Eicosanoids

Question 1

name the 3 major classes of eicosanoids

Answer 1

1. prostaglandins (PGs)
2. thromboxanes (TXs)
3. leukotrienes (LTs)

Question 2

describe generation of arachidonic acid

Answer 2

• Phospholipid A2 cleaves PIP2 and releases arachidonic acid (the precursor of the prostaglandins)
  
  • note that PLC (phospholipase C) is an independent system that cleaves PIP2 to form IP3 and DAG

Question 3

describe the role of eicosanoids

Answer 3

• produce a wide range of biological effects of the inflammatory response
  
  • predominantly those of the joints, skin and eyes
  • intensity and duration of pain and fever

Question 4

name the immediate dietary precursor of arachidonate

Answer 4

• the immediate precursor of arachidonate is linoleic acid (these are the w-6)

Question 5

describe the function of COX-1

Answer 5

• COX-1 is a constitutive enzyme found in almost all tissues
• COX-1 is involved with normal physiological functions of PG and TX such as:
  
  • gastric protection and limiting acid secreting
  • maintenance of renal blood flow
  • vascular homeostasis and hemostasis

Question 6

describe the function of COX-2

Answer 6

• non-constitutive and can be induced in a limited number of tissues (such as liver and macrophages) in response to immune and inflammatory mediators (TNF, cytokines, tumor promoters, endotoxin)

Question 7

describe the role of prostacylin and thromboxanes

Answer 7

• prostacylcin (PGI2) produced by endothelial cells
  
  • inhibits platelet aggregation
  • vasodilation
• thromboxane A2 (TXA2) produced by platelets
  
  • promotes platelet aggregation
  • vasoconstriction

Question 8

describe the role of aspirin in vascular health

Answer 8

• aspirin inhibits COX-1 and COX-2 irreversibly by acetylation of a serine amino acid side chain in the active site
  
  • this causes a decrease in platelet aggregation due to reduced synthesis of TXA2 by platelets since they cannot synthesize new COX-1 enzyme
  • no significant effect on prostacyclin (PGI2) formation in endothelial cells since endothelial cells can synthesize new COX-1 and COX-2
• end result = reduced blood clots

Question 9

describe the 2 different types of PUFAs

Answer 9

• 2-series (linoleic acid)
  
  • derived from arachidonic acid
  • produce the eicosanoids designated by the subscript 2 as in PGI2 and TXA2
• 3-series (linolenic acid)
  
  • derived from eicosapentaenoic acid (EPA)
  • produce the eicosanoids designated by the subscript 3 as in PGI3 and TXA3

Question 10

explain the difference between EPA-derived eicosanoids and arachidonic acid derived eicosanoids

Answer 10

• TXA3 (from EPA) is less potent than TXA2 in platelet aggregation
• PGI3 (from EPA) = potency of PGI2
• net effect of PGI3 and TXA3 = reduced platelet aggregation and blood clotting

Question 11

describe the synthesis of leukotrienes

Question 12

describe the synthesis of cysteinyl-leukotrienes

Answer 12

• LTA is used in mast cells and eosinophils to form LTC by addition of the tripeptide GSH (glutathione)
• successive cleavage of glutamate and glycine lead to LTD and LTE, respectively
• LTC, LTD, LTE and LTF contain either a peptide or cysteine in their structure and are therefore called cysteinyl-leukotrienes

Question 13

describe the slow-reacting substance of anaphylaxis (SRS-A)

Answer 13

• the cysteinyl-leukotrienes are released during anaphylaxis and they are components of the slow-reacting substance of anaphylaxis (SRS-A)
• LTC, LTD and LTE increase vascular permeability but also lead to severe bronchoconstriction, vasoconstriction and lung edema

Question 14

describe asthma treatment and drug targets to inhibit leukotriene action

Answer 14

• the release of arachidonic acid (cortisol)
  
  • also leads to less PG and TX synthesis
• inhibitors of 5-lipoxygenase activity
  
  • results in reduced leukotriene synthesis
• cysteinyl-leukotriene receptor antagonists