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 .

ileum Small intestine. uterus. [cAMP] Most re ceptors AC. ileum. Th2 cells Kidney. pa ncreas. some AC and [cAMP] EP4 (PGE2) AC. spleen. liver.vm/illustration/2018/a/z . ileum. uterus. lung. lung. b rain. ovary. [cAMP] FP (PGF2) phosphoinositol turnover.Prostaglandin Receptors Receptor (PG) DP1 (PGD2) Signal Transduction AC. VSM. liver Platelets. stomach. lung. l ung. [cAMP] Distribution Platelets. stomach. l ung. [Ca2+] AC. thymus. lung. [Ca2+] http://www. VSM. nervous tissue. pe ripheral blood mo nonuclear cells Corpus luteum. hea rt. VSM. co lon.caymanchem. pancreas Platelets. sp leen. testis. testis uterus Lung. kidney. spleen. thymus. thymus. stomach. placenta Kidney. basophils. brain. eye. uterus Eosinophils. [cAMP]. uterus. skeletal muscle. retina. spleen. s tomach. lung. skeletal muscle. small intestine. pa hea rt. thymus. heart. kidney. small intestine. hea rt. kidney. skele tal muscle. [cAMP] IP (PGI2) TP (TXA2) phosphoinositol turnover. spleen. [Ca2+] AC. kidney. l iver. uterus DP2 (PGD2) EP1 (PGE2) EP2 (PGE2) EP3 (PGE2) Mobilize intrace llular [Ca2+] phosphoinositol turnover. hea rt. adrenal.

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.html .com/arthritis/nsaids/actions.5 to 4 h inhibits expression larger 39 nmol/min/mg affected http://elfstrom.

the more selective for .4 2.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 7.7 -3 0 50 100 150 200 250 NSAID Relative specificity ratio COX-1 to COX-2 Generally.2 1 -1 .4 -1 .9 1. the more serious side-effects appear http://elfstrom.

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? .

leukotrienes. and thromboxanes synthesized (substrates.Review Questions      How are prostaglandins. 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? . enzymes.

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