Title: EICOSANOIDS (prostaglandins, thromboxanes, leukotrienes)
1EICOSANOIDS(prostaglandins, thromboxanes,
leukotrienes)
2Eicosanoids
- Major classes of eicosanoids.
- Precursors of eicosanoids.
- Major pathways of eicosanoid synthesis
(cyclooxygenase and lipoxygenase). - Important functions of eicosanoids.
- Important inhibitors of eicosanoid synthesis
3Eicosaniods
- Derived from 20-crabon polyunsaturated fatty
acids - Paracrine or autocrine messengers molecules
- Short half-lives (10 secs 5 mins) so that
functions are usually limited to actions on
nearby cells. - Bind to specific cell surface G-protein coupled
receptors, and generally increase cAMP levels.
May also bind to nuclear receptors and alter gene
transcription. - Wide variety of functions
4Major Classes of Eicosanoids
- Prostaglandins
- Thromboxanes
- Prostacyclins
- Leukotrienes
- HETES
5Effects of Eicosaniods
- Induction of inflammation
- Mediation of pain signals
- Induction of fever
- Smooth muscle contraction (including uterus)
- Smooth muscle relaxation
- Protection of stomach lining
- Simulation of platelet aggregation
- Inhibition of platelet aggregation
- Sodium and water retention
6Precursors of Eicosanoids
- Arachidonic acid (?6)
- Eicosatrienoic acid (g-linolenic acid, ?6)
- Eicosapentaenoic Acid (?3)
7- Dietary Linoleic Acid (C18 ?9,12) (from plant
oils)
8Arachidonic acid release from membrane lipids
Phosphatidyl choline
Phosphatidylinositol bisphosphate
9Pathways for Arachidonic Acid Metabolism
10Prostaglandins Structural Features
- PGA, PGD, PGE, PGF, PGG, PGH, PGI
- Depending on the functional groups present at X
and Y - PGF 1, 2 or 3
- Depending on the number of double bonds present
in the linear hydrocarbon chain
11PGF 1, 2 or 3
12Thromboxane A2 (TXA2) - structure
13CYCLO-OXYGENASE PATHWAY PG and TX synthesis
2GSH
2GSSG
14Some Functions of Prostaglandins
- PGI2, PGE2, PGD2
- ? Vasodilation, cAMP
- ? Platelet and leukocyte aggregation, IL1 and
IL2, T-cell proliferation, lymphocyte migration - PGF2a
- ? Vasoconstriction, Bronchoconstriction, smooth
muscle contraction - TXA2
- ? Vasoconstriction, Platelet aggregation,
lymphocyte proliferation, bronchoconstriction
15Lipoxygenase pathway
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17Some Functions of Leukotrienes
- LTB4
- ? Vascular permeability, T-cell proliferation,
leukocyte aggregation, IL -1, IL-2, IFN-g - LTC4 and LTD4
- ? Bronchoconstriction, Vascular permeability,
IFN-g
18Leukotrienes and allergies
- Leukotrienes are a hundred times more potent than
histamine - Histamine provided a rapid response to an
allergen - In the later stages leukotrienes are principally
responsible for - inflammation, smooth muscle constriction,
constriction of the airways and mucous secretion
form mucosal epithelium
19Anti inflammatory Drugs inhibit Eicosanoid
Synthesis
20Mechanism of Aspirin Action
21- COX-1 is constitutively expressed in nearly all
tissues responsible for normal physiological
functions - Little or no COX-2 is present in normal resting
cells. COX-2 is induced by inflammatory stimuli
(cytokines, bacterial lipopolysaccharides). - 20 of patients on long term NSAID treatment
develop gastric ulcers - It was postulated that inhibitors selective for
COX-2 should relieve pain and inflammation
without gastric complications
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23Aspirin and cardiovascular disease
- Low dose aspirin has an anti -thromobogenic
effect and lowers the risk of heart attacks and
strokes. - It inhibits the formation of TXA2 in platelets,
by inhibition of COX-1 which cannot be overcome
because platelets have no nucleus. - Endothelial cells have a nucleus and synthesis
more COX-1 enzyme needed for the normal
prostaglandin functions
24Omega-6/omega-3 fatty acid balance
- w6 and w3 are not interconvertible in humans
(mammals). - Diets rich in w3 fatty acids result in high
content of these fatty acids in membrane
phospholipids - Recommended ratio 1-4 1 (w6 w3)
- Typical western diet 14-25 1 (w6 w3)
25Omega-6/omega-3 fatty acid balance
A diet rich in omega-6 FAs shifts the
physiological state to one that is
proinflammatory, prothrombotic and proaggregatory
leading to heart disease in susceptible
individuals
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27Thank you!