Metabolism of Eicosanoids

ILOs
By the end of the course, the student should be able to:
1. Define eicosanoids.
2. Outline the cyclooxygenase and lipoxygenase pathways responsible for
the formation of the various classes of eicosanoids.
3. Describe the mechanism of action of anti-inflammatory and antiallergic
drugs on the pathway of eicosanoid synthesis.

1
-Eicosanoids are physiologically active compounds formed from polyunsaturated
fatty acids with C20 (C20 PUFA) e.g. arachidonic acid.
-Arachidonic acid is liberated from membrane phospholipids by phospholipase A2 or
synthesized from the essential fatty acid linoleate by desaturation and chain
elongation.

Eicosanoids are classified into two main groups:

1-Cyclic compounds: including, prostaglandins (PG), prostacyclins (PGI) and

thromboxanes (TX). These are formed from C20 PUFA eg. arachidonic acid by the
action of the enzyme prostaglandin H synthase. This enzyme has two activities;
cyclooxygenase (COX) and peroxidase.
- COX is present in two isoforms, COX-1 and COX-2. COX-1 is a constitutive
enzyme found in most tissues (mainly in gastric mucosa, platelets, vascular
endothelium and kidney). COX-2 is an inducible enzyme and is generated in
response to inflammation by activated macrophages and monocytes.

2-Acyclic compounds: including leukotrienes (LT) and the lipoxins (LX). These are
formed from from C20 PUFA by the action of lipoxygenase.

Diagram for Synthesis of Eicosanoids derivedfrom Arachidonic acid

Phospholipase A2
Phospholipids Lysophospholipids

Lipoxygenase Arachidonic acid

Prostaglandin H synthase
Prostacyclins Prostaglandin (H) Thromboxanes
(PGI2) Prostacyclin (PGH2) Thromboxane (TXA2)
synthase synthase
Isomerase
Reductase
PGE2 PGF2 
Leukotrienes (LTA4) LTC4 LCD4 LTE4

G-SH Glu Gly

Lipoxins (LXA4)

2
Effects of Some Eicosanoids

Type Site of Synthesis Main Functions

PGE2 Most tissues -Vasodilatation (decrease blood
pressure)
- Smooth muscle relaxation. In bronchi
it relieves bronchial asthma.
-Mediator of inflammatory reactions
which protect the body against infection
with production of vasodilatation,
hyperemia, edema, pain and fever

PGF2 Most tissues - Vasoconstriction

-Smooth muscle contraction (in bronchi
it may cause bronchoconstriction; in the
uterus it is used in induction od labour)
PGI2 Endothelium of - Vasodilatation
(Prostacyclin I2) blood vessels - Inhibits platelet aggregation
TXA2 Platelets - Vasoconstriction
(Thromboxane A2) - Platelet aggregation
Normally there is a balance between the
action of prostacyclins and
thromboxanes.

Leukocytes, - They stimulate migration of

platelets and mast eosinophils and neutrophils
cells (chemotaxis), making them the
Leukotrienes
principal mediators of
polymorphnuclear-infiltration in
inflammatory reactions.
- Components of slow-reacting
substance of anaphylaxis (SRS-A)
(severe allergic reaction that may
result in respiratory distress
(bronchoconstriction or spasm), low
blood pressure and shock)
Lipoxins Arterial walls -Anti-inflammatory
-Decrease immune response

3
Clinical Aspects (Anti-inflammatory and Antiallergic Drugs)
1- Steroidal anti-inflammatory drugs: They inhibit phospholipase A2 activity
(decrease availability of arachidonic acid) e.g. hydrocortisone, prednisone and
betamethasone.
2- Nonsteroidal anti-inflammatory drugs (NSAID): They inhibit prostaglandin
production by inhibiting cyclooxygenase, they include:
a- Aspirin is more potent inhibitors against COX-1 than COX-2. It inhibits the
cyclooxygenase by acetylation of the serine residue of the enzyme, thus decreasing
the synthesis of prostaglandins which act as messenger molecules in the process of
inflammation.
b- Other NSAIDs: inhibit cyclooxygenase by binding noncovalently to the enzyme
e.g. indomethacin and ibuprofen, they produce inhibition of the both COX-1 and
COX-2.
3- Singulair is leukotriene receptor antagonist, it blocks the action of leukotriene
LTD4, LTC4 and LTE4 on the cysteinyl leukotriene receptor, relieves bronchospasm
and inhibits allergic pathway (used to treat bronchial asthma and allergies).