8. eicosanoids

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Prostaglandins and related compounds are collectively

known as eicosanoids. The term eicosanoid is derivedfrom eicosa meaning twenty, referring to the 20

carbon atoms in most of the molecules.

Most are produced from arachidonic acid, a 20-carbon

polyunsaturated fatty acid with four double bonds byusing interrelated pathway.

The eicosanoids are considered local hormones or

paracrine (Para=near) hormones. They have specific

effects on target cells close to their site of formation.

They are rapidly metabolized to inactive products, so

they are not stored and they are not transported to

distal sites within the body.

Eicosanoids:


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Prostaglandins (PGE2, PGF2 etc.)

Prostacyclins (PGI2)

Thromboxanes (TXA2)

Leukotrienes

Epoxyeicosatrienoic acid (EETs)

Prostacyclin and thromboxane are often considered as

the members of the prostaglandin group since they are

also cyclized derivatives (known as prostanoids).

The leukotrienes retain the straight chain configuration

of arachidonic acid.

Examples of eicosanoids:


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Inflammation

PainFever

Regulation of blood pressure

Blood clotting

Immune system modulationControl of reproductive processes & tissue growth

Regulation of sleep/wake cycle

Functions of eicosanoids:

Note- Paracrines:

Chemicals secreted by a cell to act on cells in the

immediate vicinity via process of diffusion


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Bronchodilation

Vasodilation

Uterine muscle contraction

Hyperalgesia

Inhibits gastric acid secretion

Increases gastric mucus secretion

Mediation of fever


PGE2

Bronchoconstriction

Inhibition of platelet aggregation

PGD2


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Contraction of uterine musclesBronchoconstriction


PGF2

Inhibition of platelet aggregation

Vasodilation

PGI2

Platelet aggregation

Bronchoconstriction

Vasoconstriction

TXA2


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- Prostaglandins all have a cyclopentane ring.

- A letter code is based on ring modifications (e.g., hydroxylor keto groups). [Prostaglandins of the E and D series are

hydroxyketones, whereas the F prostaglandins are 1,3-

diols.]

- A subscript refers to the number of double bonds in thetwo side-chains.

- The Greek letter (as in PGF2) designates the position of

the hydroxyl group at C9.

Thromboxanes are similar but have instead a 6-membered

ring.

PGE2 (Prostaglandin E2) is an example of a prostaglandin,

produced from arachidonic acid.

Structure of prostaglandin:


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COOH

O

HOOH

PGE2


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Prostaglandins & related compounds are transported out of

the cells that synthesize them.

Most affect other cells by interacting with plasma membrane

G-protein coupled receptors.

Depending on the cell type, the activated G-protein may

stimulate or inhibit formation of cAMP, or may activate Ca++

release.

Prostaglandin receptors:


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Arachidonic acid, a 20-carbon fatty acid, is the primary

precursor of eicosanoids. Arachidonic acid is present as a

component of the phospholipids of cell membranes.

Free arachidonic acid is released from tissue phospholipids

by hydrolysis catalyzed by phospholipase A2 of cell

membrane or cytoplasm in response to various stimuli, eg,

physical injury, immune reactions.

Synthesized also from essential dietary fatty acids, esp.

linoleic acid.

There are two major pathways in the synthesis of theeicosanoids from arachidonic acid:

- Cyclooxygenase pathway

- Lipoxygenase pathway

Eicosanoid synthesis:


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Cell Membrane Phospholipids

Arachidonic Acid

Phospholipase A2

Cyclo

oxyg

enase

Lipoxygenase

Prostaglandins

Thromboxanes

Prostacyclins

Leukotrienes


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All eicosanoids with ring structures, that is, the

prostaglandins, thromboxanes, and prostacyclins, are

synthesized via the cyclooxygenase pathway.

Cyclooxygenase (COX) exists in at least two forms.

Cyclooxygenase-1 (COX-1) is found in many tissues;

the prostaglandins produced in these tissues by COX-1appear to be important for a variety of normal

physiologic processes- protective prostaglandins in the

kidney and stomach, as well as the functional

thromboxane of platelets.COX-1 is known as house keeping enzyme.

Cyclooxygenase pathway:


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In contrast, Cyclooxygenase-2 (COX-2) is foundprimarily in inflammatory cells (White blood cells); the

products of its actions play a major role in tissue injury,

eg, inflammation.

COX-2, not normally found in most tissues, expressed

under conditions of tissue damage and plays an active

role in the inflammatory response.


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Several lipoxygenases (most common 5-lipoxygenase)

can act on arachidonic acid to form leukotrienes or

lipoxins, depending on the tissue.

Leukotrienes assist in the pathophysiology of asthma.

Lipoxygenase pathway:


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8. eicosanoids

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