Eicosanoids Flashcards
Are eicosanoids long lived or short lived signaling molecules?
Eicosanoids are degraded rapidly, so they must function locally (paracrine, autocrine)
What are eicosanoids derived from?
20-carbon unsaturated essential fatty acids
Name the types of eicosanoids?
- Prostaglandin
- Prostacyclin (prostaglandin with extra ring)
- Thromboxane
- Leukotriene
- Epoxide
Where are the following Eicosanoids produced in?
- Prostanoids (PG, PGI, TX)?
- Leukotrienes?
- Epoxides?
- Prostanoids: Most cells
- Leukotrienes: WBC
- Epoxides: Macrophages
What does the 2 represent in the Eicosanoid name PGH2
Series (denotes # of double bonds in linear portion of the molecule)
Linolenic is what type of omega fatty acid?
w-3
Linolenic is metablized into what fatty acid that becomes incorporated into plasma membrane phospholipids?
Eicosapentaenoic acid (EPA) (20:5, w-3)
Linoleic acid is what type of omega fatty acid?
w-6
Linoleic acid is metabolized into what type of fatty acid?
- Arachidonic Acid (AA) (20:4; w-6)
- Dihomo y-linolenic acid (DGLA) (20:3; w-6)
What are the series numbers for DGLA, EPA, and AA?
- DGLA: Series 1
- EPA: Series 3
- AA: Series 2 (more inflammatory)
- 1+3=4 good health
Release of fatty acids from membrane is done by what molecule?
Phospholipase A2 (PLA2); rate-limiting enzyme
What type of protein receptor is required in the activation of PLA2
Gq-protein coupled receptor
In the activation of PLA2, G-alpha (q) activates….List the process
- G-alpha (q) activates PLC
- PLC cuts PIP into DAG (remains in membrane) and IP3
- IP3 binds to Ca2+ channel at the endoplasmic reticulum and causes release of Calcium into the cytosol
- Ca2+ Binds with PLA2 and brings it to the cell membrane where it hydrolyzes fatty acid
What enzyme converts Arachidonic Acid (AA) into Leukotrienes?
5-lipoxygenase
AA are converted to two types of leukotrienes: Name these
- Leukotriene A4
- A family of LTs called Cysteinyl Leukotrienes
Cysteinyl Leukotrienes act at cell-surface receptors on target cells to cause what?
- Contract bronchial and vascular smooth muscle
- Enhance mucus secretion in airway and gut
- Recruit Leukocytes to site of inflammation
- Increase capillary permeability
What is the action and purpose of the drug Zyflo?
- 5-lipoxygenase inhibitor therefore inhibits leukotriene formation
- Used for prophylactic and chronic treatment of asthma
What is the action and purpose of the drug Singulair?
- Cysteinyl leukotriene receptor antagonist; prevents binding to bronchial smooth muscle cells and inflammatory cells
- Used for chronic treatment of bronchospasms (asthma) and allergic rhinitis
Synthesis of Prostanoids (Prostaglandins and Thromboxanes) is catalyzed by?
Prostaglandin endoperoxide synthase (PGH synthase)
PGH synthase is one polypeptide with what two catalytic activities?
- Fatty acid cyclooxygenase (COX) 1 or 2 depending on tissue type
- Peroxidase: provides reducing power to produce PGH
PGH synthase acts on which fatty acids to create PGH(1-3)
PGH synthase can act on AA, EPA, and DGLA to produce PGH(series #)
PGH(series #) converts fatty acids into what eicosanoids?
- PGH converts fatty acids (AA, EPA, DGLA) into Prostaglandins and/or Thromboxanes
- Conversion is dependent upon enzymes that are expressed in the particular cell
- Cells of a particular tissue synthesize only one or two types of prostanoids
What happens to Prostanoids after they become nonfunctional?
Prostanoids become nonfunctional near their site of release and are then degraded in the capillary beds on the lungs
Platelets synthesize and secrete what type of Eicosanoid? What is its action?
- Thromboxane (TXA)
- Stimulates neighboring platelets and enhance platelet aggregation
To prevent platelet aggregation in undamaged area of vasculature, endothelial cells synthesize and secrete what? How does it work?
- The prostaglandin Prostacyclin (PGI)
- PGI binds to platelets and interferes with thromboxane signaling
If AA is used to synthesie TXA2 and PGI2 what type of response will be favored in terms of platelet aggregation?
- Stronger Platelet Aggregation
- TXA2 will have a stronger aggregation effect
- PGI2 will have weak antiplatelet effect
If EPA is used to synthesis TXA or PGI, what will be the response in terms of platelet aggregation?
- Weaker platelet aggregation
- TXA3 will have weak aggregation effect
- PGI3 will have stronger antiplatelet effect
Where is Cox-1 expressed and what is its function?
- Cox-1 is constitutively expressed in most tissues
- Required for maintenance of health gastric tissues, renal homeostasis, and platelet function
Where is Cox-2 expressed? What is its function?
- Cox-2 is expressed in a limited number of tissues (including inflammatory cells)
- Mediates inflammation, sensitivity to pain, and fever
Drugs that inhibit Cox-1 (e.g. NSAIDS) can have what side effect?
- Can impair protective signaling of gastric mucosa
- causing stomach ulcers and GI bleeding with extended use
Glucocorticoids (steriod hormones) increase the synthesis of what protein?
Lipocortin (Annexin- 1) which prevents PLA2 from hydrolyzing fatty acids at the membrane
Glucocorticoids ALSO decrease synthesis of Cox-1 or Cox-2
Decrease synthesis of Cox-2 (but not Cox-1)
What are the two classes of competitive inhibitors?
- Irreversible inhibitors: Create a new covalent bond as a result of binding that permanently inactivates enzyme activity (Ex: ASA)
- Reversible inhibitors: Bind reversibly to active site of enzyme; can compete with substrate for binding (Ex: Ibuprofen)
Drugs that inhibit COX activity are primarly what?
Competitive inhibitors: interferes with active site of enzyme so substrate is unable to bind
Aspirin has what mechanism of action? What is the clinical benefit?
- Irreversibly inhibits COX-1 and COX-2 (acetylates serine in active site)
- Benefit: Anti-inflammatory, analgesic, antipyretic; anti-platelet activity
Why is low dose Aspirin therapy used to reduce the risk of heart attacks?
- ASA inhibits COX-1 and COX-2 thus inhibiting the formation of TXA -> decreased aggregation of platelets
- Platelets do not contain nuclei thus they can’t synthesize new COX enzymes after ASA administration whereas other cells can continue to produce COX
- Anti-platelet activity of ASA lasts longer than its antiflammatory activity
What is the mechanism of action and clinical benefit of Ibuprofen/Naproxen?
- NSAIDs that reversibly (competitively) inhibit COX-1 and COX-2
- Beneift: Anti-inflammatory, Analgesic, Antipyretic
- Brand name: Advil
What is Celebrex’s mechanism of action? Clincal Benefit?
- NSAID that is a reversible, competitive, inhibitor of COX-2 (not COX-1) at sites of inflammation
- Benefit: Inhibits inflammation without GI side effects
- *increased risk of heart attack has been associated
Where does Acetaminophen act? Clincal benefit?
- Brand name: Tylenol
- Acts in the CNS (does not inhibit COX-1 or COX-2)
- Benefit: reduces pain/fever, minimal anti-inflammatory effects
- Does not affect platelet function
- Linoleic acid (w-6) comes from eating what types of food?
- Linolenic (w-3) comes from eating what types of food?
- Linoleic: Nuts
- Linolenic: Fatty fish
What drug prevents transcription of COX-2
Glucocorticoid
What drug blocks the substrate channel of COX-2 but not COX-1?
Celebrex
What drug acetylates the active site of COX-1 and COX-2 enzymes?
Aspirin
What drug inhibits 5-lipoxygenase?
Zyflo
What drug blocks substrate channel of both COX-1 and COX-2?
Ibuprofen
