Eicosanoids

1. Presented By:
Supta Sarkar
HHM-2013-10
M.Sc Foods & Nutrition

2. LOOK INSIDE…
• Introduction
• Classification
• Biosynthesis
-Prostanoid pathway
-Leukotriene pathway
• Functions
• Application
• Conclusion

3. INTRODUCTION
• "Eicosanoid" is derived from a Greek word “eicosa”
meaning "twenty”.
• Eicosanoids is the collective term for the signaling
molecules made by oxidation.
• Eicosanoids are oxygenated derivatives of 3
different 20-carbon fatty acids:
1. Eicosapentanoic acid
2. Arachidonic acid
3. Di-homo-gamma-linolenic acid

4. • Eicosapentaenoic acid (EPA), an ω-3 fatty acid
with 5 double bonds;
• Arachidonic acid (AA), an ω-6 fatty acid, with 4
double bonds;
• Dihomo-gamma-linolenic acid (DGLA), an ω-6,
with 3 double bonds.
Eicosanoids are derived from either omega-3
(ω-3) or omega-6 (ω-6) fatty acids.

5. CLASSIFICATION
• Eicosanoids are classified into two main
groups-
1) Prostanoids
2) Leukotrienes and Lipoxins
• Prostanoids are further sub-classified into
three groups-
a) Prostaglandins(PGs)
b) Prostacyclins(PGIs)
c) Thromboxanes (TXs)

6. BIOSYNTHESIS
• Two families of enzyme catalyze fatty acid
oxygenation to produce the eicosanoids:
• Cyclooxygenase, or COX, generates
the prostanoids.
• Lipoxygenase, or LOX, in several forms.
* 5-lipoxygenase (5-LO) generates the
leukotrienes and via transcellular biosynthesis is
also involved in lipoxin generation.

7. • Eicosanoids are not stored within cells, but
are synthesized as required.
• Derive from the fatty acids that make up the cell
membrane and nuclear membrane.
• Eicosanoid biosynthesis begins when a cell is
activated by mechanical trauma, cytokines, growth
factors or other stimuli. (The stimulus may even be
an eicosanoid from a neighboring cell.)
• This triggers the release of a phospholipase at
the cell membrane.
• The phospholipase travels to the nuclear membrane.
• There, the phospholipase catalyzes
ester hydrolysis of phospholipid or diacylglycerol
(by phospholipase C).
• This frees a 20-carbon fatty acid.

8. • This hydrolysis appears to be the rate-
determining step for eicosanoid formation.
• The fatty acids may be released by any of several
phospholipases.
• Of these, type IV cytosolic phospholipase
A2 (cPLA2) is the key actor, as cells lacking
cPLA2 are, in general, devoid of eicosanoid
synthesis.
• The phospholipase cPLA2 is specific for
phospholipids that contain AA, EPA or GPLA at
the SN2 position.
• Interestingly, cPLA2 may also release the
lysophospholipid that becomes platelet-activating
factor.

9. PROSTANOID PATHWAYS
• Cyclooxygenase (COX) catalyzes the conversion of
the free fatty acids to prostanoids by a two-step
process.
• First, two molecules of O2 are added as two
peroxide linkages, and a 5-member carbon ring is
forged near the middle of the fatty acid chain. This
forms the short-lived, unstable intermediate
Prostaglandin G (PGG).
• Next, one of the peroxide linkages sheds a single
oxygen, forming PGH.

10. • All three classes of prostanoids originate from PGH.
All have distinctive rings in the center of the
molecule. They differ in their structures.
• The derived prostaglandins contain a single,
unsaturated 5-carbon ring.
• In prostacyclins, this ring is conjoined to another
oxygen-containing ring. In thromboxanes the ring
becomes a 6-member ring with one oxygen.
• The leukotrienes do not have rings.
• Several drugs lower inflammation by blocking
prostanoid synthesis

12. LEUKOTRIENE PATHWAYS
• The enzyme 5-lipoxygenase (5-LO) uses 5-
lipoxygenase activating protein (FLAP) to
convert arachidonic acid into 5-
Hydroperoxyeicosatetraenoic acid (5-HPETE),
which spontaneously reduces to 5-
hydroxyeicosatetraenoic acid (5-HETE).
• The enzyme LTA synthase acts on 5-HPETE to
convert it into leukotriene A4 (LTA4), which may be
converted into LTB4 by the enzyme leukotriene A4
epoxide hydrolase.

13. • Eosinophils, mast cells, and alveolar macrophages
use the enzyme leukotriene C4 synthase to
conjugate glutathione with LTA4 to make LTC4,
which is transported outside the cell, where
a glutamic acid moiety is removed from it to
make LTD4.
• The leukotriene LTD4 is then cleaved by
dipeptidases to make LTE4.
• The leukotrienes LTC4, LTD4 and LTE4 all contain
cysteine and are collectively known as the
cysteinyl leukotrienes.

15. FUNCTION
• Eicosanoids exert complex control over many
bodily systems, mainly in inflammation or
immunity, and as messengers in the central
nervous system.
• They are found in most living things.
• In humans, eicosanoids are local hormones that
are released by most cells, act on that same cell
or nearby cells (i.e., they are autocrine and
paracrine mediators), and then are rapidly
inactivated.

16. On the basis of functions eicosanoids
are again said as 2 types:

17. FUNCTIONS BASED ON FATTY ACID
DERIVATION:

18. Action of prostanoids
• Prostanoids mediate local symptoms
of inflammation: vasoconstriction or vasodilation,
coagulation, pain and fever.
• COX-2 is responsible for pain and inflammation,
while COX-1 is responsible for platelet clotting
actions.
• Inhibition of cyclooxygenase, specifically the
inducible COX-2 isoform, is the hallmark
of NSAIDs (non-steroidal anti-inflammatory
drugs).
• Prostanoids activate the PPARγ members of the
steroid/thyroid family of nuclear hormone
receptors, directly influencing gene transcription.

19. *Aspirin inhibits the COX pathway and consequently
diverts arachidonic acid metabolites to the LO
pathway.
*This also leads to a decrease in the
levels of PGE2, the anti-inflammatory PG.
*LTC4 synthase overexpression further increases the
number of cysteinyl LTs, tilting the balance toward
inflammation and broncho constriction causing
asthma
Role of Aspirin in Inflammation & Broncho-
constriction

20. Role of Aspirin in inflammation &
Broncho-constriction:

21. Action of leukotrienes
• Leukotrienes play an important role in
inflammation. There is a neuroendocrine role
for LTC4 in luteinizing hormone secretion.
• LTB4 causes adhesion and chemotaxis of
leukocytes and stimulates aggregation,
enzyme release, and generation
of superoxide in neutrophils.
• Blocking leukotriene receptors can play a role
in the management of inflammatory diseases
such as asthma (by the drugs montelukast and
zafirlukast), psoriasis, and rheumatoid
arthritis.

22. • The slow reacting substance of anaphylaxis comprises
the cysteinyl leukotrienes. These have a clear role
in pathophysiological conditions such as
asthma,allergic rhinitis and other nasal allergies, and
have been implicated in atherosclerosis and
inflammatory gastrointestinal diseases.
• They are potent bronchoconstrictors, increase vascular
permeability in postcapillary venules, and
stimulate mucus secretion. They are released from the
lung tissue of asthmatic subjects exposed to specific
allergens and play a pathophysiological role
in immediate hypersensitivity reactions.
• Along with PGD, they function in effector
cell[disambiguation needed] trafficking, antigen presentation,
immune cell activation, matrix deposition, and fibrosis.

23. Eicosanoid
Major site(s) of
synthesis
Major biological activities
PGD2
mast cells,
eosinophils, brain
Induces inflammatory responses principally by
recruiting eosinophils and basophils; induces
bronchoconstriction; involved in androgenetic
alopecia, inhibitors of PGD2 being studied to treat
male pattern baldness
PGE1
Induces vasodilation and inhibits platelet
aggregation
PGE2
kidney, spleen,
heart
Increases vasodilation and camp production,
enhancement of the effects of bradykinin and
histamine, induction of uterine contractions and of
platelet aggregation, maintaining the open
passageway of the fetal ductus arteriosus;
decreases t-cell proliferation and lymphocyte
migration and secretion of il-1α and IL-2

24. Eicosanoid Major site(s) of synthesis Major biological activities
PGF2α kidney, spleen, heart
increases vasoconstriction,
bronchoconstriction and smooth muscle
contraction
PGH2
precursor to thromboxanes A2 and B2,
induction of platelet aggregation and
vasoconstriction
PGI2
heart, vascular
endothelial cells
inhibits platelet and leukocyte aggregation,
decreases T-cell proliferation and
lymphocyte migration and secretion of IL-1α
and IL-2; induces vasodilation and
production of cAMP
TXA1
induces vasodilation and inhibits platelet
aggregation
TXA2 platelets
induces platelet aggregation,
vasoconstriction, lymphocyte proliferation
and bronchoconstriction
TXB2 platelets induces vasoconstriction

25. Eicosanoid Major site(s) of synthesis Major biological activities
LTB4
monocytes, basophils,
neutrophils, eosinophils,
mast cells, epithelial cells
powerful inducer of leukocyte chemotaxis
and aggregation, vascular permeability, T-
cell proliferation and secretion of INF-γ, IL-1
and IL-2
LTC4
monocytes and alveolar
macrophages, basophils,
eosinophils, mast cells,
epithelial cells
component of SRS-A, microvascular
vasoconstrictor, vascular permeability and
bronchoconstriction and secretion of INF-γ,
recruitment of leukocytes to sites of
inflammation, enhance mucus secretions in
gut and airway
LTD4
monocytes and alveolar
macrophages, eosinophils,
mast cells, epithelial cells
same as LTC4
LTE4 mast cells and basophils same as LTC4
**SRS-A = slow-reactive substance of anaphylaxis

26. Pharmacological applications of Eicosanoids
• Cardiovascular uses- pulmonary arterial hypertension,
peripheral vascular disease. For keeping the ductus arteriosus
open until surgery in neonates carrying certain cardiac
malformations and platelet anti-aggregating agents.
• Digestive Uses- indicated in the treatment of gastro duodenal
ulcer and for the prevention of NSAID-induced ulcers.
• Gynecological and obstetrical uses - They induce cervical
dilatation and uterine contractions, particularly in late
pregnancy. Used for medical termination of pregnancy and
induction of labour.

27. • Ophthalmologic Use- lower intraocular pressure.
• Anti- inflammatory use- Inhibitors of cyclo-
oxygenases have anti-inflammatory properties
and include nonsteroidal anti-inflammatory drugs
or NSAID. The useful effects in therapeutics are-
anti-inflammatory effect
analgesic effect
antipyretic effect
inhibition of platelet aggregation and decrease of
thromboembolic risk (well-known with aspirin at
low doses)

28. • Ulcerative Colitis- Mesalamine also called mesalazine
or 5 aminosalicyclic acid has antiinflammatory
properties in the colon and is used in the treatment of
ulcerative colitis (Crohn's disease). Its mechanism of
action is complex and as yet incompletely known: in
addition to cyclo-oxygenases, it also inhibits
lipoxygenases.
• Bronchial Asthma- PGE2 agonists and leukotrienes
receptor antagonists are used for the treatment of
bronchial asthma.

29. SUMMARY:

30. CONCLUSION
Eicosanoids are oxygenated derivatives of 3 different 20-
carbon fatty acids
Eicosanoids are classified in to 2 main groups:
Prostanoids, and Leukotrienes & Lipoxins
COX & LOX enzymes catalyze fatty acid oxygenation to
produce the eicosanoids.
Exert complex control over many bodily systems, mainly
in inflammation or immunity, and as messengers in
the CNS.