S1B4 - Eicosinoids

Question 1

What is the basic description of an eicosanoid?

Answer 1

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

Question 2

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

Answer 2

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

Question 3

What is the most common substrate for eicosinoid synthesis?

Answer 3

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

Question 4

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

Answer 4

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.

Question 5

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

Answer 5

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.

Question 6

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

Answer 6

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

1. The other important prostaglandins
2. The thromboxanes

Question 7

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

Answer 7

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

Question 8

What does the subscript “2” refer to on PGH₂?

Answer 8

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.

Question 9

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

Answer 9

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

Question 10

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

Answer 10

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.

Question 11

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

Answer 11

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)

Question 12

Describe thromboxane A_2.

Answer 12

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

Question 13

What are some actions of prostaglandins?

Answer 13

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.

Question 14

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

Answer 14

PGI2 inhibits platelet aggregation, TXA2 stimulates platelet aggregation.

Question 15

What are leukotrienes and lipoxins?

Answer 15

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

Question 16

What are the three lipoxygenases? What are their products?

Answer 16

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).

Question 17

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

Answer 17

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.

Question 18

Why are leukotrienes called leukotrienes?

Answer 18

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.

Question 19

What do leukotrienes mediate?

Answer 19

Leukotrienes mediate inflammatory disorders.

Question 20

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

Answer 20

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.

Question 21

Which leukotrienes increase vascular permeability?

Answer 21

LTB₄, LTC₄, LTD₄ and LTE₄ increase vascular permeability.

Question 22

What pathway are lipoxins derived from?

Answer 22

The lipoxins are also derived from the lipoxygenase pathway.

Question 23

What are examples of lipoxin actions?

Answer 23

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.

Question 24

Describe eicosanoid receptors.

Answer 24

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

Question 25

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

Answer 25

**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.

Question 26

Name four eicosanoids which cause increased vascular permeability.

Answer 26

Arachidonic acid products (eicosanoids) which produce **increased vascular permeability** include: * **Leukotrienes B₄, C₄, D₄, and E₄** * **PGD₂**

Question 27

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

Answer 27

**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

Question 28

What enzyme releases arachidonic acid from membrane phospholipids?

Answer 28

**Phospholipase A₂** releases arachidonic acid from membrane phospholipids.

Question 29

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

Answer 29

**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.

Question 30

What is another name for prostacyclin?

Answer 30

Prostacyclin is also known as **PGI₂.**

Question 31

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

Answer 31

**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)

Question 32

Which class of medications inhibits phospholipase A₂?

Answer 32

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

Question 33

Name five types of medications which inhibit cyclooxygenase.

Answer 33

**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)