EICOSANOIDS

Eicosanoids

 Eicosanoids = Prostanoids+ Leukotrienes

 Prostanoids = Prostaglandins and Thromboxanes

 collectively known as eicosanoids to reflect their origin from polyunsaturated

fatty acids with 20 carbons.

(Greek Eicosa= 20)

General functions

 extremely potent compounds  physiologic (inflammatory response)

pathologic (hypersensitivity)

 ensure gastric integrity and renal function

 regulate smooth muscle contraction (intestine and uterus are key sites)
 regulate blood vessel diameter
 maintain platelet homeostasis
 Eicosanoids as local hormones
(differences from true hormones)

i. produced in very small amounts in almost all tissues rather than in

specialized glands.
ii. act locally rather than after transport in the blood to distant sites
iii. not stored
iv. have an extremely short half-life, being rapidly metabolized to inactive
products

 actions are mediated by plasma membrane G protein–coupled receptors

 Nomenclature
 Prostaglandins are named as
PG + a third letter + subscript number

Third letter  e.g. A, D, E, F  designates the type and arrangement of

functional groups in the molecule.
subscript number  number of double bonds in the molecule.

 PGI2 is known as prostacyclin

 Thromboxanes  TX
 Leukotrienes  LT
 SYNTHESIS OF EICOSANOIDS

 dietary precursor  essential fatty acid, an ω-6 fatty acid linoleic acid

 linoleic acid  desaturated and elongated to arachidonic acid (also an ω-6)

 arachidonic acid  eicosanoids

 Membrane phospholipids
Phospholipase A2

Arachidonic acid
5- Lipoxygenase Cyclooxygenase

Leukotrienes Prostaglandins
Thromboxane Prostanoids
Prostacyclins

The major fates of Arachidonic acid

 1. CYLOOXYGENASE PATHWAY

first step  Synthesis of PGH2 by PGH2 synthase

 free arachidonic acid  oxidative cyclization  PGH2

 Enzyme prostaglandin endoperoxide synthase (PGH2 synthase)

 PGH2 synthase  an endoplasmic reticulum membrane-bound protein

 has two catalytic activities
1. fatty acid cyclooxygenase (COX)  requires two molecules of O2
2. peroxidase, dependent on reduced glutathione
 O2

Arachidonic acid PGG2

cyclooxygenase
peroxidase, Glutathione

PGH2

PGE2 PGI2

PGF2 TXA2 PGD2

Second step  PGH2 is converted to a variety of prostaglandins and

thromboxanes by cell-specific synthases
Isozymes of PGH synthase:
 Two isozymes  COX-1 and COX-2

COX-1
 Constitutively made in most tissues
 required for maintenance of healthy gastric tissue, renal homeostasis, and
platelet aggregation.

COX-2
 inducible in a limited number of tissues in response to products of activated
immune and inflammatory cells

Note: induction of COX-2  increase in prostaglandin synthesis  pain, heat,

redness, and swelling of inflammation, and the fever of infection.
 FUNCTIONS AND IMPORTANCE OF
PROSTANOIDS
1. TXA2 (Thromboxane A2)
 Released by platelets
 Promotes platelet aggregation
 Vasoconstriction
 Mobilizes intracellular calcium
 Contraction of smooth muscle

2. PGI2 (Prostacyclin)
 Produced by endothelial cells of vessels
 Vasodilation
 Inhibits platelet aggregation
3. PGF2α (Prostaglandin F2α)
 Produced by most tissues
 Cause
 Vasoconstriction and bronchoconstriction
 Contraction of smooth muscle
 Stimulates uterine contractions

4. PGE2 (Prostaglandin E2)

 Produced by most tissues
 Cause
 Vasodilation
 Protects gastric mucosa
 Potentiates pain sensation
 Used to induce labor
 Regulates renal function
 Required for fever response
 Regulates renal function
 2. SYNTHESIS OF LEUKOTRIENES

 Arachidonic acid  a variety of linear hydroperoxy acids  involving a family

of lipoxygenases (LOXs)

 For example,
 5-lipoxygenase converts arachidonic acid to 5- hydroperoxy-6,8,11,14
eicosatetraenoic acid (5-HPETE)

 5-HPETE is converted to a series of leukotrienes

(the nature of the final products varying according to the tissue)
 O2
Arachidonic acid 5-HPETE
5- Lipoxygenase

LTA4 LTB4
glutathione
LTC4

LTD4

LTE4
 FUNCTIONS AND IMPORTANCE OF
LEUKTRIENES
LTA4 (Leukotriene A4)
 Produced in leukocytes, platelets, mast cells, and heart and lung vascular tissues

LTC4  LTD4  LTE4

 Contraction of smooth muscle
 Bronchoconstriction
 Vasoconstriction
 Increased vascular permeability
 Cysteinyl LTs makeup slow- reacting substance of anaphylaxis
 Involved in the pathophysiology of asthma and seasonal allergies
LTB4 (Leukotriene B4)
 Increased chemotaxis of neutrophils
 Release of lysosomal enzymes from white blood cells
 Adhesion of white blood cells
 CLINICAL CORRELATION

Anti inflammatory drugs inhibit synthesis of eicosanoids

1. Glucocorticoids  cortisol (a steroidal anti-inflammatory agent)

 inhibits phospholipase A2 activity
 arachidonic acid, is not made available from membrane
phospholipids.

2. Non steroidal anti inflammatory drugs [NSAIDS]

 like Aspirin, indomethacin, and ibuprofen
 inhibit both COX-1 and COX-2
 prevent the synthesis of the parent prostaglandin, PGH2
 Systemic inhibition of COX-1, with subsequent damage to the stomach and the
kidneys, and impaired clotting of blood, is the basis of aspirin’s toxicity.

COX-2 selective inhibitors (for example, celecoxib)

 reduce pathologic inflammatory processes while maintaining the physiologic
functions of COX-1
 use has been associated with increased risk of heart attacks.
 Role of prostaglandins in platelet
homeostasis
1. TXA2 (Thromboxane A2)
 Released by platelets
 Promotes platelet aggregation
 Vasoconstriction

2. PGI2 (Prostacyclin)
 Produced by endothelial cells of vessels
 Vasodilation
 Inhibits platelet aggregation

 The opposing effects of TXA2 and PGI2 limit thrombi formation to sites of vascular
injury
 Aspirin has an anti-thrombogenic effect

in platelets in endothelial cells

inhibits COX-1 (irreversible acetylation) inhibit COX-2 (irreversible acetylation)

inhibits TXA2 synthesis inhibits PGI2 synthesis

 inhibition cannot be overcome in  inhibition can be overcome in

platelets (lack nuclei) endothelial cells (have a nucleus)

This difference is the basis of low-dose aspirin therapy used to lower the
risk of stroke and heart attacks by decreasing formation of thrombi