Eicosonoid Met

7/31/2019 Eicosonoid Met

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Professor Biochemistry

Lecture-Eicosanoids metabolism


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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 andSRS-A in hypersensitivity (APPLICATION)


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Case1 A 26-year-old primigravid woman at 42 weeks' gestation

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 cervixis long, thick, and closed.

Prostaglandin (PGE2) gel is placed into the vagina, andelectronic 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


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Metabolism of the Eicosanoids

The eicosanoids consist of :

Prostaglandins (PGs)

Thromboxanes (TXs)

leukotrienes (LTs)

The PGs and TXs are collectively called asprostanoids.


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Structural Characteristic features

Prostaglandins wereoriginally shown to besynthesized in the prostategland.

Thromboxane's fromplatelets (thrombocytes).

Leukotriene's from

leukocytes.

Hence the derivation oftheir names.

But they are present in almost all tissues.


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Synthesis


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Eicosanoids

In Greek (eicosi=20) .They are 20 carboncompounds derived from arachidonic acid.

All mammalian cells synthesize eicosanoids.

Most potent biologically active substances,

Low concentrations 1ng/ml of PG will causesmooth muscle contraction.

Diverse roles of PG confer on them the status as

local hormones.


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Classification of Prostaglandins

1. All PGs have 20carbonatoms.2. They have cyclopentane

ring.3. All of them have OH group

at 15 position4. Trans double bond at 13

position5. Series-1: one double bond6. Series 2: most common

variety occurring in thebody having two doublebond

7. Series-3: having threedouble bonds

8. PG/D/E/F


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Common types

Only 5 PGs are widely distributed in the body.

PGD2

PGE2 PGF2 PGI2 Thromboxane A2


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Synthesis The phospholipids which

are stored in cell

membranes on variousstimuli by the Action ofPhospholipase A2 producearachidonic 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.


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Regulation PLA2 is :

Activated byepinephrine,thrombin and

Inhibited by steroids.

Cyclooxygenase is :

Activated bycatecholamine'sand

Inhibited by NSAIDlike aspirin andindomethacin.


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Suicidal enzyme

Cyclooxygenase is a suicidal enzyme undergoes self-catalyzed cell destruction, (switching off) rapidlyinactivates the enzyme. This would preventexcessive production of PGS.


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Isoforms of Cxcloxygenase Cxcloxygenase exists in

two different forms:Cox1, Cox2.

COX1 is constitutiveproduces PGS thatmediate gastric, renal,and platelet function.

COX2 inducible formmediates inflammatoryresponse .


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DEGRADATION

Almost all the eicosanoids are inactivated rapidly

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


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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 inhibitingcAMP and thereby

decreasing.


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ComparisonPGI

2TXA

2

Structure cyclopentane Oxane ring

Site of formation Endothelium PlateletscAMP level Increased Decreased

Plateletaggregation

inhibited Enhanced

Blood vessels Vasodilatation ConstrictionBronchioles Relaxation Constriction


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BIOLOGICAL FUNCTIONS


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Effect on CVS

Platelet aggregation andthrombosis PG I2(prostacyclins) synthesized by the vascular

endothelium inhibitplatelet aggregation Thromboxane's promoteplatelet 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.


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Pain and fever

Pyrogens (fever producing

agents ) promote PG synthesisleading to formation of PGE2 inthe hypothalamus, the site ofregulation of body temperature.

PGE2 along with histamine andbradykinincause pain.

Influence on Inflammation:

PGE1 and E2 induce thesymptoms of inflammation(erythema and wheal areproduced at the site of injury)due to vasodilatation byincreasing capillarypermeability.


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Reproduction

PGE2 and F2 stimulate the uterine contractionsand cervical dilatation so used for the medicaltermination of pregnancy and induction of labor.

Effects on respiratory functions:-

PG E is a bronchodilator so used in thetreatment of bronchial asthma .

Influence on renal system:-

PG E increases GFR and promotes urine output.Excretion of sodium and potassium is alsoincreased.


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Regulation of gastric secretion

PGEinhibits gastric secretion and increasesintestinal motility.

so used for the treatment of acid peptic disease.

Effect on metabolism:-

PG E decreases lipolysis and increasesglycogenformation and promotescalcium mobilization from

the bones.


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Learning check

Aspirin is useful inprevention of MI andcerebral stroke.

With the help of theadjacent diagram

explain?


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


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Explanation These are Eicosa penteanoic acidwhich decreases

cholesterol and Triglyceride.

Also inhibits TXA2 so reducesplatelet aggregation and

thrombosisreducing risk of MI.


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Leukotrienes

These are a family ofconjugated trienes

formed from arachidonicacid in leukocytes,platelets, macrophagesby lipoxygenase pathwayin response to bothimmunologic and nonimmunologic stimuli.

They have threeconjugated doublebonds.

5HPETE (5-hydro peroxy-eicosa-tetra-enoic acid)


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Functions

1. Mediators ininflammation and

anaphylaxis.

2. Smooth musclecontraction.

3. Bronchospasm

4. SRS-A slow reactingsubstance ofanaphylaxis containsLTC4, LTD4, LTE4.

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Eicosonoid Met