CPR 13 - Eicosanoids Flashcards
What are the three major classes of eicosanoids and from where are their names derived?
What types of cells synthesize eicosanoids?
How potent are eicosanoids and how do they generally function?
At which glycerol carbon in a phospholipid is the unsaturated fatty acid usually esterified? What types of head groups can phospholipids have?
What releases arachidonic acid from a phospholipid? Why is this significant?
Provide an overview of eicosanoid synthesis.
- A GPCR receives a signal leading to the activation of PLA2
- PLA2 begins cutting arachidonic acids off of phospholipids in the membrane
- A PGH2 synthase, either COX-1 or COX-2 (only in liver and macrophages), will then use its cyclooxygenase and peroxidase activity to convert arachidonic acid into PGG2 which is subsequently converted to PGH2 and used to make thromboxanes (only in platelets) and prostaglandins
- 5-lipoxygenase will also convert the archidonic acid into LTA4 which will then be used to make leukotrienes.
List the compounds that can inhibit or stimulate eicosanoid biosynthesis and how they do this.
- Glucocorticoids, like cortisol, inhibit PLA2 from cleaving arachidonic acid off of membrane lipids. This inhibits synthesis of all eicosanoids
- NSAIDs, like aspirin, inhibits COX1 and COX2 activity which will inhibit production prostaglandins and thromboxanes
- Corticosteroids will inhibit COX2 which will inhibit production of prostaglandins only (COX2 is not found in platelets)
- Cytokines, endotoxin, growth factors, and tumor promoters will stimulate COX2 to create more PGH2 and threfore stimulate the synthesis of prostaglandins and thromboxanes
Which COX enzyme is constitutively active and why?
In which tissues is COX2 active? What does induction of COX2 lead to?
Liver and macrophages
Increased prostaglandin synthesis which results in pain, heat, redness, swelling, and fever
What are the major physiological effects of TXA2 and PGI2?
Why can aspirin be used to treat clotting problems if it inhibits both pro and anticoagulation pathways?
- Aspirin inhibits COX irreversibly by covalent acetylation of a serine in the active site of the enzyme. This means that new COX has to be made for prostacylin and thromboxane synthesis to continue.
- Low Dose aspirin (81 mg) will inhibit COX1 and COX2 in both endothelial and platelet cells. However, endothelial cells can overcome this by making more COX. Platelets cannot do this
- Therefore, low dose aspirin inhibits the synthesis of both prostacyclin and thromboxane but it inhibits thromboxane synthesis to a much greater extent
Which PUFA is considered to be healthier and why? What food is a major source of this PUFA?
- A diet rich in ω-3 (α-linolenic acid) will lead to the incorporation of more EPA into membrane phospholipids. Therefore, when PLA2 is activated, more PGI3/TXA3 will be produced than PGI2/TXA2
- PGI3 and PGI2 have about the same potency but TXA3 is less potent than TXA2. Therefore, the net physiological effect of a diet higher in ω-3 fatty acids results in the reduction of platelet aggregation/blood clotting.
Discuss the synthesis of cysteinyl-leukotrienes.
What is the physiological significance of cysteinyl-leukotrienes?
What are the major complications with asthma?
Discuss the importance of leukotrienes to asthma treatment.
