lipoxygenase

**Arachidonic acid pathway** - Membrane phospholipids are cleaved by phospholipase A2 to release arachidonic acid. Corticosteroids inhibit PLA2 (via lipocortin/annexin-1), which blocks both the COX and LOX pathways. - Cyclooxygenase (COX-1/COX-2) makes prostaglandins, prostacyclin, and thromboxane. - Lipoxygenase makes leukotrienes and lipoxins.

**5-Lipoxygenase (5-LOX)** - Located in leukocytes (neutrophils, eosinophils, mast cells, macrophages, basophils). - It requires FLAP (5-lipoxygenase-activating protein) and Ca2+. - Steps: arachidonic acid → 5-HPETE → LTA4. - LTA4 is then converted to: - LTB4 (via LTA4 hydrolase). It is a potent neutrophil chemoattractant that also promotes adhesion. - LTC4 → LTD4 → LTE4 (the cysteinyl leukotrienes, formerly "slow-reacting substance of anaphylaxis"). They cause bronchoconstriction, increased vascular permeability, and mucus secretion, and they act on CysLT1 receptors.

**Other lipoxygenases** - 12-LOX (platelets) makes 12-HETE. - 15-LOX makes 15-HETE and, together with 5-LOX, lipoxins (LXA4, LXB4). Lipoxins are anti-inflammatory and pro-resolving. Aspirin-triggered lipoxins form after COX-2 acetylation.

**Clinical significance** - **Asthma:** Cysteinyl leukotrienes drive bronchoconstriction. - Zileuton inhibits 5-LOX. It is hepatotoxic, so monitor LFTs. - Montelukast and zafirlukast block CysLT1 receptors. Montelukast is useful in aspirin-exacerbated respiratory disease and exercise-induced asthma. It carries a boxed warning for neuropsychiatric events. - **Aspirin-exacerbated respiratory disease (Samter triad: asthma, nasal polyps, aspirin sensitivity):** COX inhibition shunts arachidonic acid toward the LOX pathway, so leukotriene production rises and bronchospasm results. - **Inflammation and allergy:** LTB4 recruits neutrophils. Cysteinyl leukotrienes contribute to anaphylaxis and allergic rhinitis. - **Other roles:** 15-LOX is implicated in oxidation of LDL in atherosclerosis. A deficiency of 12R-LOXand eLOX3 (ALOXE3/ALOX12B) causes autosomal recessive congenital ichthyosis.

**High-yield pearls** - Corticosteroids block everything upstream (PLA2). NSAIDs block only COX. Zileuton blocks only 5-LOX. - LTB4 = neutrophil chemotaxis. LTC4/D4/E4 = bronchoconstriction and vasodilation with increased permeability. - Mnemonic: "LTB4 is Because of neutrophils; C4, D4, E4 are the Cysteinyl (Constrict) ones."