Eicosanoids

Question 1

Are eicosanoids long lived or short lived signaling molecules?

Answer 1

Eicosanoids are degraded rapidly, so they must function locally (paracrine, autocrine)

Question 2

What are eicosanoids derived from?

Answer 2

20-carbon unsaturated essential fatty acids

Question 3

Name the types of eicosanoids?

Answer 3

1. Prostaglandin
2. Prostacyclin (prostaglandin with extra ring)
3. Thromboxane
4. Leukotriene
5. Epoxide

Question 4

Where are the following Eicosanoids produced in?

1. Prostanoids (PG, PGI, TX)?
2. Leukotrienes?
3. Epoxides?

Answer 4

1. Prostanoids: Most cells
2. Leukotrienes: WBC
3. Epoxides: Macrophages

Question 5

What does the 2 represent in the Eicosanoid name PGH₂

Answer 5

Series (denotes # of double bonds in linear portion of the molecule)

Question 6

Linolenic is what type of omega fatty acid?

Answer 6

w-3

Question 7

Linolenic is metablized into what fatty acid that becomes incorporated into plasma membrane phospholipids?

Answer 7

Eicosapentaenoic acid (EPA) (20:5, w-3)

Question 8

Linoleic acid is what type of omega fatty acid?

Answer 8

w-6

Question 9

Linoleic acid is metabolized into what type of fatty acid?

Answer 9

• Arachidonic Acid (AA) (20:4; w-6)
• Dihomo y-linolenic acid (DGLA) (20:3; w-6)

Question 10

What are the series numbers for DGLA, EPA, and AA?

Answer 10

• DGLA: Series 1
• EPA: Series 3
• AA: Series 2 (more inflammatory)
• 1+3=4 good health

Question 11

Release of fatty acids from membrane is done by what molecule?

Answer 11

Phospholipase A₂ (PLA₂); rate-limiting enzyme

Question 12

What type of protein receptor is required in the activation of PLA₂

Answer 12

G_q-protein coupled receptor

Question 13

In the activation of PLA₂, G-alpha (q) activates….List the process

Answer 13

1. G-alpha (q) activates PLC
2. PLC cuts PIP into DAG (remains in membrane) and IP₃
3. IP3 binds to Ca²⁺ channel at the endoplasmic reticulum and causes release of Calcium into the cytosol
4. Ca²⁺ Binds with PLA₂ and brings it to the cell membrane where it hydrolyzes fatty acid

Question 14

What enzyme converts Arachidonic Acid (AA) into Leukotrienes?

Answer 14

5-lipoxygenase

Question 15

AA are converted to two types of leukotrienes: Name these

Answer 15

1. Leukotriene A₄
2. A family of LTs called Cysteinyl Leukotrienes

Question 16

Cysteinyl Leukotrienes act at cell-surface receptors on target cells to cause what?

Answer 16

1. Contract bronchial and vascular smooth muscle
2. Enhance mucus secretion in airway and gut
3. Recruit Leukocytes to site of inflammation
4. Increase capillary permeability

Question 17

What is the action and purpose of the drug Zyflo?

Answer 17

• 5-lipoxygenase inhibitor therefore inhibits leukotriene formation
• Used for prophylactic and chronic treatment of asthma

Question 18

What is the action and purpose of the drug Singulair?

Answer 18

• Cysteinyl leukotriene receptor antagonist; prevents binding to bronchial smooth muscle cells and inflammatory cells
• Used for chronic treatment of bronchospasms (asthma) and allergic rhinitis

Question 19

Synthesis of Prostanoids (Prostaglandins and Thromboxanes) is catalyzed by?

Answer 19

Prostaglandin endoperoxide synthase (PGH synthase)

Question 20

PGH synthase is one polypeptide with what two catalytic activities?

Answer 20

1. Fatty acid cyclooxygenase (COX) 1 or 2 depending on tissue type
2. Peroxidase: provides reducing power to produce PGH

Question 21

PGH synthase acts on which fatty acids to create PGH(1-3)

Answer 21

PGH synthase can act on AA, EPA, and DGLA to produce PGH_{(series #)}

Question 22

PGH_{(series #)} converts fatty acids into what eicosanoids?

Answer 22

• 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

Question 23

What happens to Prostanoids after they become nonfunctional?

Answer 23

Prostanoids become nonfunctional near their site of release and are then degraded in the capillary beds on the lungs

Question 24

Platelets synthesize and secrete what type of Eicosanoid? What is its action?

Answer 24

• Thromboxane (TXA)
• Stimulates neighboring platelets and enhance platelet aggregation

Question 25

To prevent platelet aggregation in undamaged area of vasculature, endothelial cells synthesize and secrete what? How does it work?

Answer 25

* The prostaglandin **Prostacyclin (PGI)** * **PGI** binds to platelets and interferes with thromboxane signaling

Question 26

If AA is used to synthesie TXA₂ and PGI₂ what type of response will be favored in terms of platelet aggregation?

Answer 26

* **Stronger Platelet Aggregation** * TXA₂ will have a stronger aggregation effect * PGI₂ will have weak antiplatelet effect

Question 27

If EPA is used to synthesis TXA or PGI, what will be the response in terms of platelet aggregation?

Answer 27

* **Weaker platelet aggregation** * TXA₃ will have weak aggregation effect * PGI₃ will have stronger antiplatelet effect

Question 28

Where is Cox-1 expressed and what is its function?

Answer 28

* Cox-1 is _constitutively_ expressed in most tissues * Required for _maintenance_ of health gastric tissues, renal homeostasis, and platelet function

Question 29

Where is Cox-2 expressed? What is its function?

Answer 29

* Cox-2 is expressed in a limited number of tissues (including inflammatory cells) * Mediates inflammation, sensitivity to pain, and fever

Question 30

Drugs that inhibit Cox-1 (e.g. NSAIDS) can have what side effect?

Answer 30

* Can impair protective signaling of gastric mucosa * causing stomach ulcers and GI bleeding with extended use

Question 31

Glucocorticoids (steriod hormones) increase the synthesis of what protein?

Answer 31

Lipocortin (Annexin- 1) which prevents PLA₂ from hydrolyzing fatty acids at the membrane

Question 32

Glucocorticoids ALSO decrease synthesis of Cox-1 or Cox-2

Answer 32

Decrease synthesis of Cox-2 (but not Cox-1)

Question 33

What are the two classes of competitive inhibitors?

Answer 33

1. **Irreversible** inhibitors: Create a new covalent bond as a result of binding that permanently inactivates enzyme activity (Ex: ASA) 2. **Reversible** inhibitors: Bind reversibly to active site of enzyme; can compete with substrate for binding (Ex: Ibuprofen)

Question 34

Drugs that inhibit COX activity are primarly what?

Answer 34

Competitive inhibitors: interferes with active site of enzyme so substrate is unable to bind

Question 35

Aspirin has what mechanism of action? What is the clinical benefit?

Answer 35

1. Irreversibly inhibits COX-1 and COX-2 (acetylates serine in active site) 2. Benefit: Anti-inflammatory, analgesic, antipyretic; anti-platelet activity

Question 36

Why is low dose Aspirin therapy used to reduce the risk of heart attacks?

Answer 36

* 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**

Question 37

What is the mechanism of action and clinical benefit of Ibuprofen/Naproxen?

Answer 37

* NSAIDs that **reversibly** (competitively) inhibit COX-1 and COX-2 * Beneift: Anti-inflammatory, Analgesic, Antipyretic * Brand name: Advil

Question 38

What is Celebrex's mechanism of action? Clincal Benefit?

Answer 38

* 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

Question 39

Where does Acetaminophen act? Clincal benefit?

Answer 39

* 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

Question 40

1. Linoleic acid (w-6) comes from eating what types of food? 2. Linolenic (w-3) comes from eating what types of food?

Answer 40

1. Linoleic: Nuts 2. Linolenic: Fatty fish

Question 41

What drug prevents transcription of COX-2

Answer 41

Glucocorticoid

Question 42

What drug blocks the substrate channel of COX-2 but not COX-1?

Answer 42

Celebrex

Question 43

What drug acetylates the active site of COX-1 and COX-2 enzymes?

Answer 43

Aspirin

Question 44

What drug inhibits 5-lipoxygenase?

Answer 44

Zyflo

Question 45

What drug blocks substrate channel of both COX-1 and COX-2?

Answer 45

Ibuprofen