EICOSANOIDS MS.PRIYA.S.S
Oct 22, 2014
EICOSANOIDS
MS.PRIYA.S.S
INTRODUCTION
• eicosanoids are signalling molecules derived from omega-3 (ω-3) or omega-6 (ω-6) fats.
• They exert complex control over many bodily systems, especially in inflammation, immunity and as messengers in the central nervous system.
• The amounts of these fats in a person's diet will affect the body's eicosanoid-controlled functions,
• There are four families of eicosanoids—the prostaglandins, prostacyclins, the thromboxanes and the leukotrienes.
• For each, there are two or three separate series, derived either from an ω-3 or ω-6 essential fatty acid.
• These series' different activities largely explain the health effects of ω-3 and ω-6 fats.
Nomenclature
• Eicosanoid" (eicosa-, Greek for "twenty";) is the collective term for oxygenated derivatives of three different 20-carbon essential fatty acids
• Eicosapentaenoic acid (EPA), an ω-3 fatty acid with 5 double bonds;
• Arachidonic acid (AA), an ω-6 fatty acid, with 4 double bonds;
• Dihomo-gamma-linolenic acid (DGLA), an ω-6, with 3 double bonds
• Two families of enzymes catalyze fatty acid oxygenation to produce the eicosanoids:
• Cyclooxygenase, or COX, which comes in at least three isoforms, COX-1, -2, -3 – leading to the prostanoids.
• Lipoxygenase, in several forms. 5-lipoxygenase (5-LO) generates the leukotrienes.
Biosynthesis
• The free fatty acid has twopossible eicosanoid fates:
• 5-lipoxygenase pathway: – Leukotrienes
• Cyclooxygenase pathway("prostanoids"): – Prostaglandins – Prostacyclin – Thromboxanes
• Eicosanoids are a class of oxygenated fatty acids, found widely in a variety of microorganisms, plants and animals.
• In humans, eicosanoids are local hormones that are released by most cells, act on that same cell or nearby cells (i.e., they are autocrine and paracrine mediators), and then are rapidly inactivated.
• Eicosanoids are not stored within cells, but are synthesized as required.
• They derive from fatty acids which are incorporated as esters into larger molecules—the phospholipids and diacylglycerols—found in the cell membrane and nuclear membrane
• The first step of eicosanoid biosynthesis occurs when cell is activated by mechanical trauma, cytokines, growth factors or other stimuli.
• This triggers the release of a phospholipase at the cell wall.
• The phospholipase travels to the nuclear membrane. There, the phospholipase catalyzes ester hydrolysis of phospholipid (by A2) or diacylglycerol (by phospholipase C).
• This frees a 20-carbon essential fatty acid
• . This hydrolysis appears to be the rate-determining step for eicosanoid formation.
Cell Membrane Phospholipids
Arachidonic Acid
Phospholipase A2
Cycloo
xyge
nase Lipoxygenase
ProstaglandinsThromboxanesProstacyclins
LeukotrienesOthers
IsoprostanesCyt. P450products
Biosynthesis of prostanoids
• Cyclooxygenase (COX) catalyzes the conversion of the free essential fatty acids to prostanoids by a two-step process.
• First, two molecules of O2 are added as two peroxide linkages, and a 5-member carbon ring is forged near the middle of the fatty acid chain.
• This forms the short-lived, unstable intermediate Prostaglandin G (PGG). Next, one of the peroxide linkages sheds a single oxygen, forming PGH.
Cell Membrane Phospholipids
Arachidonic Acid
Prostaglandin H2
Thromboxane A2
Prostaglandin E2
Prostaglandin D2
Prostacyclin (PGI2)
Prostaglandin F2α
Phospholipase A2
Cyclooxygenase I&II
isomerase
TXA2
synthasePGI2
synthase
reductase
• NSAIDs inhibits the cyclooxygenase activity whereas catecholamins enhance the activity of prostaglandin synthesis by activating cyclooxygenase .
Biosynthesis of leukotrienes
• The enzyme 5-lipoxygenase (5-LO) uses 5-lipoxygenase activating protein (FLAP) to convert arachidonic acid into 5-hydroperoxyeicosatetraenoic acid (5-HPETE), which spontaneously reduces to 5-hydroxyeicosatetraenoic acid (5-HETE).
• The enzyme 5-LO acts again on 5-HETE to convert it into leukotriene A4 (LTA4), which may be converted into LTB4 by the enzyme leukotriene A4 epoxide hydrolase.
• Eosinophils, mast cells, and alveolar macrophages use the enzyme leukotriene C4 synthase to conjugate glutathione with LTA4 to make LTC4, which is transported outside the cell, where a glutamic acid moiety is removed from it to make LTD4.
• The leukotriene LTD4 is then cleaved by dipeptidases to make LTE4.
• The leukotrienes LTC4, LTD4 and LTE4 all contain cysteine and are collectively known as the cysteinyl leukotrienes.
Cell Membrane Phospholipids
Arachidonic Acid
5- HPETE
Leukotriene A4 5-HETE
Phospholipase A2
5-Lipoxygenase
Dehydrase
Hydrolase
Leukotriene C4 Leukotriene D4 Leukotriene E4
Leukotriene B4
Glutathione S-transferase
Peptidase Peptidase
15-LO12-LO
Lipoxins
12-HPETE 15-HETE
Pharmacological/Physiological Effects
I. Cardiovascular System
1. TXA2: vasoconstrictor.
2. PGE2 and PGI2: vasodilators.
3. LTC4 and D4: increased vascular permeability. ↓Cardiac contractility. ↓ blood pressure.
4. Protective effect of vasodilator prostaglandins especially in kidney.
5. Renin release by MD and baroreceptor mechanisms.
ARACHIDONIC ACID
Platelet TXA2
EndothelialPGI2
VasoconstrictionPlatelet Aggregation
VasodilationAnti-Platelet Aggregation
COX -1 COX -2
ASPIRIN
_ _
Pharmacological/Physiological Effects
II. Platelets
Pharmacological/Physiological Effects
III. Pulmonary
1. LTC4 and D4: Bronchoconstriction + ↑mucus secretion + ↑vascular permeability
2. PGE2 , PGI2: bronchodilators.
IV. GI Tract
1. PGE2 + LT’s contract smooth muscle
2. PGE2: watery diarrhea, vomiting and cramps (↑cAMP)
3. PGE2+ PGI2: inhibit gastric acid secretion; Cytoprotective effect (↑ mucosal blood flow; ↑cAMP; ↑ mucus secretion; ↑ protein synthesis). Misoprostol: used to treat peptic ulcers.
V. Reproductive Organs
1. PGE2: relaxes and PGF2: contracts, non pregnant uterus. Both contract pregnant uterus.
2. Role in promoting labor; in miscarriages (premature labor); inducing abortions.
3. Role in maintaining patent ductus arteriosus.
4. Increased concentration in semen: (?) Role in facilitating conception.
Pharmacological/Physiological Effects
VI. Pain and Inflammation
1. PGE2, PGI2, LTB4: sensitize nerve endings to painful stimuli.
2. Hyperemia, Edema, Hotness due to increased eicosanoids at inflammation sites.
3. LTB4: chemotactic factor for neutrophils and mononuclear cells. Promotes aggregation and degranulation of PMN’s, adhesion to vessel wall and migration
Pharmacological/Physiological Effects