EICOSANOIDS

Eicosanoids are signaling molecules made by the enzymatic or non-enzymatic oxidation

of arachidonic acid or other polyunsaturated fatty acids (PUFAs) that are similar to
arachidonic acid, around 20 carbon units in length. The main classes of Eicosanoids
include prostaglandins, thromboxanes , leukotrienes, and lipoxins, each involved in
distinct cellular functions and pathways. Eicosanoids exert their effects by binding to
specific receptors on the surfaces of target cells, thereby influencing cellular activity
and contributing to the regulation of biological responses.
Eicosanoids function in diverse physiological systems and pathological processes by
acting as autocrine signaling agents to impact their cells of origin or as paracrine
signaling agents to impact cells in the proximity of their cells of origin. Such processes
include; immune responses, regulating the abortion of pregnancy, regulating childbirth,
contributing to perceptions of pain, regulating cell growth.

STRUCTURE OF EICOSANOIDS

Generally, Eicosanoids are derived from 20-carbon (eicosa) polyunsaturated fatty acids,
most frequently Arachidonic acid.

Arachidonic Acid

Eicosanoids are divided into four main classes based on their structure;

Prostaglandins
Thromboxanes
Leukotrienes
Lipoxins
Structure Of Prostaglandins

Prostaglandins have a 20-carbon skeleton that includes cyclopentane (a five-membered

carbon ring). The basic framework of prostaglandins is the prostanoic acid skeleton,
consisting of a cyclopentane ring with two side chains (one alpha chain and one omega
chain).

Prostaglandins
Structure Of Thromboxanes
Thromboxanes have a unique structure compared to other eicosanoids, characterized by a
six-membered ether-containing ring. The thromboxane structure is based on a 20-carbon
skeleton derived from arachidonic acid. The defining feature is Oxane, a six-membered ring
with an oxygen atom.

Thromboxane

Stucture Of Leukotrienes

Leukotrienes are based on a 20-carbon skeleton derived from arachidonic acid. They have
a characteristic linear structure, with conjugated double bonds (triene) and specific
functional groups that determine their biological activity.
Types Of Leukotrienes

LTA4 - Contains an epoxide group within the conjugated triene system. It has a formula of
C20H30O3

LTA4

LTB4 – Derived from LTA4 by the addition of a hydroxyl group. The hydroxyl group is located
at carbon 12.

LTB4

LTC4 - Derived from LTA4 by conjugation with glutathione. Contains a cysteinyl-leukotriene

structure.

LTC4
LTD4 - Formed from LTC4 by removal of the glutamic acid residue. Contains a cysteinyl-
leukotriene structure with an amino acid modification

LTD4

LTE4 - Formed from LTD4 by removal of the glycine residue. Contains a cysteinyl-
leukotriene structure with an amino acid modification.

LTE4

Structure Of Lipoxins
Lipoxins are derived enzymatically from arachidonic acid, an ω-6 fatty acid. Structurally,
they are defined as arachidonic acid metabolites that contain three hydroxyl residues and
four double bonds.
 Lipoxin

SYNTHESIS OF EICOSANOIDS

Eicosanoids typically are not stored within cells but rather synthesized as required. They
derive from the fatty acids that make up the cell membrane and nuclear membrane. These
fatty acids must be released from their membrane sites and then metabolized initially to
products which most often are further metabolized through various pathways to make the
large array of products we recognize as bioactive eicosanoids. The key enzymes involved in
eicosanoid biosynthesis are cyclooxygenases (COX), lipoxygenases (LOX), and
cytochrome P450 (CYP) enzymes.

Cyclooxygenase (COX) Pathway

The COX pathway is responsible for the production of prostaglandins (PGs) and
Thromboxanes(TXs) from Arachidonic Acid. This pathway is initiated by the enzyme
phospholipase A2 (PLA2), which cleaves Arachidonfrom the phospholipid membrane. The
free Arachidonic Acid is then converted into prostaglandin G2 (PGG2) through a series of
enzymatic reactions.
Lipoxygenase (LOX) Pathway
The Lipoxygenase pathway involves the enzymatic oxidation of Arachidonic Acid,
eicosapentaenoic acid, or docosahexaenoic acid by lipoxygenase enzymes. Lipoxygenase
enzymes are classified based on their positional specificity of oxygenation on the fatty acid
chain. For example, 5-lipoxygenase (5-LOX) primarily acts on Arachidonic Acid, while 15-
lipoxygenase (15-LOX) acts on both Arachidonic Acid and eicosapentaenoic acid.
In the Lipoxygenase pathway, the fatty acid is converted into hydroperoxyeicosatetraenoic
acids (HPETEs), which serve as intermediates for the synthesis of leukotrienes and
lipoxins. 5-LOX converts Arachidonic Acid to 5-HPETE, which is further metabolized into
leukotriene A4 (LTA4). LTA4 can be enzymatically converted into various leukotrienes, such
as leukotriene B4 (LTB4), leukotriene C4 (LTC4), and leukotriene D4 (LTD4).

Cytochrome P450 (CYP) Pathway

The CYP route entails the cytochrome P450 enzymes' metabolism of PUFAs, mainly
Arachidonic Acid. In order to create epoxyeicosatrienoic acids (EETs) and
hydroxyeicosatetraenoic acids (HETEs), these enzymes catalyze the oxygenation of
Arachidonic Acid.
MECHANISMS OF ACTION OF EICOSANOIDS
Understanding the mechanisms of eicosanoids is crucial for developing targeted therapies
for inflammatory and cardiovascular diseases.
Eicosanoids primarily act through G-protein-coupled receptors (GPCRs). Different classes
of eicosanoids have specific receptors:
Prostaglandins: EP, FP, IP, DP, TP receptors
Thromboxanes: TP receptors
Leukotrienes: BLT and CysLT receptors Lipoxins: ALX/FPR2 receptors
Interaction with Receptors:
Prostaglandins (e.g., PGE2) bind to EP receptors (EP1, EP2, EP3, EP4). Signal Transduction
Pathways:
EP1: Increases intracellular calcium.
EP2 and EP4: Activate adenylate cyclase, increasing cAMP.
EP3: Inhibits adenylate cyclase, decreasing cAMP.
Example: PGE2 binding to EP2 receptor activates adenylate cyclase, increasing cAMP
levels, leading to vasodilation and inhibition of platelet aggregation.
Thromboxane A2 (TXA2) binds to TP receptors on platelets and smooth muscle cells.
Signal Transduction Pathways:
Activates phospholipase C (PLC), leading to the production of inositol triphosphate (IP3)
and diacylglycerol (DAG).
IP3 increases intracellular calcium, promoting platelet aggregation and vasoconstriction.
Example: TXA2 binding to TP receptor results in increased calcium levels in platelets,
leading to aggregation.
Leukotrienes (e.g., LTB4) bind to BLT receptors (BLT1, BLT2).
Signal Transduction Pathways:
BLT1: Activates G-proteins, leading to chemotaxis and activation of immune cells. CysLT1
and CysLT2: Induce bronchoconstriction and increase vascular permeability. Example:
LTB4 binding to BLT1 receptor attracts neutrophils to sites of inflammation.
Lipoxin A4 (LXA4) binds to the ALX/FPR2 receptor.
Signal Transduction Pathways:
ALX/FPR2: Modulates immune cell activity, reducing inflammation and promoting
resolution. Example: LXA4 binding to ALX receptor inhibits leukocyte recruitment and
promotes clearance of inflammatory cells.

FUNCTIONS OF EICOSANOIDS
Eicosanoids are involved in various physiological processes such as inflammation,
immunity, pain modulation, blood clotting, and smooth muscle function.

Prostaglandins
PGE2
<Inflammation: Causes vasodilation and increased vascular permeability.
<Pain and Fever: Sensitizes pain receptors and raises body temperature.
<Gastrointestinal Protection: Reduces gastric acid secretion and increases mucus
production.
PGD2
<Allergic Responses: Involved in asthma and allergies.
<Sleep Regulation: Promotes sleep.
PGF2α
<Uterine Contraction: Induces labor.
<Bronchoconstriction: Affects bronchial muscle tone.
PGI2 (Prostacyclin)
<Vasodilation: Lowers blood pressure.
<Inhibits Platelet Aggregation: Prevents clot formation.
Leukotrienes
LTB4
<Chemotaxis: Attracts immune cells to inflammation sites.
<Leukocyte Activation: Enhances the immune response.
Cysteinyl Leukotrienes (LTC4, LTD4, LTE4)
<Bronchoconstriction: Contributes to asthma.
<Increased Vascular Permeability and Mucus Production: Leads to edema and mucus
secretion.
Lipoxins
LXA4 and LXB4
<Resolution of Inflammation: Promote the clearance of immune cells and inhibit further
recruitment.

REGULATIONS OF EICOSANOIDS

The regulation of eicosanoids involves multiple levels of control to maintain homeostasis

and respond appropriately to physiological and pathological stimuli. Here are the main
regulatory mechanisms:
1.Factors Influencing Synthesis:
Cytokines: Inflammatory cytokines, such as interleukin-1β (IL-1β) and tumor necrosis
factor- alpha (TNF-α), stimulate eicosanoid synthesis by upregulating enzyme expression
and increasing substrate availability.
Hormonal Regulation: Hormones such as glucocorticoids can suppress eicosanoid
synthesis by inhibiting the expression of COX-2 and other inflammatory enzymes

2. Inhibition by Drugs:
Pharmacological agents such as nonsteroidal anti-inflammatory drugs (NSAIDs) and
selective COX-2 inhibitors can inhibit eicosanoid synthesis by blocking the activity of COX
enzymes. NSAIDs, including aspirin, ibuprofen, and naproxen, inhibit both COX-1 and
COX-2 enzymes, while COX-2 inhibitors selectively target COX-2, reducing inflammation
and pain.

3. Autoregulation of Synthesis:
Some eicosanoids, such as prostaglandins, can regulate their own synthesis through
negative feedback mechanisms. For example, certain prostaglandins inhibit the
expression or activity of enzymes involved in their synthesis to prevent excessive
production.

4.Downregulation of Receptors:
Prolonged exposure to high levels of eicosanoids can lead to downregulation of their
receptors on target cells, reducing cellular responsiveness to these signaling molecules.
5. Desensitization Mechanisms:
Cells can develop desensitization mechanisms to dampen their response to continuous
stimulation by eicosanoids, helping to prevent overactivation of signaling pathways.

6.Regulation of COX and LOX Enzymes:

The expression and activity of COX and LOX enzymes are regulated by various factors,
including cytokines, hormones, and dietary factors.
Inflammatory stimuli can induce the upregulation of COX-2 expression, leading to
increased prostaglandin production during inflammation.
CLINICAL SIGNIFICANCE OF EICOSANOIDS
Understanding their clinical significance is crucial for both diagnosis and treatment
strategies.
Eicosanoids in Disease States:

Inflammation: Eicosanoids, particularly prostaglandins and leukotrienes, are central

mediators of inflammation, contributing to the hallmark symptoms of redness, swelling,
heat, and pain. -Excessive or dysregulated eicosanoid production can lead to chronic
inflammatory conditions such as rheumatoid arthritis, inflammatory bowel disease, and
psoriasis.
Cardiovascular Disease: Eicosanoids, including thromboxanes and prostacyclins, play
pivotal roles in regulating vascular tone, platelet aggregation, and thrombosis.
-Imbalances in the synthesis or action of these eicosanoids contribute to the pathogenesis
of cardiovascular diseases such as hypertension, atherosclerosis, and myocardial
infarction.
Cancer: Eicosanoids, especially prostaglandins, have been implicated in various stages of
cancer development and progression, including tumor initiation, promotion, angiogenesis,
and metastasis.
Prostaglandins promote tumor cell proliferation, survival, and invasiveness, and their
levels are often elevated in various cancers, including colorectal, breast, and prostate
cancer.
Therapeutic Applications:

Nonsteroidal Anti-inflammatory Drugs (NSAIDs):

NSAIDs, such as aspirin, ibuprofen, and naproxen, exert their anti-inflammatory and
analgesic effects by inhibiting COX enzymes, thereby reducing the synthesis of
prostaglandins.
-Leukotriene Inhibitors are used as maintenance therapy in asthma management,
particularly in patients with allergic asthma.
CONCLUSION

In summary, eicosanoids are crucial signaling molecules derived from polyunsaturated

fatty acids, particularly arachidonic acid. They play diverse and vital roles in maintaining
physiological homeostasis and mediating pathological processes such as inflammation,
immunity, and thrombosis.
We have seen how prostaglandins, thromboxanes, leukotrienes, and lipoxins each
contribute uniquely to cellular responses and how their synthesis is tightly regulated by
enzymatic activity and gene expression. The clinical relevance of eicosanoids is
underscored by their involvement in a range of diseases, from asthma to cardiovascular
disorders, making them significant targets for therapeutic intervention.

REFERENCES
Biochemistry by Jeremy M. Berg, John L. Tymoczko, and Lubert Stryer (2015).
Lehninger Principles of Biochemistry by David L. Nelson and Michael M. Cox (2021).
NCBI Bookshelf - Arachidonic Acid Metabolism. Available at: NCBI Bookshelf.