Eicosanoids

Dr. Vijaya Srinivasan,Assistant Professor,Dept. Of Biochemistry,

SRMC & RI

COOH

20

Eicosanoids

1

Arachidonic Acid

Means 20, in Greek means 20 carbon fatty acid

Prostaglandins Leukotrienes

CYCLOOXYGENASE LIPOXYGENASE

History Of Eicosanoids

Noble laureate,won Nobel prize in medicine and physiology .

First to discover the prostaglandins. He found the presence of PG in human semen .

Presumed that they were synthesized by the prostate glands and hence named as PG but realized that it was present in all the tissues except for erythrocytes.

Ulf Von Euler

Classification Of Eicosanoids

Eicosanoids

Prostanoids • Leukotrienes• Lipoxins

Prostaglandins(PGs)

Prostacyclins(PGI)

Thromboxanes(Tx)

Prostaglandins

• Prostaglandins are group of hormone like substances,like hormones they play a role in a wide variety of physiological processes.

• Prostaglandins act in a manner similar to that of hormones by stimulating target cells into action .

• However they differ from hormones in that they act locally near the site of synthesis and are metabolized very rapidly

Structure Of Prostaglandins

• Prostaglandins are derived from 20 carbon fatty acid namely prostanoic acid.

COOH

CH32011

13

9

OH

14

Prostanoic acid

Chemistry Of Prostaglandins

Prostaglandins are divided into four main groups

• PG-E : PGE1,PGE 2 and PGE3

• PG-F : PGF1α,PGF2α and PGF3α

• PG-A :PGA1,PGA2,19-OH PGA2

• PG-B : PGB1,PGB2,19-OH PGB1 and 19-OH PGB2.

COOH

CH32011

13

9

OH

14

o

OH

PGE-1

COOH

CH32011

13

9

OH

14

OH

OH PGF-1α

COOH

CH32011

13

9

OH

14

o PGE-A

COOH

CH32011

13

9

OH

14

PG- B

10

O

15

15

Synthesis Of Prostaglandins Membrane bound phospholipids

Arachidonic acid

Phospholipase A2

Prostaglandins andThromboxanes

Cyclooxygenase

Leukotrienes andLipoxins

Lipoxygenase

Regulation Of Synthesis Of Prostaglandins

Membrane bound phospholipids

Arachidonic acid

Phospholipase A2

Stimulants • Bradykinin• Epinephrine• Angiotensin• Hypoxia• Trauma

+

-InhibitorsCorticosteroids

Prostaglandins andThromboxanes

Cyclooxygenase

-AspirinIndomethacinIbuprofen

Leukotrienes andLipoxins

Lipoxygenase

Cyclooxygenase inhibition by Asprin

OCOCH3

CO2H

Acetylsalicylic acid(aspirin)

O - CCH3

CO2H

O

HOH2C

COX

Ser-530 CH2OCOCH3

COX

Irreversible inhibition of COX by acetylationof the active site

People take a daily dose of aspirin for its anti-clotting effect. This is due to inhibition of thromboxane formation in blood platelets.

COX -2 Inhibitor - NSAID

O

O

SO2CH3

Rofecoxib (Vioxx)

N

N

SO2NH2

CH3

F3C

Celecoxib (Celebrex)

NSAID-non steroidal antiinflammatory drugs

COX has 2 domains: catalytic domain and membrane binding domain.Membrane has a long & narrow channel by which AA enters active site.COX inhibitors inhibit this channel.

Mechanism Of Action Of Prostaglandins

• Prostaglandins bind to specific receptors on the plasma membrane of target cells and bring about changes in the concentration of second messengers which may be cyclic AMP, Ca2+ or cyclic GMP which then mediate biological effects.

• PGEs : They mostly act through second messenger Cyclic AMP.

• PG – Fs and Tx – A2: These use Ca++as second messenger in some tissues.

• PG – F2α : Action is mediated through Cyclic GMP as second messenger.

CONTD…

Functions Of Prostaglandins

Prostaglandins have numerous and diverse functions.

Antihypertensive action : • The prostaglandins (PGE,PGA and PGI2) are

vasodilators. • Increased blood flow and decreased peripheral

resistance so there is a fall in blood pressure. • PGs are used in treatment of hypertension.

Role of PG in inflammation:

• PGE1 and PGE2 induce the symptoms of inflammation (redness,swelling,edema) due to arteriolar vasodilation.

• PG are considered as natural mediators of inflammatory reactions of rheumatoid arthritis ,psoriasis(skin),conjuctivitis(eyes).

• Corticosteroids are frequently used to inhibit the inflammatory response.

PG and Reproduction

• PGE 2 and PGF2 are widely used for medical termination of pregnancy and induction of labour, it increases the uterine contraction.

Action on GI secretions Gastric secretions :

• PG’s PGE1,E2 and A1 inhibit gastric secretion whether basal or stimulated by feeding histamine or pentagastrin.

• Decrease in the acid and pepsin content.Action is exerted directly on secretory cells through C –AMP.

• PGs are used for preventing gastric ulcers.

Intestinal Secretion :

• Mucus secretion is increased.• There is substantial movement of water

and electrolytes into the intestinal lumen.• It increases the motility of the intestine thus

causes diarrhoea.

Cont’d…

Effect of PG on pain and fever

• Pyrogens (fever producing agents)promote PG synthesis leading to the formation of PGE2 in the hypothalamus, the site for regulation of body temperature.

• PGE2 along with histamine and bradykinin causes pain. Migraine is due to PGE2.Asprin and other non steroidal drugs inhibit PG synthesis and thus control fever and relieve pain.

Effect of PG on respiratory function

• PGE is a bronchodilator whereas PGF acts as broncho constrictor of smooth muscles. PGE and PGF oppose the action of each other in the lungs.PGE1 and E2 are used in the treatment of asthma.

Effect on renal function

Intravenous infusion of PGE and PGA produces

• Substantial increase in renal plasma flow .• Increase in GFR.• Increased urinary flow.

Effect on metabolism

• PGE inhibits lipolysis.

• PGE has also some insulin like effects on carbohydrate metabolism.

Thromboxanes

• Thromboxanes are also derived from prostanoic acid but instead of 5- carbon cyclopentane ring of PG ,thromboxanes have a 6- membered oxane ring.

O

O

OH

COOH

OH11

9

12

56

Function Of Thromboxanes

• Thromboxanes are synthesized in platelets and upon release cause vasoconstriction and platelet aggregation.

• It stimulates steroid production by adrenal cortex.

• Exerts PTH like effects on bone ,it causes increased mobilization of calcium from bones.

Prostacyclins VsThromboxanes

Prostacyclins (PG I2)

Coronary arteries

Dilates

ThromboxanesBlood pressurelowers Raises

PlateletAggregation

constricts

StimulatesInhibits

Cyclic AMPIn target cells

Cyclic AMP In target cells

Leukotrienes(LTs)

• They are a family of conjugated trienes formed from eicosanoic acids in leukocytes,mast cells and macrophages by lipoxygenase pathway in response to immunologic and non inflammatory stimuli.

• They have no ring in their structure but have three conjugated double bonds.

Mechanism Of Synthesis of Leukotrienes

lipoxygenase

5 –Hydroperoxy eicosa tetra – enoic acid(5HPETE)

O2

Arachidonic acid

H20

Leukotriene A4GSH

Leukotriene C4

Glutamate

Leukotriene B4

Glycine

Leukotriene E4

Functions Of Leukotrienes• LTs act as mediators of inflammation and

anaphylaxis.• Elicits erythema and wheal and flare reaction

and increases vascular permeability.• Inhalation of LTs causes bronchospasm.• LTs-C4 and D4 are potent stimulators of mucus

secretion.• LTs- B4 stimulate chemotaxis of neutrophils and

eosinophils which are found at the site of inflammation.

Slow Reacting Substance Of Anaphylaxis

• SRS-A : is a mixture of thionyl peptides-LTC4, LTD4 &LTE4.

• More potent than histamine• Constrictor of bronchial airway

musculature.• Increase vascular permeability.• Attraction and activation of leucocytes.

Lipoxins

• They are a group of compounds produced by leukocytes.

• They are conjugated tetraenes.• They are formed by the combined action

of more than one lipoxygenase.• Lx A4 is the most common type, it is

chemotactic in nature.

THANK

YOU