EICOSANOIDS ( prostaglandins , thromboxanes , leukotrienes )
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Transcript of EICOSANOIDS ( prostaglandins , thromboxanes , leukotrienes )
EICOSANOIDSEICOSANOIDS
((prostaglandins, , thromboxanes, , leukotrienes))
EicosanoidsEicosanoids
EicosaniodsEicosaniods• 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
Major Classes of EicosanoidsMajor Classes of Eicosanoids
• Prostaglandins
• Thromboxanes
• Prostacyclins
• Leukotrienes
• HETES
• 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
Effects of EicosaniodsEffects of Eicosaniods
Precursors of EicosanoidsPrecursors of Eicosanoids
• Arachidonic acid (ω6)• Eicosatrienoic acid (-linolenic acid, ω6)
• Eicosapentaenoic Acid (ω3)
Dietary Linoleic Acid (C18: ∆9,12) (from plant oils)
Elongase
Desaturase
Arachidonic Acid (C20: ∆5, 8, 11,
14)
Membrane Phospholipids
Phosphatidyl choline
Arachidonic acid
Phospholipase A2 Ca++
Phosphatidylinositol bisphosphate
Phospholipase C
1,2 Diacylglycerol
Arachidonic acid Monoacylglycerol
DAG lipase
Arachidonic acid
MAG lipase
Arachidonic acid release from membrane Arachidonic acid release from membrane lipidslipids
Stimulus
Pathways for Arachidonic Acid MetabolismPathways for Arachidonic Acid Metabolism
Arachidonic acid
Cyclo-oxygenase Pathway
PGG2
ProstaglandinsThromboxanes
lipoxygenase Pathway
HPETE
Leukotrienes
HETE
Lipoxins
Prostaglandins – Structural FeaturesProstaglandins – 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
PGF 1, 2 or 3
Thromboxane AThromboxane A22 (TXA (TXA22) - structure) - structure
CYCLO-OXYGENASE CYCLO-OXYGENASE PATHWAY PATHWAY
PG and TX synthesisPG and TX synthesis
2GSH
2GSSG
PGD2PGD synthase
PGF2a
PGE 9-keto reductase
PGE2PGE synthase
PGI2PGI synthase
TXA2TXA synthase
Some Functions of ProstaglandinsSome Functions of Prostaglandins
PGI2, PGE2, PGD2
• ↑ Vasodilation, cAMP
• ↓ Platelet and leukocyte aggregation, IL1 and IL2, T-cell proliferation, lymphocyte migration
PGF2• ↑ Vasoconstriction, Bronchoconstriction,
smooth muscle contraction
TXA2
• ↑ Vasoconstriction, Platelet aggregation, lymphocyte proliferation, bronchoconstriction
LipoxygenaseLipoxygenase pathway pathway
Some Functions of LeukotrienesSome Functions of Leukotrienes
LTB4
• ↑ Vascular permeability, T-cell proliferation, leukocyte aggregation, IL -1, IL-2, IFN-
LTC4 and LTD4
• ↑ Bronchoconstriction, Vascular permeability, IFN-
• 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
Leukotrienes and allergiesLeukotrienes and allergies
Anti inflammatory Drugs inhibit Anti inflammatory Drugs inhibit Eicosanoid SynthesisEicosanoid Synthesis
LeukotrienesProstaglandins, thromboxanes
NSAIDs
Cyclo-oxyg
enase Lipoxygenase
Membrane lipids
Arachidonic Acid
Steroids
Phospholipase A2
Mechanism of Aspirin ActionMechanism of Aspirin Action
• 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
Aspirin and cardiovascular diseaseAspirin and cardiovascular disease
Omega-6/omega-3 fatty acid balance Omega-6/omega-3 fatty acid balance
• 6 and 3 are not interconvertible in humans (mammals).
• Diets rich in 3 fatty acids result in high content of these fatty acids in membrane phospholipids
Recommended ratio: 1-4: 1 (6 : 3)
Typical western diet: 14-25: 1 (6 : 3)
A diet rich in omega-6 FAs shifts the physiological state to one that is
proinflammatory, prothrombotic andproaggregatory… leading to heart disease
in susceptible individuals
Omega-6/omega-3 fatty acid balance Omega-6/omega-3 fatty acid balance
Thank you!Thank you!