Chapter 30: Eicosanoids; Prostaglandins and Thomboxanes Flashcards
Pleiotropic action of eicosanoids
- Vascular
- Gastrointestinal
- Reproductive
Prostaglandins and thromboxanes
- Produced in all mammalian cells except RBCs
- Oxygenated derivatives of polyunsaturated, long chain FAs
- Produced rapidly from cell membrane in phospholipis in response to an event (not produced by an endocrine gland)
- Short half-life (rapidly degraded)
- Local homrones (paracrine mediatiors of inflammation and pain)
- Act locally & rapidly degraded
- Pleiotropic actions
- G-protein linked receptors
Prostaglandin receptor mechanisms
- Eicodanoids act rapidly in an autocrine and paracrine fashion
- Bind to receptors on the cell surface
- Receptor density and type on different cells determine specificity
- Receptors are G protein-linked and contain sequences…..
cAMP production
- Local hormone (prostaglandin) binds to receptor (most likely 7-pass serpentine receptor)
- G-protein is activated, then activated adenylate cyclase
- cAMP activates protein kinase A
- Binding of cAMP to the regulatory subunit causes catalytic subunits to dissociate
- Catalytic subunits can then go on to phosphorylate intracellular proteins
- Active site of the enzyme is tucked away inside tetramer
- When cAMP binds to regulatory subunits, catalytic subunits come apart and expose the active site
Eicosanoids and IP3
- Bind to receptors, activate G protein (in this case a GP or GQ)
- GQ activates phospholipase C
- Phospholipase C hydrolyzes PIP2 to IP3 and DAG
- Prostaglandins exert hteir effects by bnidnig to cell surface receptors (mostly G protein linked)
- DAG activates protein kinase C
- IP3 binding causes PKC to move to the cell membrane
Arachidonic acid (C20:4) is derived from
- Essential linoleic acid (omega-6 FA)
Essential fatty acid (C18:2) is abundant in
- US diet
Arachidonic acid is a
- 20 carbon (C20:4) FA
- Contains four double bonds
Arachidonate is present in
- Membranes “stored” in phospholipids
Arachidonate is liberated by
- Phospholipase A2
Arachidonic acid (C20:4) functions as
- Proinflammatory
- Associated with pathology of endothelial cells
Alpha-linoleic acid (omega-3) functions as
- Cardio-protective fatty acid
Arachidonic acid (C20:4) activates
- Protein kinase C
- Phospholipase D
- Functions as a signaling molecule itself
Liberation of arachidonate
- Released form membrane phospholipids by phospholipase A2 (rate limiting)
- Can also be released by a combination of phopsholipase C and diacylglycerol lipase or phopsholipase C, diacylglycerol kinase and phospholipase A2
- Anti inflammatory drufs inhibit these lipase pathways thereby explaining their potent anti-inflammatory proterties
Oxygenation of arachidonic acid
- After liberation from a phopsholipid, arachidonic acid may be oxygenated
- The cyclooygenase pathway leading to prostaglanding and thomboxanes
- Lipoxygenase pathway leading to leukotrienes
In circulatory system
- Endothelial cells are producing prostocylin
- Produced in enothedelial cells, prostocyclin keeps blood veseels open and favors blood flow
Platelets producing thromboxane A2 mediate
- Vasoconstricton
Arachidonic acid is the majore percursor of
- Eicosanoids
- PGH2 is unstable and rapidly broken down
Cyclooxygenase pathway
- 3 unique but related cyclooxygenase isoenzymes convert arachidonic acid to unstable postalgandin endoperoxide, PGH2
Cycloogygenase I (COX I)
- Constitutive
- House keeping
- Permanently turned on (good things we want COX to do)
- Maintain blood flow, protect stomach, etc.
Cyclooxygenase II (COX II)
- Inducible (induced in macrophages and other cells)
- Inflammatory/trauma response
- Overproduced in response to inflammation/trauma without affecting COX I
COX III
- Found in heart and kidney
- Inhibited by acetaminophen
Regulation of blood flow
- Blood pressure and coagulation
- PGI2 (endothelium - v/d) vs TXA2 (platelets - v/c)
- Aortic thromboxane levels increase during MI
PGE2 inhibition of acid secretion and stimulates mucus secretion
- Cytoprotection
- Eicosanoid levels elevated in rectal mucosa and stool in inflammatory bowel disease
Promote luteolysis and regulation of female reproductive cycle
- Induce labor
Eicosanoids
- Stimulation of inflammation
- Modulation of synaptic transmission
Pleiotropic action of eicosanoids involves
- Regulation of blood flow
- PGE2 inhibition of acid secretion & stimulates mucus secretion
- Promote luteolysis and regulation of female reproductive cycle
- Stimulation of inflammation
- Modulation of synaptic transmission
Regulation of platelet and endothelial cell interactions occurs by
- TXA2
- PGI
If endothelial cells become damaged
- Significant amounts of platelet aggregation try to plug the leak
- Overproduce thromboxane A2
- Levels of prostacyclin are diminished
Once endothelial cells are repaired after damage
- Equilibrium of thromboxane A2 and prostacyclin activity is restored
Inhibition of eicosanoid production occurs via
- Anti-inflammatory drugs
NSAIDS
- Exert their effects by inhibiting COX activity
Aspiring
- Irreversibly acetylates specific serine moieties on both COX enzymes
- Inhibits COX I and modifies activity of COX II
Ibuprofen (Advil)
- Inhibits COX I and II non-covalently
Corticosteroids (lke prednisone)
- Block eicosanoid synthesis, perhaps by stimulating the synthesis of several inhibitory proteins called annexins (target phospholipase A2)
Corticosteriods
- PLase A2
John Vane was responsible for
- Aspirin = COX inhibition
- Colon cancer?
- Myocardial infraction
- GIT toxicity is a problem
- Worked to identify the target to these drugs
Ibuprofen inhibits
- COX I and COX II (non-covalent)
Specific COX II inhibitors sort
- After
- Remember the Vioxx story
Anti-inflammatory drugs target
- Eicosanoid synthesis
Both prostaglandins and leukotrienes are derived from
- Membrane phospholipid; arachidonic acid
Aspirin and other nonsteroidal antiinflammatory drugs (NSAIDS) and corticosteroids inhibit
- Eicosanoid production
