Arachidonic Acid

Arachidonic acid (AA) is a 20-carbon polyunsaturated fatty acid (omega-6) that serves as the precursor for both Prostaglandins and Leukotrienes — two major classes of Mast Cell Mediators.

Where It Comes From

Arachidonic acid is stored in cell membrane phospholipids. When a mast cell is activated, the enzyme phospholipase A2 (PLA2) cleaves arachidonic acid from the membrane, making it available for conversion into inflammatory mediators.

This is why the delayed mediator release (minutes to hours after activation) takes time — the cell needs to liberate the precursor from its membrane and then enzymatically convert it.

The Two Pathways

Once freed from the membrane, arachidonic acid is processed by two competing enzyme systems:

COX Enzymes (COX-1, COX-2) → Prostaglandins and thromboxanes The products include PGD2 (the dominant mast cell prostaglandin), PGE2, PGF2α, and thromboxane A2.

5-Lipoxygenase (5-LOX) → Leukotrienes The products include LTA4, LTB4, and the cysteinyl leukotrienes LTC4, LTD4, LTE4.

These pathways compete for the same substrate. If one pathway is blocked (e.g., by NSAIDs inhibiting COX), more arachidonic acid is available for the other pathway. This is the biochemical basis of the NSAID shunt — COX inhibition increases leukotriene production.

Clinical Significance

Understanding arachidonic acid metabolism explains:

• Why NSAIDs are problematic in mast cell patients (pathway shunting)
• Why Montelukast targets a completely different arm of inflammation than antihistamines
• Why some dietary approaches focus on omega-6/omega-3 ratios (omega-3 fatty acids compete with arachidonic acid for the same enzymes, potentially reducing pro-inflammatory mediator production)