S1B4 - Eicosinoids Flashcards Preview

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Flashcards in S1B4 - Eicosinoids Deck (33):
1

What is the basic description of an eicosanoid?

Eicosanoids are important bio-active agents synthesized from polyunsaturated fatty acids, 20 carbons long. (eicosa means 20).

2

What are the important eicosanoids? What pathway is each important eicosinoid synthesized by?

The important eicosanoids include:

1. Prostaglandins

  • synthesized by the cyclooxygenase (COX) pathway

2. Prostacyclins

  • synthesized by the cyclooxygenase (COX) pathway

3. Thromboxanes

  • synthesized by the cyclooxygenase (COX) pathway

4. Leukotrienes

  •  synthesized by the lipoxygenase pathway

5. Lipoxins

  •  synthesized by the lipoxygenase pathway

3

What is the most common substrate for eicosinoid synthesis?

The cyclooxygenase and lipoxygenase pathways  start with a 20 carbon polyunsaturated fatty acid, usually arachidonic acid.

4

What is arachidonic acid derived from? What enzyme is needed for this? What is the rate limiting step in this process?

The arachidonic acid is derived from membrane phospholipid.

1. Arachidonic (and the other C20 fatty acid precursors) are released from membrane phospholipids by the action of phospholipase A2.

2. The hydrolysis of arachidonic acid from membrane phospholipid is the rate limiting step in prostaglandin synthesis.

a. Agents which stimulate the production of prostaglandins do so by stimulating the activity of phospholipase A2.

5

What are two minor precursors to arachidonic acid? How are they obtained?

Two other C20 PUFAs may serve as precursors for this process.

1. Eicosatrienoic acid:

2. Eicosapentaenoic acid (EPA):

a. EPA is obtained from the diet.

b. It is an ω-3 fatty acid.

3. Usually, these other 2 C20 PUFAs are only minor precursors.

6

What is the first prostaglandin product and what is it the common intermediate of?

PGH2 is the first prostaglandin product, and the common intermediate of:

1. The other important prostaglandins

2. The thromboxanes

7

What is the enzyme that synthesizes PGH2 and what are its components?

Prostaglandin synthase PGS, also called prostaglandin G/H synthase, has two components:

1. Cyclooxygenase (COX) which catalyzes the synthesis of PGG2.

2. PG hydroperoxidase which catalyzes the formation of PGH2 from PGG2.

a. PG hydroperoxidase requires GSH

8

What does the subscript "2" refer to on PGH2?

The subscript “2” refers to the number of double bonds in the side chains.

1. The number of double bonds in the side chains depends on the PUFA precursor.

2. If the precursor is eicosatrienoic acid, the product would be PGH1.

3. If the precursor is eicosapentaenoic acid, the product would be PGH3.

9

What are two forms of cyclooxygenase (COX)? Where are they found?

There are two forms of COX

1. COX-1

a. A constitutive enzyme.

b. Found in gastric mucosa, platelets, vascular endothelium and kidney.

2. COX-2

a. An inducible enzyme.

b. Mainly expressed in:

i. Activated macrophages and monocytes which have been stimulated by PAF, interleukin-1 or bacterial lipopolysaccharide.

ii. Smooth muscle cells, epithelial and endothelial cells, and neurons.

c. COX-2 induction is inhibited by Glucocorticoids

10

What class of drugs inhibit COX? WHich version is more susceptible to these drugs?

The NSAIDs inhibit COX

1. Aspirin, ibuprofen, acetaminophen, etc.

2. Most NSAIDs inhibit COX-2 more than COX-1.

a. Aspirin inhibits COX-1 more than COX-2

b. Aspirin’s mechanism of action involves acetylation of the COX enzyme.

3. Steroidal anti-inflammatory drugs (hydrocortisone, prednisone, etc.) act by inhibiting phospholipase A2 activity.

11

What are the main non-PGH types of prostaglandins and whre are they found?

Synthesis of other prostaglandins

A. Different cell types produce different enzymes which result in D, E, and F series of prostaglandins and of prostacyclin (PGI2).

B. For example:

1. PGE2 and PGF2 are major prostaglandins produced in kidney and spleen.

2. PGE2 also produced by macrophages, mast cells and B cells.

3. PGD2 is produced by mast cells.

4. PGI2 and PGF2 are major prostaglandins produced by blood vessels.

a. PGI2 is an important inhibitor of platelet aggregation. (think Platelet Gathering Inhibitor)

12

Describe thromboxane A2.

Synthesis of thromboxane A2 (TXA2)

1. Major prostaglandin produced by platelets.

2. TXA2 stimulates platelet aggregation.

3. The half-life of TXA2 is very short

a. It is rapidly converted to the inactive TXB2

13

What are some actions of prostaglandins?

Some actions of prostaglandins

A. Mediators of inflammation

1. Induce redness and heat (arteriolar vasodilation)

2. Increase capillary permeability

3. Pyrogens activate synthesis of prostaglandins.

B. Stimulate uterine contraction.

C. Inhibit gastric acid secretion.

D. PGI2 inhibits platelet aggregation, TXA2 stimulates platelet aggregation.
 

14

Which prostaglandin inhibits platelet aggregation, and which prostaglandin stimulates platelet aggregation?

PGI2 inhibits platelet aggregation, TXA2 stimulates platelet aggregation.

15

What are leukotrienes and lipoxins?

Leukotrienes and lipotoxins are products derived from arachidonic acid via the lipoxygenase pathway.

A image thumb
16

What are the three lipoxygenases? What are their products?

There are three lipoxygenases

1. They are each specific for the carbon number at which they add a hydroperoxide group.

a. 5-, 12- or 15-lipoxygenase.

b. The products are the corresponding hydroperoxyeicosatetraenoic acids (HPETEs).

17

What are the HPETEs? Which is the most important in humans?

The HPETEs are highly reactive intermediates which are rapidly converted to their analogous hydroxyeicosatetraenoic acids (HETEs), or to leukotrienes.

  1. 5-HPETE
  2. 12-HEPTE
  3. 15-HEPTE

The most important products of the lipoxygenases in humans is 5-HPETE, since these are converted into the leukotrienes.

18

Why are leukotrienes called leukotrienes?

Leukotrienes (LT) are so named because

a. They are important secretory products of leukocytes,

b. And each one contains a conjugated trienoic group.

c. The subscript number refers to the total number of double bonds.

d. The leukotrienes are also expressed in numerous other cell types.

19

What do leukotrienes mediate?

Leukotrienes mediate inflammatory disorders.

20

What is slow-reacting substance of anaphylaxis (SRS-A)?

Slow-reacting substance of anaphylaxis (SRS-A)

a. SRS-A is a mixture of LTC4, LTD4 and LTE4.

b. SRS-A is a potent stimulator of bronchial airway musculature.

21

Which leukotrienes increase vascular permeability?

LTB4, LTC4, LTD4 and LTE4 increase vascular permeability.

22

What pathway are lipoxins derived from?

The lipoxins are also derived from the lipoxygenase pathway.

23

What are examples of lipoxin actions?

Examples of lipoxin actions include:

a. Inhibition of angiogenesis.

b. Clearance of pulmonary edema.

c. Protection of reperfusion injury.

Current drugs for asthma include 5-LOX inhibitors, and LT-receptor antagonists.

24

Describe eicosanoid receptors.

Eicosanoids act via 7 trans-membrane G protein-coupled receptors.

25

Name two types of eicosanoids derived from arachidonic acid after activation by cyclooxygenase?        
 

Prostaglandins and thromboxanes are eicosanoids produced from the action of cyclooxygenase (COX-1 & COX-2) on arachidonic acid. Note that prostacyclin (PGI2) is a member of the prostaglandin family.

26

Name four eicosanoids which cause increased vascular permeability.        
 

Arachidonic acid products (eicosanoids) which produce increased vascular permeability include:

  • Leukotrienes B4, C4, D4, and E4
  • PGD2

27

Which prostaglandin is primarily produced by mast cells during an allergic response?        
 

PGD2 is the major prostaglandin produced by mast cells during an allergic response which:

  • Decreases vascular tone (vasodilation)
  • Increases vascular permeability (potentiates edema formation)
  • Increases bronchial tone (bronchoconstriction/bronchospasm)
  • Increases mucus production

28

What enzyme releases arachidonic acid from membrane phospholipids?        
 

Phospholipase A2 releases arachidonic acid from membrane phospholipids.

29

What effect do leukotrienes C4, D4, and E4 have on bronchial tone?        
 

LTC4, LTD4, LTE4 (leukotrienes C4, D4, and E4) mediate bronchial smooth muscle contraction resulting in increased bronchial tone and bronchospasm.

Slow-reacting substance of anaphylaxis (SRS-A) is a mixture of LTC4, LTD4 and LTE4.

30

What is another name for prostacyclin?        
 

Prostacyclin is also known as PGI2.

31

Name four eicosanoid products derived from arachidonic acid after activation by 5-lipoxygenase?        
 

Leukotrienes are eicosanoids produced from the action of 5-lipoxygenase (5-LOX) on arachidonic acid. They include:

  • LTB4 (leuoktriene B4)
  • LTC4 (leukotriene C4)
  • LTD4 (leukotriene D4)
  • LTE4 (leukotriene E4

32

Which class of medications inhibits phospholipase A2?

Corticosteroids inhibit phospholipase A2 (PLA2), the enzyme which degrades membrane phospholipids into arachidonic acid. Corticosteroids also block the transcription of pro-inflammatory genes.

33

Name five types of medications which inhibit cyclooxygenase.        
 

Inhibitors of cyclooxygenase (COX-1 and COX-2) include:

  • Aspirin (irreversible inhibition of COX-1 and COX-2)
  • NSAIDs (reversible inhibition of COX-1 and COX-2)
  • COX-2 selective inhibitors (e.g - Celecoxib),
  • Acetaminophen (primarily in the CNS)
  • Corticosteroids (inhibit both COX and PLA2)