Prostaglandin Leukotriene and Thromboxane Synthesis Pathway overview Prostaglandin

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 Zileuton Arachidonic acid Prostaglandin H 2 synthase Lipoxygenase Prostaglandins (PG) Leukotrienes (LT) Thromboxane A 2 synthase Thromboxanes (TXA)

Prostaglandin Receptors http: //www. caymanchem. com/app/template/scientific. Illustrations%2 CIllustration. vm/illustration/2018/a/z

Pathway Details IL-1 (inflammation) IL-1 R Membrane phospholipids Phospholipase A 2 (or PLC) Anti-inflammatory steroids Glucocorticoids (mediated by lipocortin-Ca 2+) Arachidonic acid NSAIDS (aspirin) Cyclooxygenase PGH 2 synthase O 2 LTA 4 Glutathione S -transferase LTB 4 LTC 4 PGG 2 2 GSH LTD 4 PG hydroperoxidase GSSG LTE 4 PGJ 2 PGD 2 synthase TXA 2 synthase PGH 2 PGD 2 TXA 2 PGI 2 synthase PGI 2 (PC) PGE 2 synthase PGF 2 a PGE 2

Differential Actions of Cyclooxygenases Housekeeping Unwanted sideeffects Constitutive COX 1 NSAIDs Inducible Inflammatory COX 2 PGI 2 Endothelial integrity Vascular patency Gastric mucosal integrity PGE 2 Bronchodilation Renal function TXA 2 Platelet function PGE 2 PGF 2 a Proteases Therapeutic antiinflammatory effects Inflammation

COX-1 and COX-2 Comparison http: //elfstrom. com/arthritis/nsaids/actions. html

COX-1 Specificity of Common NSAIDs 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 Ar Ar PGH 2 PGD 2 PGE 2 PGF 2 a PGI 2 (PC) PGE 2 TXA 2 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 n n n 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?