Eicosanoid Metabolism & Function

Question 1

What are eicosanoids?

Answer 1

• Among the most potent regulators of cellular function in nature
• Produced by almost every cell in the body
• Includes prostaglandins (PG) and thromboxane (TX), leukotrienes (LT)
• Act mainly as local hormone, affecting them cells that produce them or neighbouring cells of a different type

Question 2

What are the functions of eicosanoids?

Answer 2

1. Inflammatory response that occurs following infection or injury
2. Regulation of water and sodium excretion, particularly in the intestine and uterus
3. Increase water and sodium excretion by the kidney
4. Regulate blood pressure
5. Regulate bronchoconstriction and bronchodilation

Question 3

What is the source/precursor of eicosanoids?

Answer 3

arachidonic acid

Question 4

How do we get arachidonic acid ?

Answer 4

• Can’t be synthesized de novo in the body
• Our diet must contain it
• Major precursor is the essential fatty acid linoleate (present in plant oils)

Question 5

How is arachidonic acid released from the lipid bilayer?

Answer 5

by activation of membrane bound phospholipase A2 or C

Question 6

How does activation of phospholipase A2 or C occur

Answer 6

When stimuli, such as histamine or cytokines, interact with a specific plasma membrane receptor on the target cell surface

Question 7

What are the 3 pathways for eicosanoid synthesis?

Answer 7

1. Cyclooxygenase pathway
2. Lipoxygenase pathway
3. Cytochrome P450 system

Question 8

Which of the eicosanoid synthesis pathways leads to the production of prostaglandins and thromboxane?

Answer 8

The cyclooxygenase pathway

Question 9

Which of the eicosanoid synthesis pathways leads to the production of leukotrienes, HETEs and lipoxins?

Answer 9

The lipoxygenase pathway

Question 10

Which of the eicosanoid synthesis pathways is responsible for the synthesis of epoxides, HETEs and diHETEs?

Answer 10

The cytochrome P450 system

Question 11

Describe the structure of prostaglandins

Answer 11

• fatty acids containing 20 C atoms
• an internal saturated 5C ring

If biologically active:
- OH at C15
- double bond between C13-14
various substituents on the ring

Question 12

Describe the structure of thromboxane

Describe the structure of thromboxane A2 (TXA2)

Answer 12

• fatty acids containing 20 C atoms
• an internal saturated 6C ring which has an attached O atom

TXA2 has O atom attached to C9 and 11 on the carbon ring

Question 13

Describe the biosynthesis of prostaglandins

Answer 13

• First biochemical reaction catalyzed by a cyclooxygenase to form PGG2
• PGG2 is reduced to form the endoperoxide-PGH2
• After this is tissue specific/cell dependent
• In vascular endothelium, PGH2 is converted to prostaglandin PGI2 by PGI synthase

Question 14

Describe the biosynthesis of thromboxane

Answer 14

• First biochemical reaction catalyzed by a cyclooxygenase to form PGG2
• PGG2 is reduced to form the endoperoxide-PGH2
• After this is tissue specific/cell dependent
• In platelets, PGH2 is converted to thromboxane TXA 2 by TXA synthase

Question 15

What is the half lives of prostaglandins and thromboxane

Answer 15

seconds to minutes

Question 16

How are prostaglandins inactivated?

Answer 16

1. Oxidation of the 15-OH group to a ketone
2. Reduction of double bond at C 13
3. b-oxidation and w-oxidation of the non-ring portions (producing dicarboxylic acids which are secreted in the urine)

Question 17

How is thromboxane A (TXA2) inactivated?

Answer 17

1. Rapid metabolism into TXB2 via cleavage of the oxygen bridge bw C9-11 to form TXB2 in urine (it has no biological activity)

Question 18

Describe the synthesis of leukotriene

Answer 18

1. Formation of 5-HPETEs from arachidonic acid catalyzed by 5-lipoxygenase
2. 5-HPETEs metabolized to leukotrienes

Question 19

Describe the synthesis of leukotriene A4 (LTA4)

Answer 19

conversion of 5-HPETEs to an epoxide in leukocytes and mast cells

Question 20

How are other leukotrienes formed from the LTA4?

Answer 20

Two pathways:

1. LTA4 is converted to LTB4
2. reduced glutathione is added to C6 to form LTC4, catalyzed by glutathione S-transferase
   - Glutamate is removed from glutathione of LTC4 by gamma-glutamyl transpeptidase to form LTD4
   - Glycine residue from LTD4 is cleaved to form LTE4

Question 21

Describe the mechanism of action of eicosanoids (PGE, PGD PGI series)

Answer 21

• Eicosanoid binds with a specific G linked receptor on the plasma membrane of a target cell
• Activates adenylate cyclase –> cAMP –> protein kinase A

Question 22

Describe the mechanism of action of eicosanoids (PGF2alpha, TXA2 and leukotrienes)

Answer 22

• Eicosanoid binds with a specific G linked receptor on the plasma membrane of a target cell
• Activates phospholipase-C
• Activates inositol phospholipid signaling pathway
• Increase in level of Ca+ in the cytosol of target cells

Question 23

What type of signals do eicosanoids produce?

Answer 23

Paracrine (released from one cell type and acts on neighboring cells of a different type)
Autocrine (released and acts on the same cell type)

Question 24

What is an example of a paracrine action by eicosanoids?

Answer 24

contraction of vascular smooth muscle cells caused by TXA2 released from circulating platelets

Question 25

What is an example of a autocrine action by eicosanoids?

Answer 25

platelet aggregation by TXA2 produced by platelets

Question 26

Which of the following increases vasodilation? | Prostaglandins, thromboxane's or leukotrienes

Answer 26

prostagalndines

Question 27

Which of the following increases vasoconstriction? | Prostaglandins, thromboxane's or leukotrienes

Answer 27

thromboxane's and leukotrienes

Question 28

Which NSAID irreversibly inhibits cyclooxygenase? | How?

Answer 28

aspirin | By transferring an acetyl group to the enzyme

Question 29

Which NSAID reversibly inhibits cyclooxygenase?

Answer 29

All other NSAIDS eg acetaminophen, ibuprofen

Question 30

How is low dose aspirin effective in prevention of acute myocardial infarction?

Answer 30

- Predominant eicosanoid in platelets is TXA2 - TXA2 is a potent stimulator of platelet aggregation - It initiates thrombus formation at sites of vascular injury which can cause occlusion of vascular lumen causing acute ischemic damage (myocardial infarction) - Aspirin covalently acetylates the active site of cyclooxygenase and blocks production of TXA2