Eicosanoid Metabolism – Function & Clinical Relevance

What is Eicosanoid Metabolism?

Eicosanoid metabolism encompasses all biochemical processes involved in the synthesis, conversion, and degradation of eicosanoids. Eicosanoids are short-lived, lipid-based signalling molecules derived from polyunsaturated fatty acids (PUFAs) containing 20 carbon atoms – hence the name (from the Greek “eikosi” meaning twenty). The principal precursor fatty acids are arachidonic acid (derived from omega-6 fatty acids), eicosapentaenoic acid (EPA), and dihomo-gamma-linolenic acid (DGLA). Unlike classical hormones, eicosanoids act locally within tissues and cells rather than being transported through the bloodstream.

Major Groups of Eicosanoids

Eicosanoid metabolism generates four main classes of bioactive compounds:

• Prostaglandins: Regulate inflammation, pain sensation, fever, and smooth muscle contraction (e.g., in the uterus and blood vessels).
• Thromboxanes: Primarily promote platelet aggregation and vasoconstriction; thromboxane A2 plays a central role in blood clotting.
• Leukotrienes: Mainly involved in allergic and inflammatory reactions, especially in the lungs (asthma) and the immune system.
• Lipoxins: Exert anti-inflammatory effects and contribute to the resolution of inflammatory responses.

Biochemical Pathways

Eicosanoid metabolism proceeds primarily through three major enzymatic pathways:

Cyclooxygenase Pathway (COX Pathway)

The enzyme cyclooxygenase (COX), also known as prostaglandin endoperoxide synthase, converts arachidonic acid into prostaglandins and thromboxanes. Two isoforms exist: COX-1 (constitutive, always present) and COX-2 (inducible, upregulated during inflammation). Non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin and ibuprofen target these enzymes specifically.

Lipoxygenase Pathway (LOX Pathway)

Lipoxygenases (LOX) catalyse the conversion of arachidonic acid into leukotrienes and lipoxins. This pathway is particularly active in immune cells such as mast cells, basophils, and eosinophils and plays a key role in allergic reactions and asthma.

Cytochrome P450 Pathway

Cytochrome P450 enzymes convert arachidonic acid into epoxyeicosatrienoic acids (EETs) and hydroxyeicosatetraenoic acids (HETEs), which regulate blood pressure, renal function, and vascular tone, among other processes.

Role in Inflammation and the Immune System

Eicosanoids are central mediators of the inflammatory response. While prostaglandins and leukotrienes derived from arachidonic acid (omega-6) generally promote inflammation, EPA and DHA (omega-3 fatty acids) give rise to predominantly anti-inflammatory eicosanoids such as resolvins and protectins. The balance between omega-6 and omega-3 fatty acids in the diet therefore has a significant influence on whether pro-inflammatory or anti-inflammatory eicosanoids predominate.

Clinical Relevance

Disruptions in eicosanoid metabolism are implicated in numerous diseases:

• Bronchial asthma: Overproduction of leukotrienes leads to bronchospasm and mucosal swelling.
• Rheumatoid arthritis and other inflammatory conditions: Elevated prostaglandin E2 levels amplify pain and inflammation.
• Cardiovascular diseases: An imbalance between thromboxane A2 (vasoconstrictive, pro-thrombotic) and prostacyclin PGI2 (vasodilatory, anti-thrombotic) increases the risk of thrombosis.
• Allergies and atopic diseases: Leukotrienes trigger typical allergic symptoms.
• Cancer: COX-2 overexpression promotes tumour growth and metastasis in various cancer types.

Therapeutic Approaches

Many important medications specifically target eicosanoid metabolism:

• NSAIDs (e.g., ibuprofen, diclofenac, aspirin): Inhibit COX-1 and/or COX-2, reducing prostaglandin synthesis to achieve analgesic, antipyretic, and anti-inflammatory effects.
• COX-2 inhibitors (coxibs, e.g., celecoxib): Selective inhibition of COX-2 with a lower risk of gastrointestinal side effects compared to conventional NSAIDs.
• Leukotriene receptor antagonists (e.g., montelukast): Block leukotriene receptors and are used in the management of asthma and allergic rhinitis.
• Corticosteroids: Inhibit the release of arachidonic acid from cell membranes by blocking phospholipase A2, thereby reducing overall eicosanoid synthesis.
• Omega-3 fatty acid supplements: Shift the eicosanoid balance towards anti-inflammatory mediators.

Diet and Eicosanoid Metabolism

The composition of the diet directly influences eicosanoid metabolism. A Western-style diet high in omega-6 fatty acids (e.g., from sunflower oil and meat) favours the production of pro-inflammatory eicosanoids. A Mediterranean-style diet richer in omega-3 fatty acids (oily fish, flaxseeds, walnuts) shifts the balance towards anti-inflammatory compounds. Health authorities recommend an omega-6 to omega-3 ratio of ideally 4:1 or lower.

References

1. Funk, C.D. (2001): Prostaglandins and leukotrienes: advances in eicosanoid biology. In: Science, 294(5548), pp. 1871–1875. DOI: 10.1126/science.294.5548.1871
2. Calder, P.C. (2009): Polyunsaturated fatty acids and inflammatory processes: New twists in an old tale. In: Biochimie, 91(6), pp. 791–795. DOI: 10.1016/j.biochi.2009.01.008
3. Rang, H.P. et al. (2020): Rang & Dale's Pharmacology. 9th edition. Elsevier, Edinburgh.