Eicosanoids
Asst. prof. S. Stoycheva
Department of Chemistry and Biochemistry
Biochemistry Section
MU-Pleven
Arachidonic acid
O
N
↓O
• Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega-6 fatty
acid 20:4(ω-6), or 20:4(5,8,11,14).
• Present in the phospholipids (especially phosphatidylethanolamine,
phosphatidylcholine, and phosphatidylinositides) of membranes of the
body's cells, and is abundant in the brain, muscles, and liver.
• Eicosanoids are signaling
molecules derived from the
oxidation of arachidonic acid.
• They play an important role in
mediating inflammatory responses,
and exert a wide spectrum of
biologic activity in different body
systems.
• Eicosanoids are not stored within
cells, and are synthesized as needed
when their biosynthesis is activated
by trauma or cytokines which
activate phospholipase A2 (PLA2).
• Fatty acids that are cleaved by
PLA2 from cell membranes are then
oxygenated by one of three
different families of enzymes to
produce eicosanoids.
General overview of synthesis pathways for eicosanoids
• The biosynthetic pathway
for the arachidonic acid-
derived eicosanoids.
• The figure shows the
structures of the relevant
eicosanoids (black), and
indicates the enzymes
involved in their
biosynthesis (blue), as well
as the GPCRs (G protein-
coupled receptors)
through which these
eicosanoids signal (red).
PGF2α can be synthesized
through a number of
different pathways.
Cyclooxygenase & Drugs Affecting the Prostanoid Pathway
• Cyclooxygenase (COX) is an enzyme that
catalyzes the rate-determining step in the
conversion of arachidonic acid to prostanoids by
a 2-step process involving oxygen.
• There are two known COX isozymes (COX-1 &
COX-2) that share 65% amino acid homology.
• Depending on the expression levels of tissue-
specific isomerases, COX activation results in the
formation of different prostanoids including
prostaglandins, prostacyclin or thromboxane.
• The cyclooxygenase cascade
• Arachidonic acid is converted by COX-1 or COX-2 to
an unstable intermediate prostaglandin H2 which is
converted to different biologically active
prostanoids depending on the presence of different
tissue-specific isomerases.
• Low dose aspirin has a selective effect to
irreversibly inhibit COX-1 (at higher doses, aspirin
also irreversibly inhibits COX-2).
• Most non-aspirin NSAIDs are relatively non-
selective & reversibly inhibit both COX-1 & COX-2.
• Coxibs are a subclass of NSAIDs that selectively &
reversibly inhibit COX-2.
Prostaglandin Effects are Mediated by GPCRs
• Most prostaglandins that are formed intracellularly by tissue
isomerases have relatively short half-lives (ranging from seconds
to minutes).
• All prostaglandins exert their effects at nearby membrane G-
protein coupled receptors (GPCRs).
• There are nine different prostaglandin receptor subtypes that
have been identified.
• Examples of signal transduction for two prostaglandins involved in
cardiovascular & platelet function.
• Signal transduction mechanisms responsible for mediating the
effects of PGI2 (prostacyclin) and TXA2 (thromboxane).
• Prostacyclin is produced by endothelial cells of the cardiovascular
system, while thromboxane is produced by platelets.
• Prostacyclin stimulates IP receptors in vascular smooth muscle &
platelets to produced a decrease in intracellular calcium, resulting
in vasodilation, and decreased platelet aggregation.
• In contrast, thromboxane stimulates TXA2 receptors to produce
an increase in intracellular calcium, resulting in vasoconstriction in
smooth muscle, and increased release of granules and
aggregation in platelets.
• Thromboxane can also induce changes in platelet shape (that
contribute to increases of platelet aggregation) by effects on Rho
kinase.
• Prostanoids serve as mediators of pain, fever &
inflammation.
• In addition, the conversion of arachidonic acid by
lipoxygenase (LOX) expressed in leukocytes is
involved in pulmonary inflammation and
bronchoconstriction in patients suffering from
asthma.
• COX-1: is constituitively expressed in most cells
& tissues, including the endothelial lining of the
GI tract, renal collecting tubules and platelets.
• COX-2: is not highly expressed in most tissues
under physiological conditions; however:
• There is significant basal COX-2 mediated
production of prostacylin (PGI2) in the vascular
endothelium of most blood vessels.
• COX-2 also serves an important role for normal renal
development and maintenance of renal physiology.
• COX-2 expression is upregulated by cytokines, and is
a major source of prostanoids produced during
inflammation and cancer.
Figure: COX, LOX and the therapeutic effects mediated
by NSAIDs & Leukotriene pathway inhibitors.
• https://www.youtube.com/watch?v=sUt7cnzJv1U
irreversible
NSAIDs inhibition
• The most commonly used drugs affecting the COX pathway are the non-steroidal anti-
inflammatory drugs (NSAIDs).
• All “classical” NSAIDs (e.g. aspirin, ibuprofen, naproxen) inhibit both COX-1 & COX-2.
• Low doses of aspirin selectively inhibit COX-1, while higher doses inhibit both isoforms.
• Aspirin's effects on COX are irreversible and result from covalent acetylation of serine residues in
the active sites of COX-1 & COX-2. The effects produced by other NSAIDs are reversible & are time-
dependent (they depend on the pharmacokinetics and dosing intervals of each particular NSAID).
• Inhibition of COX results in reduced synthesis of all prostanoids.
• NSAID therapeutic effects include reducing inflammation, fever, pain and platelet aggregation.
• NSAID side effects include effects on the GI tract, kidney and cardiovascular system.
COX-2 Selective Drugs (Coxibs)
• Coxibs are a subtype of NSAIDs that are selective inhibitors of the COX-2
isoform.
• Differences in the topography of the active sites for COX-1 vs COX-2 are
what permitted the development of drugs highly selective for inhibition of
COX-2.
• Because COX-2 is upregulated during inflammation, and is not highly
expressed in the GI tract, COX-2 drugs have the ability to produce an anti-
inflammatory effect with a lower incidence of GI side effects compared to
non-selective NSAIDs.
• The use of COX-2 selective inhibitors (coxibs) has been associated with an
increased risk of thrombosis, myocardial infarction & stroke.
• These health-risks are associated with the use of non-selective NSAIDs as
well, especially at higher doses.
Lipoxygenase/Leukotriene Pathway
• Activation of 5-lipoxygenase
(LOX) in (primarily expressed in
leukocytes) results in the
conversion of arachidonic acid
to leukotrienes that function as
inflammatory mediators resulting
in:
• bronchoconstriction
• increased secretion of mucus
• leukocyte chemotaxis
• histamine release
• This pathway has its greatest
clinical relevance in
the pathophysiology of asthma.
EETs
• The epoxyeicosatrienoic acids
(EETs) are eicosanoids produced
by cytochrome P450
epoxygenase.
• EETs act as “short range”
hormones in the cardiovascular
system & kidney where they
produce vasodilation by causing
activation of Ca-activated K
channels.
• The pathophysiology &
therapeutic relevance of EETs is
less well understood compared
to other eicosanoids.
• Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
infection leads to severe tissue damage, which releases cell
Eicosanoids and COVID-19 debris.
• Both primary infection and the accumulation of cell debris
initiate the endoplasmic reticulum (ER) stress response and up-
regulate inflammatory enzymes, including microsomal
prostaglandin E synthase-1 (mPGES-1) and prostaglandin-
endoperoxide synthase 2 [cyclooxygenase 2 (COX-2)], which
subsequently produce eicosanoids, including prostaglandins
(PGs), leukotrienes (LTs), and thromboxanes (TXs).
• These proinflammatory lipid autacoids induce cytokine storms
that mediate widespread inflammatory responses and organ
damage in severe coronavirus disease 2019 (COVID-19)
patients.
• By contrast, epoxyeicosatrienoic acids (EETs), which are
stabilized by inhibition of their metabolizing enzyme, soluble
epoxide hydrolase (sEH), are anti-inflammatory and proresolving
mediators that promote the termination (resolution) of
inflammation by suppressing the ER stress response,
inflammatory enzyme induction, and proinflammatory cytokine
production.
• EETs also shift arachidonic acid metabolism to favor the
production of specialized proresolving mediators (SPMs), which
initiate downstream anti-inflammatory and proresolving
programs.
• EETs and sEH inhibitors may counterregulate the unabated
systemic inflammatory response and organ failure associated
with COVID-19 infection.
• DHET, dihydroxyeicosatrienoic acid; TNF-α, tumor necrosis
factor-α.
Thank you!
