eicosanoids (,, ) eicosanoids (prostaglandins, thromboxanes, leukotrienes)

26
EICOSANOIDS EICOSANOIDS ( (prostaglandins , , thromboxanes , , leukotrienes ) )

Upload: felix-edwards

Post on 28-Dec-2015

231 views

Category:

Documents


2 download

TRANSCRIPT

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!