Prostaglandin, Leukotriene, and Thromboxane Synthesis

Pathway overview
Prostaglandin receptors Pathway details

Differential actions of cyclooxygenases

COX-1 and COX-2 comparison COX-1 specificity of common NSAIDs Tissue comparison

Eric Niederhoffer SIU-SOM

Pathway Overview
Anti-inflammatory steroids Glucocorticoids NSAIDs aspirin

Linoleic acid Arachidonic acid

NSAIDs Benoxaprofen Zileuton

Prostaglandin H2 synthase

Lipoxygenase

Prostaglandins (PG) Leukotrienes (LT) Thromboxane A2 synthase Thromboxanes (TXA)

NSAIDs Dazoxiben

Prostaglandin Receptors
Receptor (PG)
DP1 (PGD2)

Signal Transduction
AC, [cAMP]

Distribution
Platelets, VSM, nervous tissue, retina, small intestine, ileum, l ung, stomach, uterus Eosinophils, basophils, Th2 cells Kidney, lung, spleen, skeletal muscle, testis uterus Lung, placenta Kidney, stomach, uterus, pa ncreas, adrenal, testis, ovary, small intestine, b rain, spleen, co lon, hea rt, liver, skeletal muscle, lung, thymus, ileum Small intestine, l ung, thymus, kidney, uterus, pa ncreas, spleen, hea rt, stomach, brain, ileum, pe ripheral blood mo nonuclear cells Corpus luteum, uterus, s tomach, kidney, hea rt, lung, eye, liver Platelets, VSM, kidney, thymus, l iver, lung, sp leen, skele tal muscle, heart, pancreas Platelets, VSM, thymus, spleen, lung, kidney, hea rt, uterus

DP2 (PGD2) EP1 (PGE2) EP2 (PGE2) EP3 (PGE2)

Mobilize intrace llular [Ca2+] phosphoinositol turnover, [Ca2+] AC, [cAMP] Most re ceptors AC, [cAMP], some AC and [cAMP]

EP4 (PGE2)

AC, [cAMP]

FP (PGF2)

phosphoinositol turnover, [Ca2+] AC, [cAMP]

IP (PGI2)

TP (TXA2)

phosphoinositol turnover, [Ca2+]

http://www.caymanchem.com/app/template/scientificIllustrations%2CIllustration.vm/illustration/2018/a/z

Pathway Details
IL-1 (inflammation)
IL-1R

Membrane phospholipids
Phospholipase A2 (or PLC)
Anti-inflammatory steroids Glucocorticoids (mediated by lipocortin-Ca2+)

Arachidonic acid
NSAIDS (aspirin)

LTA4
Glutathione S-transferase

Cyclooxygenase
PGH2 synthase

O2
LTB4 LTC4

PGG2 2GSH
PG hydroperoxidase

LTD4

GSSG LTE4 PGJ2 PGD2 synthase TXA2 synthase PGH2 PGD2 TXA2
PGI2 synthase PGE2 synthase PGF2 synthase

PGI2 (PC)

PGE2

PGF2a

Differential Actions of Cyclooxygenases

Housekeeping Unwanted sideeffects

PGI2 PGE2

Endothelial integrity Vascular patency Gastric mucosal integrity

Bronchodilation Renal function Platelet function

Constitutive

COX1

NSAIDs
Inducible Inflammatory

TXA2
PGE2 PGF2a

COX2

Inflammation

Proteases
Therapeutic antiinflammatory effects

COX-1 and COX-2 Comparison

Parame ter Regulation Range of gene induction Rate of gene activation Effect of glucocorticosteroids Relative size of active site Rate of arachidonic acid consumpt ion Effect of aspirin on COX activity COX-1 usually constitutive 2 to 4-fold 24 h inhibits expression smaller 34 nmol/min/mg inhibited COX-2 inducible 10 to 80-fold 0.5 to 4 h inhibits expression larger 39 nmol/min/mg affected

http://elfstrom.com/arthritis/nsaids/actions.html

COX-1 Specificity of Common NSAIDs

Piroxica m Tolme tin Aspirin Sulindac Indome tha cin Ibupr ofe n Ace ta minophe n Sodium salicylate Flur bipr ofe n Carpr ofe n Diclofe nac Naproxe n M eloxicam -5 0 250 174 166 100 60 15 7.4 2.9 1.2 1 -1 .4 -1 .7 -3 0 50 100 150 200 250

NSAID

Relative specificity ratio COX-1 to COX-2

Generally, the more selective for COX-1, the more serious side-effects appear

http://elfstrom.com/arthritis/nsaids/actions.html

Tissue Comparison
Brain/nerve Synovial cells Vascular beds Ar PGH2 PGD2 PGE2 Ar PGH2 PGI2 (PC) Ar PGH2 PGE2

PGE2 PGI2 (PC)

PGF2a

TXA2

So what would happen if we gave a patient a large dose of aspirin or Coxib to reduce inflammation/pain in these tissues?

Review Questions

How are prostaglandins, leukotrienes, and thromboxanes synthesized (substrates, enzymes, cofactors)? What is the nomenclature for prostaglandin receptors? How do NSAIDs work? How do steroids work? What are the important characteristics of COX-1 and COX-2?