anatomy
poorva
Eicosanoids-3.pptxEicosanoids
Srujana Rayalam DVM, PhD
Dept. of Pharmaceutical Sciences
PCOM-GA campus
PHAR 113G Anatomy, Physiology & Pathophysiology I
8/30/2019 9:14 AM
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Learning Objectives
Describe the role of arachidonic acid mobilization in generation of eicosanoids
Contrast the roles of cyclooxygenase & synthase enzymes in prostanoid biosynthesis
Describe the key steps in biosynthesis of prostanoids and leukotrienes and list the end products
Outline how other eicosanoid mediators are generated from arachidonic acid
Outline the main features of eicosanoid receptors & their signaling mechanisms
Contrast the effects of eicosanoids on inflammation & smooth muscle tone
Eicosanoids - Introduction
Oxygenation products of polyunsaturated long-chain fatty acids
Display an extraordinarily wide spectrum of biologic activity
Arachidonic acid - the most abundant of the eicosanoid precursors
a 20-carbon (C20) fatty acid containing four double bonds
Numerous autocrine & paracrine signaling roles
Key roles in inflammation but also have roles in fever, regulation of blood pressure, blood clotting, immune system modulation, control of reproductive processes
Eicosanoid Biosynthesis
1st step in biosynthesis is mobilization of arachidonic acid from membrane phospholipid
Effected by phospholipase A2
Diverse stimuli induce activation of phospholipase A2
Characteristically through increase in intracellular Ca2+
Corticosteroids are anti-inflammatory because they prevent inducible Phospholipase A2 expression, reducing ARA release.
Mobilization of arachidonic acid is rate-limiting step in eicosanoid biosynthesis
Eicosanoid Biosynthesis
Different eicosanoids generated from arachidonic acid by 3 distinct enzyme pathways
Cyclo-oxygenase pathway → prostanoids
Lipoxygenase pathway → leukotrienes, hydroxyeicosatrienoic acids (HETEs)
Cytochrome P450 pathway → epoxyeicosatrienoic acids (EETs), HETEs
Non-enzymatic conversion yields isoprostanes
Pathways of arachidonic acid (AA) release and metabolism
Basic & Clinical Pharmacology (11th edition)
Prostanoid biosynthesis: COX pathway
Two different isoforms of cyclo-oxygenase (COX) responsible for first steps
COX-1 expressed constitutively in most cells
Mainly serves “house-keeping” role
COX-2 expressed in inducible manner
Major role in inflammation
Also has other key roles
Two-step metabolism by cyclo-oxygenase → prostaglandin H2 (unstable endoperoxide)
COX and LOX Inhibitors
Cyclooxygenase inhibitors include aspirin and ibuprofen. They inhibit both COX-1 and COX-2 and thus inhibit prostaglandin synthesis
Aspirin is an irreversibly inhibitor
Selective COX-2 inhibitors are 200-300 fold more potent in blocking COX-2 than COX-1.
While COX-1 is responsible for the production of prosta glandins that are involved in both inflammation and homeostatic functions, COX-2 generates prostaglandins that are involved only in inflammatory Reactions.
Lipoxygenase inhibitors. Pharmacologic agents that inhibit leukotriene production (e.g., Zileuton) are useful in the treatment of asthma.
Prostanoid biosynthesis: COX pathway
Two-step metabolism by cyclooxygenase → prostaglandins G2 and H2 (both unstable endoperoxides)
unstable
endoperoxides
Basic & Clinical Pharmacology (11th edition)
Prostanoid biosynthesis: COX pathway
Subsequent metabolism by synthase specific for each prostanoid
e.g., prostacyclin synthase → prostacyclin (prostaglandin I2)
Different cell types express different types of synthase
Yield different prostanoid products – usually predominance of 1–2 prostanoids
e.g., vascular endothelial cells → prostacyclin
blood platelets → thromboxane A2
Different prostanoids induce different actions through specific receptors
Isoprostanes also capable of stimulating some prostanoid receptors
Prostanoid biosynthesis: COX pathway
Metabolism of PGH2 by specific synthases
Basic & Clinical Pharmacology (11th edition)
Leukotriene biosynthesis: LOX pathway
Metabolism of arachidonic acid by 5-lipoxygenase → leukotrienes
Initial 2-step reaction → leukotriene A4 (unstable endoperoxide)
Requires participation of 5-lipoxygenase activating protein (FLAP)
Prominent pathway in leukocytes
Leukotriene A4 subsequently converted to other products
Hydrolysis → leukotriene B4
Glutathione conjugation → leukotriene C4 → leukotriene D4 → leukotriene E4
LTD4 and LTE4 are referred to as “cysteinyl leukotrienes”
Leukotriene biosynthesis: LOX pathway
Requires participation of 5-lipoxygenase activating protein (FLAP); Prominent pathway in leukocytes
Basic & Clinical Pharmacology (11th edition)
Leukotriene biosynthesis: LOX pathway
Distinct forms of lipoxygenase yield further products
12-lipoxygenase (abundant in platelets) → converts arachidonic acid to lipoxins
Lipoxins are anti-inflammatory in nature
Can also yield 12-HETE & hepoxilins
Different lipoxygenase products induce different actions through specific receptors
Epoxygenase Products
Specific isozymes of microsomal cytochrome P450 mono-oxygenases convert AA to
5-hydroxyeicosatetraenoic acid (5-HETE)
epoxyeicosatrienoic acid (EET)
Biosynthesis is altered by pharmacologic, nutritional, and genetic factors that affect P450 expression
Biological functions of EET’s & HETE’s less well understood
EETs appear to play role in local vasodilatation
Isoprostanes
Products of non-enzymatic pathway
Produced by the reaction of free radicals with arachidonic acid
Markers and mediators of oxidative stress
Vasoconstrictive effects
Generated in larger quantities than prostaglandins
Complexities in Prostanoid Biosynthesis
Goodman & Gilman’s the Pharmacological Basis of Therapeutics (12th edition)
Eicosanoid Receptors & Signaling
Eicosanoid action mediated by specific GPCRs
Depending on the cell type, the activated G-protein may stimulate or inhibit formation of cAMP, or may activate a phosphatidylinositol signal pathway leading to intracellular Ca++ release.
Prostacyclin (IP) receptor: ↑ cAMP
Prostaglandin F2α (FP) receptor: ↑ Ca2+
Thromboxane A2 (TP) receptor: ↑ Ca2+
Leukotriene B4 (BLT1) receptor : ↑ Ca2+
Cysteinyl leukotriene (CysLT1 & CysLT2) receptors: ↑ Ca2+
Prostaglandin E2 (EP) receptors: Gs, Gq or Gi
Basic & Clinical Pharmacology (11th edition)
Eicosanoids act mainly in an autocrine and a paracrine fashion
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Complexities in Eicosanoid Signaling
Basic & Clinical Pharmacology (11th edition)
Multiple subtypes of prostaglandin E2 & D2 receptors
Diverse signaling mechanisms
Effects of Eicosanoids
Smooth muscle (vascular and respiratory tract)
Thromboxane A2, prostaglandin D2 & prostaglandin F2α → vasoconstriction (by ↑Ca2+)
PGI2 (prostacyclins) and PGE2 promote vasodilation by ↑ cAMP
Cysteinyl leukotrienes → contraction (↑ Ca2+)
particularly LTC4 and LTD4, are potent bronchoconstrictors
Uterine smooth muscle contraction
Prostaglandin F2α and PGE2
Labor induction
Effects of Eicosanoids
Fever: PGE2 ↑ body temperature (aspirin blocks synthesis of PGE2)
Inflammation: Redness, Pain, Heat, Swelling
Chemotaxis
PGE2, prostacyclin & PGD2 will ↑ leukocyte infiltration
Cysteinyl leukotrienes will ↑ eosinophil infiltration & mast cell activation
Summary: Production of arachidonic acid metabolites and their roles in inflammation
Robbins and Cotran (9th edition)
Review
Arachidonic acid mobilization
Roles of cyclooxygenase & synthase enzymes
Biosynthesis of prostanoids and leukotrienes
Eicosanoid receptors
Effects of eicosanoids on inflammation & smooth muscle tone
