Professor Biochemistry LectureEicosanoids metabolism

Learning Objectives
At the end of the class the student will be able to define

and describe : Eicosanoids ; prostanoids; leucotrienes; (KNOWLEDGE) Synthesis ; catabolism and regulation of prostanoids and leucotrienes) (KNOWLEDGE) Functions of Eicosanoids (prostaglandins; prostacyclins; leucotrienes) and their role as local hormones (COMPREHENSION) Role of Aspirin as effective anti platelet aggregator and SRS-A in hypersensitivity (APPLICATION)

 A 26-year-old primigravid woman at 42 weeks' gestation

Case1

comes to the delivery ward for induction of labor. At 35 weeks was positive for group B Streptococcus. The patient is started on lactated Ringer's IV solution. Sterile vaginal examination shows that the patient's cervix is long, thick, and closed. Prostaglandin (PGE2) gel is placed into the vagina, and electronic fetal heart rate monitoring is continued. In approximately 60 minutes, the uterus shows to be contracting. Which of the following was most likely the cause of the uterine contractions. A. Infection B. IV fluids C. Prostaglandin (PGE2) gel E. Vaginal examination

Metabolism of the Eicosanoids

The eicosanoids consist of : Prostaglandins (PGs) Thromboxanes (TXs) leukotrienes (LTs) The PGs and TXs are collectively called as prostanoids.

Structural Characteristic features

Prostaglandins were

originally shown to be synthesized in the prostate gland.

Thromboxane's from

platelets (thrombocytes).
Leukotriene's from

leukocytes.
Hence the derivation of

their names.
But they are present in almost all tissues.

Synthesis

Eicosanoids
In Greek (eicosi=20) .They are 20 carbon compounds derived from arachidonic acid.

All mammalian cells synthesize eicosanoids.

Most potent biologically active substances, Low concentrations 1ng/ml of PG will cause smooth muscle contraction. Diverse roles of PG confer on them the status as local hormones.

Classification of Prostaglandins
1. All PGs have 20carbon

2.
3.

4.
5. 6.

7.

8.

atoms. They have cyclopentane ring. All of them have OH group at 15 position Trans double bond at 13 position Series-1: one double bond Series 2: most common variety occurring in the body having two double bond Series-3: having three double bonds PG/D/E/F

Common types
Only 5 PGs are widely distributed in the body.
PGD2 PGE2

PGF2
PGI2 Thromboxane A2

Synthesis

The phospholipids which

are stored in cell membranes on various stimuli by the Action of Phospholipase A2 produce arachidonic acid. This is the rate limiting action. PGHSynthase: contains two separate enzyme activities, cycloxygenase and peroxidase. PGH2 is a precursor for prostaglandins (PG) , prostacyclins (PGI) and thromboxanes.

Regulation
PLA2 is : Activated by

epinephrine, thrombin and Inhibited by steroids. Cyclooxygenase is : Activated by catecholamine's and Inhibited by NSAID like aspirin and indomethacin.

Suicidal enzyme
Cyclooxygenase is a suicidal enzyme undergoes self

-catalyzed cell destruction, (switching off) rapidly inactivates the enzyme. This would prevent excessive production of PGS.

Isoforms of Cxcloxygenase
Cxcloxygenase exists in

two different forms: Cox1, Cox2. COX1 is constitutive produces PGS that mediate gastric, renal, and platelet function. COX2 inducible form mediates inflammatory response .

DEGRADATION
Almost all the eicosanoids are inactivated rapidly

mainly in the lung and liver by the enzyme 15 hydroxy dehydrogenase.

Mechanism of action
These are local hormones they function through G-Protein Coupled Receptors in most tissues.
PGs and PGI act by increasing cAMP.

TXA act by inhibiting cAMP and thereby decreasing.

Comparison
Structure Site of formation cAMP level Platelet aggregation Blood vessels

PGI2 cyclopentane Endothelium Increased inhibited

Vasodilatation

TXA2 Oxane ring Platelets Decreased Enhanced

Constriction

Bronchioles

Relaxation

Constriction

BIOLOGICAL FUNCTIONS

Effect on CVS

Platelet aggregation and thrombosis

PG I2(prostacyclins) synthesized by the vascular

endothelium inhibit platelet aggregation Thromboxane's promote platelet aggregation and blood clotting that might lead to thrombosis. Thus prostacyclins and thromboxanes are antagonist in their actions. PGI2 acts vasodilator while thromboxanes as vasoconstrictors.

Pain and fever

Pyrogens (fever producing

agents ) promote PG synthesis leading to formation of PGE2 in the hypothalamus, the site of regulation of body temperature.
PGE2 along with histamine and

bradykinin cause pain.

Influence on Inflammation: PGE1 and E2 induce the

symptoms of inflammation (erythema and wheal are produced at the site of injury) due to vasodilatation by increasing capillary permeability.

Reproduction
PGE2 and F2 stimulate the uterine contractions

and cervical dilatation so used for the medical termination of pregnancy and induction of labor. Effects on respiratory functions: PG E is a bronchodilator so used in the treatment of bronchial asthma . Influence on renal system: PG E increases GFR and promotes urine output. Excretion of sodium and potassium is also increased.

Regulation of gastric secretion

PGE inhibits gastric secretion and increases

intestinal motility. so used for the treatment of acid peptic disease. Effect on metabolism: PG E decreases lipolysis and increases glycogen formation and promotes calcium mobilization from the bones.

Learning check
Aspirin is useful in

prevention of MI and cerebral stroke. With the help of the adjacent diagram explain?

Mechanism of action of Aspirin

Aspirin inhibits cyclo

oxygenase. platelets cannot regenerate cyclo-oxygenase so TXA2 is not formed hence no platelet aggregation. therefore aspirin is useful in prevention of MI. By inhibiting cyclo-oxygenase aspirin reduces PGI2. But endothelial cells after few hours will resynthesize cyclooxygenase. So aspirin completely blocks TXA2 and partially inhibits PGI2.

Learning check
How marine fish lipids reduce the risk of MI?

Explanation
These are Eicosa penteanoic acid which decreases

cholesterol and Triglyceride. Also inhibits TXA2 so reduces platelet aggregation and thrombosis reducing risk of MI.

Leukotrienes
These are a family of

conjugated trienes formed from arachidonic acid in leukocytes, platelets, macrophages by lipoxygenase pathway in response to both immunologic and non immunologic stimuli. They have three conjugated double bonds.
5HPETE (5-hydro peroxy-eicosa-tetra-enoic acid)

Functions
1. Mediators in

inflammation and anaphylaxis. 2. Smooth muscle contraction. 3. Bronchospasm 4. SRS-A slow reacting substance of anaphylaxis contains LTC4, LTD4, LTE4.