Eicosanoids Flashcards
What is the major site of synthesis of PGI2 (prostacyclin)
Endothelium of blood vessels
What are the major biological activities of PGI2? (prostacyclin)
Vasodilation;
Inhibits platelet aggregation;
Increases formation of cAMP
What is the major site of synthesis of TXA2 (thromboxane A2)?
Platelets
What are the major biological activities of TXA2?
Promotes platelet aggregation; Decreases formation of cAMP; Vasoconstriction; Mobilizes intracellular Ca2+; Contraction of smooth muscle
Within the cell, what part of membrane phospholipids does arachidonic acid predominantly reside?
C-2 position
Activation of what releases Arachidonic Acid from the membrane phospholipid?
Phospholipase A2
Where are minor eicosanoids derived from?
Alpha-linolenic acid
Which enzyme cleaves PIP2 to generate IP3 and DAG?
Phospholipase C
Which enzyme cleaves PIP2 to generate Arachidonic acid and Lyso-PIP2?
Phospholipase A2;
Note: arachidonic acid released on cytoplasmic side of membrane
What is the rate limiting enzyme in prostaglandin and thromboxane synthesis?
Cyclooxygenase
What inhibits Phospholipase A2?
Corticosteroids (I.e. cortisol)
How does Asprin inhibit COX?
Irreversibly by acetylation
What does Asprin acetylate during inhibition of COX?
Serine residue in the active site
Arachidonic acid gets converted to what? By which enzyme? (in the synthesis of prostaglandins and thromboxanes)
PGG2;
Cyclooxygenase
PGG2 gets converted to what? By what enzyme?
PGH2;
Peroxidase
PGH2 gets acted upon by which enzyme to form TXA2?
Thromboxane synthase
PGH2 gets acted upon by which enzyme to form PGI2?
Prostacyclin Synthase
What does the drug celecoxib act upon?
Selective COX-2 inhibitor use to treat chronic inflammation assoc with some disease.
Why is COX-2 non-constitutive?
Because it can be INDUCED
What is COX-2 induced in response to?
Immune and inflammatory mediators (TNF, Cytokines, tumor promoters, endotoxins)
Induction of COX-2 leads to increased prostaglandin synthesis which results in what?
Pain, heat, redness, swelling and fever
Irreversible inhibition of COX-1 by low dose Asprin results in what two important effects?
- platelet aggregation decrease
- no significant effect on prostacyclin (PGI2) formation in endothelial cells
Why does Aspirin cause a platelet aggregation decrease?
Reduced synthesis of TXA2
When COX-2 is specifically inhibited, how are prostacyclin and thromboxane affected?
Less prostacyclin is released from endothelial cells; however thromboxane formation in platelets which only have COX-1 is not inhibited. This leads to increase platlet aggregation, increasing risk of clot formation.
