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