Arachidonic Acid Metabolism and NSAIDs

Question 1

What are COX enzymes responsible for?

Answer 1

One step in the conversion of membrane phospholipids into prostanoids

Question 2

Describe step 1 of the prostaglandin synthesis pathway

Answer 2

Phospholipid is cleaved to release arachidonic acid (catalysed by PLA2)

Question 3

How is PLA2 (the enzyme cutter of phospholipid) regulated?

Answer 3

Inflammatory mediators can upregulate cPLA2 expression

Glucocorticoids can down regulate cPLA2 or can induce protein repressor proteins

Question 4

Describe step 2 of prostaglandin synthesis pathway?

Answer 4

Another prostaglandin synthase (H2) converts arachidonic acid into prostaglandin H2 via G2.

Question 5

What are the two activities of prostaglandin synthase H2?

Answer 5

cycloxygenase and peroxidase (often simpy called COX)

Question 6

Where are COX enzymes found?

Answer 6

Bound to ER and nuclear envelope membranes

Question 7

Where is COX 1 expressed?

Answer 7

Most tissues

Question 8

What is COX-2 regulated by?

Answer 8

Regulated at an mRNA level - induced by growth factors and inflammatory mediators such as IL-4, TNF-apha, LPS, including immune cells endothelial cells and fibroblasts

Question 9

What suppresses COX-2 expression?

Answer 9

Anti inflammatory glucocorticoids suppress COX-2 but not COX-1

Question 10

How does PGH2 become prostanoids?

Answer 10

Prostaglandin synthase enzymes responsible

Question 11

How are differenct mixes of prostanoids produced in different tissues?

Answer 11

Tissue specificity is controlled by different synthases e.g. PGD2 (mast cells)
PGE2 (macrophages, fibroblasts, endothelial cells)
PGF2alpha (uterus)
PGI2 (endothelial cells)
TXA2 (platelets)

Question 12

Describe the transport stage in PG synthesis

Answer 12

PGs synthesised in the cell

Transported via ABC transporters aka P-glycoproteins

Question 13

What are the main effects of each prostaglandin receptor being stimulated?

Answer 13

Vasodilatation, inhibition of platelet aggregation
PGE2 - inhibition of gastric acid secretion
PGF2alpha - smooth muscle contraction

TXA2 (thromboxane) - vasoconstriction, platelet aggregation

Question 14

What part of the prostanoid pathway do enzymes inhibit?

Answer 14

Inhibit COX enzymes therefore the breakdown of arachidonic acid to PGH2 is not able to happen ; as a result all prostanoid synthesis ceases

Question 15

Do NSAIDs show selectivity?

Answer 15

Most show no selectivity or are COX-1 seletive (hence the many side effects).
It is more desirable for selective COX-2 inhibitors, the coxibs are selective for COX-2 but are more expensive so less readily synthesised or available

Question 16

What is the house-keeping role of COX-1?

Answer 16

Gastric cytoprotection (mucus and bicarbonate secretion, reduced H+ secretion)
Renal blood flow autoregulation (vasodilatory PGs)
Preventing platelet aggregation (apart from TXA2)

Question 17

What is the role of COX-2?

Answer 17

Induced in inflammatory response

Question 18

What are the problems potentially with some coxibs?

Answer 18

COX-2 present in vascular endothelium in present in some tissues including CNS and blood vessels.
May have increased CVS risk even though reduced GIT risk