EICOSANOIDS

MS.PRIYA.S.S

INTRODUCTION
eicosanoids are signalling molecules derived from omega-3 (-3) or omega-6 (-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 eicosanoidcontrolled 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 -3 or -6 essential fatty acid. These series' different activities largely explain the health effects of -3 and -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 -3 fatty acid with 5 double bonds; Arachidonic acid (AA), an -6 fatty acid, with 4 double bonds; Dihomo-gamma-linolenic acid (DGLA), an -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. 5lipoxygenase (5-LO) generates the leukotrienes.

Biosynthesis
The free fatty acid has two possible 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 moleculesthe phospholipids and diacylglycerolsfound 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 ratedetermining step for eicosanoid formation.

Cell Membrane Phospholipids

Phospholipase A2

Arachidonic Acid

Prostaglandins Thromboxanes Prostacyclins

Others

Leukotrienes

Isoprostanes Cyt. P450 products

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

Phospholipase A2

Arachidonic Acid
Cyclooxygenase I&II

Prostaglandin H2
TXA2 synthase isomerase PGI2 synthase reductase

Thromboxane A2 Prostaglandin D2

Prostacyclin (PGI2) Prostaglandin F2

Prostaglandin E2

 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 5hydroperoxyeicosatetraenoic acid (5HPETE), 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

Phospholipase A2

12-HPETE

12-LO

15-LO

Arachidonic Acid
5-Lipoxygenase

15-HETE Lipoxins

Leukotriene B4
Hydrolase

5- HPETE
Dehydrase

Leukotriene A4

5-HETE

Glutathione S-transferase

Leukotriene C4

Leukotriene D4
Peptidase Peptidase

Leukotriene E4

Pharmacological/Physiological Effects
1. 2. 3.
4. I. Cardiovascular System TXA2: vasoconstrictor. PGE2 and PGI2: vasodilators. LTC4 and D4: increased vascular permeability. Cardiac contractility. blood pressure. Protective effect of vasodilator prostaglandins especially in kidney. Renin release by MD and baroreceptor mechanisms.

5.

Pharmacological/Physiological Effects
II. Platelets
ARACHIDONIC ACID
COX -1

COX -2

Platelet TXA2

ASPIRIN

Endothelial PGI2

Vasoconstriction Platelet Aggregation

Vasodilation Anti-Platelet Aggregation

Pharmacological/Physiological Effects
III. Pulmonary
1. IV. GI Tract PGE2 + LTs contract smooth muscle PGE2: watery diarrhea, vomiting and cramps (cAMP) PGE2+ PGI2: inhibit gastric acid secretion; Cytoprotective effect ( mucosal blood flow; cAMP; mucus secretion; protein synthesis). Misoprostol: used to treat peptic ulcers.

1. LTC4 and D4: Bronchoconstricti on + mucus secretion + vascular permeability 2. PGE2 , PGI2: bronchodilators.

2.

3.

Pharmacological/Physiological Effects
1.
V. Reproductive Organs PGE2: relaxes and PGF2: contracts, non pregnant uterus. Both contract pregnant uterus. Role in promoting labor; in miscarriages (premature labor); inducing abortions. Role in maintaining patent ductus arteriosus. Increased concentration in semen: (?) Role in facilitating conception.

2.
3. 4.

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 PMNs, adhesion to vessel wall and migration