Eicosanoids — Prostaglandins, Thromboxanes and Leukotrienes

Eicosanoids: Prostaglandins, Thromboxanes and Leukotrienes

1. Definition, nomenclature & historical overview

• Eicosanoids (Greek eikosi = "twenty") are oxygenation products of 20-carbon polyunsaturated fatty acids; they are the most universally distributed autacoids ("local hormones": autos = self, akos = remedy — formed locally, act locally near the site of synthesis, brief action, destroyed locally) in the body — virtually every cell and tissue can synthesise one or more (G&G 14e Ch.41, p.815; KDT 8e Ch.13, p.197).
• The umbrella term covers prostaglandins (PGs), prostacyclin (PGI₂), thromboxanes (TX), leukotrienes (LTs), lipoxins (LXs), HETEs/EETs (CYP products), isoprostanes, and the ω-3-derived resolvins/protectins/maresins (G&G 14e Ch.41, p.815; R&D 10e Ch.17, p.386).
  • Prostanoids = the cyclooxygenase products only, i.e. PGs + TXs + prostacyclin (have a cyclopentane ring) (R&D 10e Ch.17, p.388; KDT 8e Ch.13, p.197).
  • Leukotrienes = straight-chain (open-chain) lipoxygenase products — named leuko (first isolated from leukocytes) + triene (3 conjugated double bonds) (KDT 8e Ch.13, p.197).
• Precursor essential fatty acids (20-carbon, with 3/4/5 double bonds): dihomo-γ-linolenic acid (DHGLA) → series-1; arachidonic acid (AA; 5,8,11,14-eicosatetraenoic acid) → series-2 (the major mammalian series); eicosapentaenoic acid (EPA; 5,8,11,14,17-) → series-3 (G&G 14e Ch.41, p.815; Katzung 16e Ch.18, p.339).
  • The numerical subscript denotes the number of side-chain double bonds (e.g. PGE₂, PGI₂, TXA₂); the letter (A–I) denotes ring substituents/structure (KDT 8e Ch.13, p.197).
  • During PG/TX/PGI₂ synthesis, 2 of AA's 4 double bonds are saturated in cyclization → subscript-2 prostanoids dominate in humans; LT synthesis involves no cyclization/double-bond reduction → LTs of importance are LTB₄, LTC₄, LTD₄ (KDT 8e Ch.13, p.197).
• History: 1930 Kurzrok & Lieb noted human semen/seminal fluid contracts and relaxes uterine strips; Goldblatt and von Euler independently found smooth-muscle-contracting/vasodepressor activity; 1935 von Euler named "prostaglandin" (mistakenly thought prostate-derived) (G&G 14e Ch.41, p.815; KDT 8e Ch.13, p.197).
  • 1962 Samuelsson & Bergström elucidated PGE₁/PGF₁α structures; 1964 biosynthesis of PGE₂ from AA achieved; 1971 Vane, Smith & Willis showed aspirin/NSAIDs act by inhibiting PG synthesis (G&G 14e Ch.41, p.815).
  • Nobel Prizes: von Euler 1970; Bergström, Samuelsson & Vane 1982 (KDT 8e Ch.13, p.197; G&G 14e Ch.41, p.815).
• Functional roles span vascular tone, renal function, haemostasis, parturition, GI mucosal integrity, stem-cell function, innate immunity and inflammation; NSAIDs (incl. aspirin) owe analgesic/antipyretic effects to blockade of PG formation (G&G 14e Ch.41, p.815).