Eicosanoids Flashcards
What is the major essential fatty acid that synthesizes arachidonic acid?
Linoleate
What is the source for all eicosanoids?
Arachidonic acid
How is arachidonic acid obtained to make eicosanoids?
Must be released from the phospholipids it is connected to by phospholipase A2 or C
What are eicosanoids?
Polysaturated fatty acids derived from the breakdown of phospholipids
What are eicosanoid biological functions?
Participate in inflammatory response and smooth muscle contraction
Short lived - act in autocrine or paracrine fashion
What are the enzymes are involved in eicosanoid synthesis?
Cyclo-oxygenase, lipoxygenase, cytochrome P450
Cyclo-oxygenase produces _____ and _____ from arachidonic acid.
Prostaglandins and thromboxanes
Lipoxygenase produces these three eicosanoids.
Leukotrienes, HETE, lipoxins
Cytochrome P450 produces _____ and _____.
diHETE and HETE
How many carbons does the ring on prostoglandin have?
5
How many carbons does the ring on thromboxane have?
6
What is the synthesis enzyme of prostoglandins and thromboxanes called?
Cyclooxygenase
What does cyclooxygenase do to the arachidonic acid?
Forms the 5 rings structure (PGG2)
What must PGG2 do to become stable?
Rapidly reduced by peroxidase to form PGH2
In vascular tissue, PGH2 becomes _____ via PGI synthase.
PGI2 (prostacyclin)
which modulates vascular tone and platelet aggregation
Platelets will convert PGH2 to _____ via TXA synthase.
TXA2
also modulates vascular tone and platelet aggregation
What are the two forms of cyclo-oxygenase (COX)?
COX-1: constitutively active, in most tissues, expressed in mature platelets
COX-2: induced form, normal low levels but up-regulated by cytokines and growth factor in inflamed tissues
What are COX 1 and 2 inhibited by?
Non-steroidal anti-inflammatory drugs (NSAIDS)
Aspirin, ibuprofen, acetaminophen
What does aspirin do to COX 1 and 2?
Transfers an acteyl group to enzyme, irreversibly inactivating it
Which NSAID are reversible inhibitors of COX?
Ibuprofen and acetaminophen
What are the COX-2 inhibitors that don’t cause GI problems or anti-platelet effects?
Celecoxib (Celebrex)
Rofecoxib (Vioxx) - not in market
What do glucocorticoids do in terms of eicosanoid synthesis?
Inhibits inflammation by (PG synth) by blocking the action of phospholipase A (which changes a phospholipid into a arachidonic acid)
What are leukotrienes?
Molecules synthesized by leukocytes which have a triene structure
What are lipoxins?
Tri-hydroxy derivatives of arachidonic acid
The lipoxygenase pathway starts with the conversion of _____ to _____ via lipoxygenase.
arachidonic acid, HPETEs
What will the HPETE convert to spontaneously?
HETE
How is lipotoxin formed from HETEs?
A series of reductions
What does lipotoxin do?
Function to induce chemotaxis and stimulate superoxide anion production in leukocytes
Epoxides are formed from certain forms of HETE called…
diHETEs (because they are diols)
What pathway are epoxides formed thorugh?
Cytochrome p450
What are epoxides implicated to do?
Not sure by probably ocular, vascular, endocrine and renal somethings and generally activate adenylyl cyclase, cAMP, or protein kinase A pathway
Prostacyclin and Thromboxane have
antagonistic biological effects
Functions of PGI, E, or D
increase vasodilation, cAMP,
decrease platelet aggregation, Leukocyte aggregation, lymphocyte migration, T cell proliferation
Function of TXA2
Increases vasoconstriction, platelet aggregation, lymphocyte proliferation and broncho-constriction
Low aspirin therapy to manage risk of thrombosis is given. What action of Eicosanoids does aspirin interfere with?
Platelet aggregation
what are the functions of Lipoxins?
Stimulate leukocyte production of superoxides and anions
induce chemotaxis
what are some functions of Leukotrienes?
increase vascular permeability, T cell proliferation, Leukocyte aggregation, Broncho constriction, release of pro-inflammatory cytokines such as IFN-y, IL-1 , IL-2
Role of HETE and diHETEE
implicated in
Ocular, vascular, endocrine and renal systems
PGE1 and 2
suppress gastric ulceration by preventing/stopping release of HCl acid from stomach mucous cells
Can’t get it up? Try …
PGE1
just inject it into your penis
works via inducing vasodilation
Mechanisms of action of eicosaniods via
activation of cAMP/PKA pathway
or increasing production of intracellular calcium
Pro or anti inflammatory? - Leukotrienes
Pro
Pro or anti inflammatory? Lipoxins
Pro
Vasoconstrictive or vasodilator? Prostaglandins
PGF - vasoconstricts
PGI, E, D - Vasodilators
Vasoconstrictor or vasodilator? Thromboxanes
Vasoconstrictor
Induces Platelet aggregation?
Thromboxanes
Broncho constrictor
PGF
TXA
LTC,LTD
Increases vascular permeability?
Leukotrienes
Stimulate uterine contraction, induce labor and control postpartum bleeding?
PGE2 and PGF2a
Maintains a patent ductus arteriosus?
PGE1
Analogs of PGI2 (Prostacyclin)
tx of primary pulmonary hypertension
