Eicosanoids (2 Questions)

Question 1

What are eicosanoids and what are they derived from?

Answer 1

Substance in seminal fluid found to induce uterine and smooth muscle contraction (1930)

Derived from C20 polyunsaturated fatty acids that contain 3-5 double bonds

Question 2

Compare Eicosanoids and Steroid Hormones

Answer 2

Question 3

In humans, the principal prostglandins are those from ______.

Answer 3

In humans, the principal prostglandins are those from arachidonic acid

Question 4

COX is also known as prostaglandin H Synthase.

What are the differences between COX-1 and COX-2?

Answer 4

There are two isoforms, COX-1 and COX-2. COX-1 is constitutively expressed while COX-2 is induced by proinflammatory stimuli (IL-1, IL-2, TNF-α).

Inhibition of COX-2 reduces inflammation; inhibition of COX-1 has deleterious effects in stomach

Question 5

Structural differences between COX-1 and COX-2

Answer 5

Question 6

COX contains a hydrophobic channel. Why is this important?

Answer 6

Arachidonate is released by a lipase and enters the hydrophobic channel

Question 7

NSAIDs are hydrophobic drugs, meaning they:

Answer 7

Drugs compete with FA substrate binding

Question 8

Two types of Mechanisms for NSAIDS:

Answer 8

Question 9

COX-1 vs. COX-2 physiologic functioning

Answer 9

COX-1

• Exclusive form in platelets and produces TXA2
• Stimulates mucin production which is gastro-protective (PGE2, PGI2)
• Constitutively expressed in most cell types

COX-2

• Some COX-1-overlapping activity
• Modulates inflammation, pain, fever (PGE2, PGI2)
• Induced in macrophages activated by cytokines and growth factors, implicated in human colorectal cancer (PGE2-mediated angiogenesis)

Question 10

COX-1 vs. COX-2 pocket

Answer 10

• COX-1 and COX-2 differ in their hydrophobic binding pockets
• The side chain of Val 523 (in COX-2) is smaller than Ile 523 (in COX-1)
• The COX-2 binding pocket can accommodate bulkier molecules that don’t fit into the COX-1 pocket

Question 11

PGI2 inhibits _______

Answer 11

PGI2 inhibits thrombosis

Question 12

Effect of Aspirin on platelets

Answer 12

The anucleate platelets cannot regenerate enzymes

• When COX-1 is irreversibly inhibited by aspirin, the platelet cannot produce thromboxane A2 for the rest of its life in the circulation (7 - 10 days)
• Low dose (~25% of normal adult dose) is sufficient to affect COX-1 in platelets, while sparing COX-1 in the endothelial cells of the gut

Question 13

How does Cortisol cause an antiinflammtory effect?

Answer 13

Question 14

What do 5, 12, and 15 HPETEs make?

Answer 14

5 = Macrophages

12 = Platelets

15 = T-Lymphocytes

Question 15

Leukotrienes that are broncho-constrictors

Answer 15

“cysteinyl-LTs”

Question 16

Endocannabinoid

Answer 16

Target is receptor in presynaptic neuron

• Analgesic effects (counter PGI2, PGF2α)
• THC is a receptor agonist