9.8.25 Eicosanoids (Gardner)

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25 Terms

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eicosanoids

chemically diverse
- act as autocoids (signaling molecules that function in an autocrine or paracrine fashion)
arachidonic acid derived
- act in autocrine or paracrine fashion; function through G protein linked receptors
- numerous subtypes
  - prostaglandins → includes prostacyclin and thromboxane
  - leukotrienes
  - lipoxins
  - epoxyeicosatrienoic acids
  - hydroperoxyeicosatetraenoic acids
  - hepoxilins

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biochemical effects

gluconeogenesis → creates glucose from non-carb precursors
lipolysis → breakdown of triglycerides into FFA
glycogenolysis → breakdown of stored glycogen to glucose
slowed heart rate
increase/decrease neuronal electrical activity
vision
increase/decrease muscle contraction
increase/decrease blood psi

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arachidonic acid metabolism

synthesized from linoleic acid
arachidonic acid → esterfied to membrane phospholipids
- e.g. phosphatidylinositol, phosphatidylcholine, phosphatidylethanoliamine
predominantly released by phospholipase A₂ (rate determining step)
- released from membrane phospholipids thru ^
- secretory or cytosolic (2 forms of PLA₂)
- stimulated by cytokines and growth factors
- inhibited by lipocortins

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arachidonic acid and esterification to membrane phospholipids pathway

stimulus binds to receptor

PLA₂ pathway
- PLA₂ acts on phosphatidylcholine and frees arachidonic acid
PLC pathway
- PLC hydrolyzes phosphatidylinositol bisphosphate (PIP2) into 2 pathways
- PLC → 1,2-diacylglycerol
  - → arachidonic acid thru diacylglycerol lipase
  - → monoacylglycerol thru diacylglycerol lipase → arachidonic acid thru monozcylglycerol lipase

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eicosanoid biosynthesis + receptors

arachidonic acid is cleaved from phospholipid thru PLA2
arachidonic acid goes through 3 different pathways
- cyclooxygenase pathway
  - enzymes = COX2/COX1 → prostaglandins
- cytochrome P450 pathway
  - enzymes = CYP → epoxyeicosatetraenoic acid
- lipooxygenase pathway
  - enzymes
    - 5-LOX → leukotrienes
    - 8/15 LOX; 12/15 LOX; 12 LOX; 12(R)-LOX → hydroperoxyeicosatetraenoic acids

<ul><li><p>arachidonic acid is cleaved from phospholipid thru PLA2</p></li><li><p>arachidonic acid goes through 3 different pathways</p><ul><li><p>cyclooxygenase pathway</p><ul><li><p>enzymes = COX2/COX1 → prostaglandins</p></li></ul></li><li><p>cytochrome P450 pathway</p><ul><li><p>enzymes = CYP → epoxyeicosatetraenoic acid</p></li></ul></li><li><p>lipooxygenase pathway</p><ul><li><p>enzymes </p><ul><li><p>5-LOX → leukotrienes</p></li><li><p>8/15 LOX; 12/15 LOX; 12 LOX; 12(R)-LOX → hydroperoxyeicosatetraenoic acids</p></li></ul></li></ul></li></ul></li></ul><p></p>

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prostanoids

prostaglandins, prostacycline and thromboxanes

modulators of adenylyl cyclase activity (controls platelet aggregation and inhibit the effect of anti-diuretic hormone)
plays a role in inflammatory responses, pain, CV and renal functions, pregnancy (F type prostaglandins → labor)
NSAIDs or w3 PUFAs inhibit synthesis
synthesized via cyclo-oxygenase pathways
- COX1
- COX2

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comparison of COX enzymes

expression

COX1 → constitutive (continually expressed under normal conditions)
COX2 → inducible, constitutive in parts of NS

tissue location

COX1 → ubiquitous expression (everywhere)
COX2 → inflamed + activated tissues

cellular localization

COX1 → ER
COX2 → ER/nuclear membrane

substrate selectivity

COX1 → arachidonic acid, eicosapentaenoic acids
COX2 → arachidonic acid, g-linolenate,a-linolenate-linoleate, eicosapentaenoic acid

role

COX1 → protection/maintenance functions
COX2 → pro-inflammatory + mitogenic functions (undergo mitosis)

induction

COX1 → N/A
COX2 → induced by LPS, TNFa, IL-1, IL-2, EGF, IFNg

inhibition

COX1 → NSAIDs
COX2 → anti-inflammatory glucocorticoids, IL-4, IL-10, IL-13, NSAIDS, acetaminophen, COX-2 selective inhibitors
- acetaminophen does NOT directly inhibit COX-2. its a co-substrate so it shunts away some of the ability of COX2 to make eicosanoids

<p>expression</p><ul><li><p>COX1 → constitutive (continually expressed under normal conditions)</p></li><li><p>COX2 → inducible, constitutive in parts of NS</p></li></ul><p>tissue location</p><ul><li><p>COX1 → ubiquitous expression (everywhere)</p></li><li><p>COX2 → inflamed + activated tissues</p></li></ul><p>cellular localization</p><ul><li><p>COX1 → ER</p></li><li><p>COX2 → ER/nuclear membrane</p></li></ul><p>substrate selectivity</p><ul><li><p>COX1 → arachidonic acid, eicosapentaenoic acids</p></li><li><p>COX2 → arachidonic acid, g-linolenate,a-linolenate-linoleate, eicosapentaenoic acid</p></li></ul><p>role</p><ul><li><p>COX1 → protection/maintenance functions</p></li><li><p>COX2 → pro-inflammatory + mitogenic functions (undergo mitosis)</p></li></ul><p>induction</p><ul><li><p>COX1 → N/A</p></li><li><p>COX2 → induced by LPS, TNFa, IL-1, IL-2, EGF, IFNg</p></li></ul><p>inhibition</p><ul><li><p>COX1 → NSAIDs</p></li><li><p>COX2 → anti-inflammatory glucocorticoids, IL-4, IL-10, IL-13, NSAIDS, acetaminophen, COX-2 selective inhibitors</p><ul><li><p>acetaminophen does NOT directly inhibit COX-2. its a co-substrate so it shunts away some of the ability of COX2 to make eicosanoids<br></p></li></ul></li></ul><p></p>

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prostanoid synthesis

arachidonic acid is cleaved from phospholipid by PLA2
arachidonic acid → PGG2
- enzyme = COX1 and 2
- cyclooxygenase rxn
PGG2 → PGH2
- enzyme = COX1 and 2
- peroxidase rxn
PGH2 becomes hella prostanoids
- → PGF2α thru PGF synthase
- → PGD₂ thru PGD synthase
- → PGE₂ thru PGE synthase
- → PGI₂ thru prostacyclin synthase
- → TXA₂ thru tromboxane synthase

<ul><li><p>arachidonic acid is cleaved from phospholipid by PLA2</p></li><li><p>arachidonic acid → PGG2 </p><ul><li><p>enzyme = COX1 and 2</p></li><li><p>cyclooxygenase rxn</p></li></ul></li><li><p>PGG2 → PGH2 </p><ul><li><p>enzyme = COX1 and 2</p></li><li><p>peroxidase rxn</p></li></ul></li><li><p>PGH2 becomes hella prostanoids</p><ul><li><p>→ PGF2<span>α thru <u>PGF synthase</u></span></p></li><li><p>→ PGD<sub>2</sub> thru <u>PGD synthase</u></p></li><li><p>→ PGE<sub>2</sub> thru <u>PGE synthase</u></p></li><li><p>→ PGI<sub>2</sub> thru <u>prostacyclin synthase</u></p></li><li><p>→ TXA<sub>2</sub> thru <u>tromboxane synthase</u></p></li></ul></li></ul><p></p>

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prostanoid production

anadamide (AEA)
- FAAH/NAAA breaks down AEA → arachidonic acid and ethanolamine which goes thru COX-2 pathway
- can be directly metabolized by COX-2 but creates a different PGH2 from AA
- PGE₂ → anti-inflam
- PGF₂ → pro-inflam
2-arachidonoylglycerol (2-AG)
- MAGL/ABHD6 breaks down 2-AG → arachidonic acid and glycerol which goes thru COX-2 pathway
- can be directly metabolized by COX-2 but creates a different PGH2 from AA
- PGE₂ → pro-inflam
- PGD₂ → anti-inflam

<ul><li><p>anadamide (AEA)</p><ul><li><p>FAAH/NAAA <strong>breaks down</strong> AEA → arachidonic acid and ethanolamine which goes thru COX-2 pathway</p></li><li><p>can be directly metabolized by COX-2 but creates a <u>different</u> PGH2 from AA</p></li><li><p>PGE<sub>2</sub> → anti-inflam</p></li><li><p>PGF<sub>2</sub> → pro-inflam</p></li></ul></li><li><p>2-arachidonoylglycerol (2-AG) </p><ul><li><p>MAGL/ABHD6 <strong>breaks down</strong> 2-AG → arachidonic acid and glycerol which goes thru COX-2 pathway</p></li><li><p>can be directly metabolized by COX-2 but creates a <u>different</u> PGH2 from AA</p></li><li><p>PGE<sub>2</sub> → pro-inflam</p></li><li><p>PGD<sub>2</sub> → anti-inflam</p></li></ul></li></ul><p></p>

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prostaglandins

prostaglandins all have a cyclopentane ring
letter code is based upon ring modifications (e.g. hydroxyl or keto groups)
the subscript refers to the # of double bonds in the 2 side chains

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thromboxane and prostacyclin

thromboxane
- 6 membered ring
prostacyclin
- only I Ietter code

<ul><li><p>thromboxane</p><ul><li><p>6 membered ring</p></li></ul></li><li><p>prostacyclin</p><ul><li><p>only I Ietter code</p></li></ul></li></ul><p></p>

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prostanoid receptors

receptors located on cell surface
- pharmacologic specificity determined by receptor density and type on different cells
all G protein coupled
multiple isoforms of receptors identified in humans via differential mRNA splicing
- EP₃ (I,II,III,IV,V,VI,e,f)
- FP (A,B)
- TP (α,β)

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prostanoid receptor signaling

IP/EP₂/EP₄/DP₁
- coupled to Gαs → increases adenylyl cyclase → increases cAMP → biological effects
TP/FP/EP
- TP → Gα12/13 → activates rhoGEF → rho activation → biological effects
- TP → Gα16 → activates PLC15-a-hydroxy PGDH
  → increase Ca2+ → biological effects
- TP/FP/EP → Gαq → activates PLC-β → increase Ca2+ - >biological effects
EP₃
- couples to Gαi → increase Ca2+ → biological effects
  - but can also → inhibit adenylyl cyclase → decrease cAMP
DP₂/CR H₂
- couples to Gαi → increase Ca2+ → biological effects
  - but can also → inhibit adenylyl cyclase → decrease cAMP

<ul><li><p>IP/EP<sub>2</sub>/EP<sub>4</sub>/DP<sub>1</sub></p><ul><li><p>coupled to Gαs → <strong>increases </strong>adenylyl cyclase → <strong>increases</strong> cAMP → biological effects</p></li></ul></li><li><p>TP/FP/EP</p><ul><li><p>TP → Gα12/13 → <strong>activates</strong> rhoGEF → rho <strong>activation</strong> → biological effects</p></li><li><p>TP → Gα16 → <strong>activates</strong> PLC<span>15-a-hydroxy PGDH</span></p><img src="https://knowt-user-attachments.s3.amazonaws.com/fa90fcad-845d-48ab-abba-5c6cffc4cf86.png" data-width="100%" data-align="center"><p> → <strong>increase</strong> Ca2+ → biological effects</p></li><li><p>TP/FP/EP → Gαq → <strong>activates </strong>PLC-β → <strong>increase</strong> Ca2+ - >biological effects</p></li></ul></li><li><p>EP<sub>3</sub></p><ul><li><p>couples to Gαi → <strong>increase</strong> Ca2+ → biological effects</p><ul><li><p>but can also → inhibit adenylyl cyclase → <strong>decrease </strong>cAMP</p></li></ul></li></ul></li><li><p>DP<sub>2</sub>/CR H<sub>2</sub></p><ul><li><p>couples to Gαi → <strong>increase</strong> Ca2+ → biological effects</p><ul><li><p>but can also → <strong>inhibit</strong> adenylyl cyclase → <strong>decrease</strong> cAMP</p></li></ul></li></ul></li></ul><p></p>

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prostanoid signaling

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prostanoid functions

PGH₂ → precursor to all other PGs
PGD₂ → bronchoconstriction, sleep control, inhibits platelet aggregation
PGE₂ → vasodilation, bronchodilation, hyperalgesia, fever, diuresis (excessive urine), immunomodulation
PGF_2α → smooth muscle contraction, bronchoconstriction, abortion (give birth)
TxA₂→ vasoconstriction, control of vascular tone, platelet activation
PGI₂ → vasodilation, control of vascular tone, inhibits platelet aggregation

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prostanoid inactiavtion

half life → seconds to minutes
major sites → liver and lungs
hydroxylation by 15-a-hydroxy PGDH and reduction by 13-PG reductase
oxidation of OH group at C₁₅ to keto group
reduction of C₁₃ and C₁₄to dihydroxy derivatives
β-oxidation → results in loss of 2 carbons
ω-hydroxylation → dicarboxylic acid derivatives
excreted in urine

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leukotrienes

produced by leukocytes
100-1000x more potent than histamine in causing bronchoconstriction
component of slow reacting substance of anaphylaxis (SRS-A → acronym for slow reacting substance)
produced via 5-lipoxgenase pathway

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leukotriene synthesis

intracellular
- arachidonic acid → 5-HPETE
  - thru 5-lipoxygenase
- 5-HPETE → LTA₄
  - thru 5-lipoxygenase
- LTA₄ → LTC₄
  - conjugated with GSH using LTC₄ synthase
  - alternate pathway: LTA₄ → LTB₄ thru hydrolase
extracellular
- LTC₄ → LTD₄
  - glutamate is removed
- LTD₄ → LTE₄
  - glycine is removed

<ul><li><p>intracellular</p><ul><li><p>arachidonic acid → 5-HPETE</p><ul><li><p>thru 5-lipoxygenase</p></li></ul></li><li><p>5-HPETE → LTA<sub>4</sub> </p><ul><li><p>thru 5-lipoxygenase</p></li></ul></li><li><p>LTA<sub>4</sub> → LTC<sub>4</sub></p><ul><li><p>conjugated with GSH using LTC<sub>4</sub> synthase</p></li><li><p>alternate pathway: LTA<sub>4</sub> → LTB<sub>4</sub> thru hydrolase</p></li></ul></li></ul></li><li><p>extracellular</p><ul><li><p>LTC<sub>4</sub> → LTD<sub>4</sub> </p><ul><li><p>glutamate is removed</p></li></ul></li><li><p>LTD<sub>4</sub> → LTE<sub>4</sub> </p><ul><li><p>glycine is removed</p></li></ul></li></ul></li></ul><p></p>

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leukotriene signaling

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leukotriene functions

LTA₄ → gives rise to all other LTs
LTB₄ → neutrophil activation, chemotatic, plasma exudation (extravasation of fluids)
LTC₄/LTD₄ → bronchoconstriction, vasoconstriction_, decrease coronary blood flow, decrease cardiac contractility, plasma exudation, promote endothelial and mesangial cell proliferation, activation of transcription factors, cytokine release
LTE₄ → mucin release
HETEs → release Ca2+ stores and promote cell proliferation

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leukotriene inactivation

LTE → 20-COOH-LTE₄
- ω-oxidation
- thru acyl-coA oxidative
20-COOH-LTE₄ → 18-COOH-dinor-LTE₄
- β-oxidation
- thru hydratase/dehydrogenase
18-COOH-dinor-LTE₄ → 16-COOH-tetranor-LTE₃
- β-oxidation
- thru 2,4-dienoyl-coA reductase
16-COOH-tetranor-LTE₃ → 14-COOH-hexanor-LTE₄
- β-oxidation
- thru coA thiolase
metabolized in the liver
excreted in the urine

<ul><li><p>LTE → 20-COOH-LTE<sub>4</sub></p><ul><li><p><span>ω-oxidation</span></p></li><li><p>thru acyl-coA oxidative</p></li></ul></li><li><p>20-COOH-LTE<sub>4</sub> → 18-COOH-dinor-LTE<sub>4</sub></p><ul><li><p><span>β-oxidation</span></p></li><li><p><span>thru hydratase/dehydrogenase</span></p></li></ul></li><li><p>18-COOH-dinor-LTE<sub>4</sub> → 16-COOH-tetranor-LTE<sub>3</sub></p><ul><li><p><span>β-oxidation</span></p></li><li><p><span>thru 2,4-dienoyl-coA reductase</span></p></li></ul></li><li><p>16-COOH-tetranor-LTE<sub>3</sub> → 14-COOH-hexanor-LTE<sub>4</sub></p><ul><li><p><span>β-oxidation</span></p></li><li><p><span>thru coA thiolase</span></p></li></ul></li><li><p>metabolized in the<u> liver</u></p></li><li><p>excreted in the <u>urine</u></p></li></ul><p></p>

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lipoxins

produced via 5-LOX alone or a combo of 15-LOX pathway + 5-LOX followed by conversion by hydrolase
platelets convert LTA₄ via 12-LOX pathway
short lived
diagram
- 1st pathway
  - AA → LTA₄
    - thru neutrophils 5-LOX
  - LTA₄ → LXA₄ or LXB₄
    - thru platelets 12-LOX
- 2nd pathway
  - AA → 15S-H(p)-ETE
    - thru epithelial cells 15-LOX
  - 15S-H(p)-ETE → LXA₄ or LXB₄
    - thru neutrophils 5-LOX
- 3rd ptahway
  - AA → 15R-H(p)-ETE
    - thru epithelial/endothelial cells COX-2/ASA (aspirin; partially inhibits COX-2)
  - 15R-H(p)-ETE → 15-epi-LXA₄ or 15-epi-LXB₄
    - thru neutrophils 5-LOX

<ul><li><p>produced via <strong>5-LOX alone</strong> or a <strong>combo of 15-LOX pathway + 5-LOX </strong>followed by <strong>conversion by hydrolase</strong></p></li><li><p>platelets convert <strong>LTA<sub>4</sub> via 12-LOX pathway </strong></p></li><li><p>short lived</p></li><li><p>diagram</p><ul><li><p>1st pathway</p><ul><li><p>AA → LTA<sub>4</sub></p><ul><li><p>thru neutrophils 5-LOX</p></li></ul></li><li><p>LTA<sub>4</sub> → LXA<sub>4</sub> or LXB<sub>4</sub></p><ul><li><p>thru platelets 12-LOX</p></li></ul></li></ul></li><li><p>2nd pathway</p><ul><li><p>AA → 15S-H(p)-ETE</p><ul><li><p>thru epithelial cells 15-LOX</p></li></ul></li><li><p>15S-H(p)-ETE → LXA<sub>4</sub> or LXB<sub>4</sub></p><ul><li><p>thru neutrophils 5-LOX</p></li></ul></li></ul></li><li><p>3rd ptahway</p><ul><li><p>AA → 15R-H(p)-ETE</p><ul><li><p>thru epithelial/endothelial cells COX-2/ASA (aspirin; partially inhibits COX-2)</p></li></ul></li><li><p>15R-H(p)-ETE → 15-epi-LXA<sub>4</sub> or 15-epi-LXB<sub>4</sub></p><ul><li><p>thru neutrophils 5-LOX</p></li></ul></li></ul></li></ul></li></ul><p></p>

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lipoxin functions

act as negative regulators of inflammation and leukotriene action
LXA₂ receptors present on neutrophils, monocytes, T cells, lung, spleen, blood vessels, G_i protein-coupled receptor
- inhibit neutrophil chemotaxis (mvmt toward site of inflammation), adhesion, transmigration
- inhibit eosinophil recruitment
- stimulate vasodilation by stimulating production of PGI₂ and PGE₂
- inhibit LTC₄ + LTD₄ stimulated vasoconstriction
- inhibit LTB₄ stimulated inflammatory effects
- inhibit function of NK cells and T cell secretion
mediate resolution of inflammatory response
- stimulates uptake and clearance of apoptotic neutrophils by macrophages
- increases non-phlogistic (non-inflammatory) activation of monocytes

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eicosanoid involvement in pathophysiology

asthma → bronchoconstriction → driven by LTC₄/D₄/E₄
inflammatory bowel disease → increase LTB₄
rheumatoid arthritis (autoimmune disease) → up-regulation of COX2 and PGE₂
glomerulonephritis → increase LTB₄, C₄, D₄
cancer → many cancers express COX-2, PGE₂, promotes tumor growth
CV disease → TxA₂ mediates thrombosis in MCI, LT production
inflammation → LTs, PGE₂, LXA_2,TxA₂, PGI₂, PGD₂ → involved in vasoconstriction (TxA₂), vasodilation, edema, chemotaxis, pain, vascular permeability, fever

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epoxyeicosatetraenoic acids (EETs)

produced via cytochrome P450 epoxygenase
occurs in CV endothelium and smooth muscle cells, ascending loop of henle, vascular endothelium in the kidney, brain astrocytes, airway and parenchymal lung tissue and other tissues lacking cycooxygenase and lipoxygenase
acts as paracrine factor regulating local vascular tone, anti-inflammatory
can act as vasodilator, lower blood psi
diagram
- AA → 5,6 EET/8,9-EET/11,12-EET/14,15-EET
  - thru CYP epoxygenase
- EET → DHET (essentially inactive form)
  - thru sEH (soluble exposide hydrolase)