ILA 11 Eicosanoid Metabolism Flashcards
Describe the functions and clinical significance of the eicosanoids: prostaglandins, prostacyclins, thromboxanes, leukotrienes, 5-HETE, and lipoxins Interpret the abbreviation nomenclature for eicosanoids Explain the roles of the significant enzymes in the biosynthesis of the eicosanoids Explain the two roles of glutathione in eicosanoid synthesis Describe the impact of NSAIDs, acetaminophen, asthma drugs, and anti-inflammatory steroids on eicosanoid biosynthesis and function
What is an eicosanoid?
considered to act as local hormones functioning through G-protein receptors
What are the two methods of arachidonic acid formation?
- From cell membrane phospholipids using Phospholipase A2
- Dietary Linoleic Acid
Slide 10
Prostaglandins are produced by which tissue types?
most tissues
Slide 11
PGE2 is known pharmaceutically as what?
Dinoprostone
Slide 11
What are the fuctions of PGE2?
- Inflamatory mediator
- Pyrogenic
- Vasodilation (lowers BP)
- Bronchodilation
- Contraction of longtitudinal muscle in intestine
- Used pharmaceutically to induce labor
Slide 11
What are the pharmaceutical names of PGF2α?
Dinoprost or Carboprost
Slide 11
What are the functions of PGF2α?
- Vasoconstriction
- Contraction of smooth muscle
- Used pharmaceutically to induce labor
Slide 11
What 2 enzymatic activities occur in Prostaglandin Synthase?
- Cycloxygenase
- PG hydroperoxidase
Slide 13
What are the 2 isozymes of Prostaglandin Synthase (PGS) and thier functions?
- PGS-1(COX-1) - constitutively expressed (clotting)
- PGS-2 (COX-2) - produced in response to inflamatory signals (pain & inflammation)
Slide 13
What enzyme catalyzes the conversion of arachidonic acid to PGG2 (step 1 of PGS)?
Cyclooxygenase
as part of the Prostaglandin Synthase Complex
Slide 14
Prostaglandins have the characteristic shape of what?
Hairpins
Slide 12
What enzyme catalyzes the conversion of PGG2 to PGH2 (step 2 of PGS)?
(Hydro)Peroxidase
Slide 15
The peroxidase reaction in step 2 of PGS requires what cofactor?
Reduced Glutathione
Slide 15
Which prostaglandins are produced from PGH2?
- PGD2
- PGE2
- PGF2α
Slide 16
What is Prostacyclin (PGI2)?
What is it a class of? Where is it primarily produced? Funcitons?
- class of prostaglandins
- endothelium of blood vessels
- Vasodilation, inhibition of platelet aggregation, increased formation of cAMP
Slide 17
What prostaglandin is prostacyclin produced from?
PGH2
What are thromboxanes (TXs) a derivative of?
PGH2
Slide 19
What primarily produces thromboxanes?
Platelets
Slide 19
What are the functions of thromboxanes?
- promotes platelet aggregation
- decreases formation of cAMP
- vasoconstriction
- mobilizes intracellular calcium
- smooth muscle contraction
Slide 19
Thromboxanes are produced from what precursor molecule?
PGH2
Slide 20
What enzyme catalyzes the synthesis of thromboxanes?
Thromboxane Synthase
Slide 20
What do NSAIDs do?
Inhibition of what to prevent what?
inhibit cyclooxygenase to prevent synthesis of prostaglandins, thromboxanes, and prostacyclin
NSAIDs have anti-inflamatory, anti pyretic, & pain relieving effects
Slide 21
How does Aspirin work?
What does it inhibit?
inhibits both COX-1 & COX-2, but inhibits COX-1 more effectively than COX-2
Slide 21
In terms of function, Acetaminophen has similar effects as NSAIDs, but lacks what effect?
Anti-inflamatory effect
Acetaminophen has pain-relieving & anti-pyretic effects like NSAIDs.
Slide 22
What do we know about Acetaminophen?
Mechanism?
- mechanism not fully understood
- indirectly blocks cyclooxygenase
- studies suggests it blocks COX-3 (isozyme of cyclooxygenase abundant in cerebral cortex & heart
Slide 22
Where are Leukotrienes (LT) produced?
- leukocytes
- platelets
- mast cells
- heart & lung vascular tissue
Slide 23
What are the functions of LTC4, LTD4, & LTE4?
- contraction of smooth muscle
- promote bronchoconstriction (important in asthma)
- vasoconstriction
- increased vascular permeability
- anaphylaxis
Slide 23
What are the functions of LTB4 & 5-HETE?
- increased chemotaxis of polymorphonuclear (PMN) leukocytes
- release of lysosomal enzymes from PMN leukocytes
- adhesion to leukocytes
Slide 23
What ezyme produces 5-HPETE from Arachidonic acid?
5-lipoxygenase
Slide 25
LTA4 is the common precursor for which leukotrienes?
LTB4 & LTC4
Slide 26
What compound is required for the synthesis of LTC4?
What happens to the compound?
Reduced Glutathione
It becomes part of the structure
Slide 26
How are LTD4 & LTE4 produced from LTC4?
by removing glutamate and then glycine both from glutathione in LTC4
Slide 27
Differentiate between glutathione function in:
leukotriene synthesis vs prostglandin synthesis
This a more complex question but was noted on the slide
In Leukotriene: the reduced glutathione is incorporated into LTC4 and then loses a glutamate & a glycine to form LTD4 & LTE4, respectively.
In Prostaglandin: the reduced glutathione is used in the reaction of PGG2 to form PGH2 using Peroxidase
Slides 15 (Prostaglandin) & 27 (Leukotriene)
What are inhibitors of leukotriene synthesis and function used to treat?
Asthma
Slide 28
How does the drug Zileuton (Zyflo) work?
What does it inhibit and prevent the synthesis of?
Inhibits 5-lipoxygenase preventing the synthesis of 5-HPETE & all leukotrienes derived from 5-HPETE
Slide 28
How do LTC4, LTD4, & LTE4 antagonists (Montelukast, Zafirlukast) work?
They block the binding of these leukotrienes to their receptors
Slide 28
Where are Lipoxins (LX) produced?
Leukocytes
Slide 30
What are the functions of LXA4 & LXB4?
- Inhibit angiogenesis
- Promote clearance of pulmonary edema
Slide 30
What are the two ways that lipoxins can be synthesized from arachidonic acid?
- Arachidonic Acid –(5-Lipoxygenase)–>5-HPETE —->LTA4–(15-Lipoxygenase)–>Lipoxins
- Arachidonic Acid –(15-Lipoxygenase)–>15-HPETE–(5-Lipoxygenase)–>Lipoxins
Slide 31
How do anti-inflamatory steroids (Prednisone) work?
What do they inhibit? Prevent synthesis of?
Inhibit Phospholipase A2 preventing synthesis of most eicosanoids
converts phospholipids to arachidonic acid
Slide 32
How do NSAIDs work?
inhibit cyclooxygenase preventing synthesis of most prostaglandins, thromboxanes, and prostacyclin
Slide 32