vasoconstrictor.

Medications Affecting the Pathway

• Glucocorticoids: Inhibit phospholipase A2 (upstream action).
• NSAIDs: Inhibit COX-1.
• Celecoxib: Selectively inhibits COX-2 (fewer GI side effects).
• Epoprostenol, Carboprost, Dinoprostone, Alprostadil: Inhibit prostaglandins/prostacyclin (mnemonic: 'Prost' in name).
• Montelukast, Zafirlukast: Inhibit leukotrienes (mnemonic: Contains 'Luk').
• Zileuton: Inhibits 5-lipoxygenase (mnemonic: A to Z, inhibits LTA4).

Key Takeaways

• Important to understand pathways and functions of bioactive products.
• Medications and their inhibition effects are crucial for understanding inflammatory responses.
• If memorizing everything is difficult, remember that Leukotriene B4 is key for neutrophil chemotaxis.