Eicosanoids Flashcards
eicosanoids def
describes the families of prostaglandins, leukotrienes
mostly derived from arachidonic acid
biosynthesis of eicosanoids
release of arachidonic acid
release of arachidonic acid (free arachidonic acid is very low, but is usually found esterified to membrane phospholipids. Phospholipase A2 is a Ca-dependent enzyme that hydrolyzes the sn2 ester bond of phospholipid and releases arachidonic acid
biosynthesis of eicosanoids
cyclooxygenase
2 isoforms COX1 and COX2
each isoforms has 2 distinct activities
1. oxygenates and cyclizes the precursor fatty acid to form cyclic endoperoxide, PGG2
2. peroxidase activity that converts PGG2 to PGH2
3. COX 1: heme protein, membrane bound, small active site, different chromosome, constitutive. COX 2: heme protein, membrane bound, large active site, inducible
Fate of PGH2: transformed enzymatically into products (PGI2, TXA2, PGE2, PGF2a) PGE2 : PGE1 :: 2 db : 1 db
biosynthesis of eicosanoids
Lipoxygenase
family of cytosolic enzymes that catalyze the oxygenation of fatty acids to corresponding lipid hydroperoxides
lipoxygenases differ in specificity depending on where they attach the hydroperoxy group and tissues differ in the lipoxygenases that they have
most important lipoxygenase is 5-lipoxygenase bc it leads to the formation of leukotrienes
activation of 5-lipoxygenase requires Ca and 5-lipoxygenase activating protein (FLAP)
biosynthesis of eicosanoids
cyp p450
metabolize arachidonic acid to EETs
inhibitors of eicosanoid biosynthesis
via phospholipase A2
activated by Ca, inhibited by drugs that reduce the availability of Ca
glucocorticoids induce synthesis of annexins that inhibit phospholipase A2 activity
inhibitors of eicosanoid biosynthesis
via cyclooxygenase
aspirin and NSAIDS inhibit COX1 and COX2
glucocorticoids decrease expression of COX 2
inhibitors of eicosanoid biosynthesis
via lipoxygenase
inhibitors of 5-lipoxygenase- zileuton (oral admin, t.5=2.5 hrs, metabolized by CYP enzymes, inhibits cys-LTs for bronchoconsttriction and increases vascular permeability and LTB4 for chemotaxis not many SE, its a prophylactic treatment of mild asthma)
Cysteinyl leukotriene receptor antagonist- zafirlukast (oral admin, t.5=10 hrs, metabolized by CYP2C9/3A4 inhibits Cys-LTs, treats mild asthma)
Eicosanoid catabolism
infuse PGE1 - 99% inactivated during one passage thru the pulmonary circulation
2 steps:
1. oxidation by PG dehydrogenase, follwed by reduction by PG reductase fast
- B and omega oxidation–>polar compound–>excreted Slow
cellular mechanism of eicosanoids
prostaglandins: wide effects by a variety of GPCRs
leukotrienes: receptors identified for LTB4, cyseinyl leukotrienes LTC4 and LTD4 coupled to GPCR activation increases intracellular CA
pain and eicosanoids
in the periphery, PGE2 and PGI1 lower the threshold of nociceptors. hyperalgesia. PGs potentiate pain producing activity of brady kinin and autocoids
in the CNS: COX2 is expressed in the dorsal horn of the sp cd and espression increases during inflammation, central PGE2 activates spinal neurons and microglia that can contribute to neuropathic pain.
fever and eicosanoids
fever results from the production of PG, primarily PGE2 from vascular endothelial cells via COX2. These PGs generate the neuronal signals that activate the thermoregulatory center in anterior hypothalamus. PGE2 synthesis is stimulated by endogenous (IL1) or exogenous (lipopolysaccharide) pyrogens
PGF2a and PGI2 induce feve but do not contribute to the pyretic response. TXA2 does not induce fever.
platelets and eicosanoids
activation of platelet membrane PLA2 causes release of arachidonic acid and its transformation into TXA2 by COX1
TXA2: promotes platelet aggregation by stimulating the TP receptor. TP receptor is coupled to increase in intracellular Ca
PGI2: inhibits platelet aggregation via stimulation of IP receptor that couples to cAMP. cell source of PGI2 is endothelial cells (PLA)–> release of arachidonic acid and metabolism by COX1 and/or COX2 (inflammation)
Repro and eicosanoids
uterus/pregnancy: associated increase in COX1 and COX2
PGI2: contributes to quiescent state of uterine activity during early pregnany, relaxation of uterine tone via increase of cAMP
PGE2: initiation and progression of labor by inducing uterine contractility, cervical ripening,
PGF2a: mediates uterine contractility during labor, conc increase in menstrual fluid and cause vasoconstriction, uterine contraction, pain
1’ dysmenorrhea: menstrual pain
CV smooth muscle and eicosanoids
prostaglandins: systemic BP falls in response to PGE2, and hypotension after IV PGI2
PGE2: and PGI2: predominantly vasodilators
TXA2: potent vasoconstrictor
PGF2a: vasocontriction
locally produced PGs counteract the effects of circulating vasoconstrictor autocoids. TO MAINTAIN blood flow to vital organs
PGs maintain patency of ductus arteriosus during fatal life. allows right blood to bypass the pulm system
PGE2: major PG that affects tone of ductus, relaxation via EP4 receptor, COX 2