They are 20 C compounds (Greek, eikosi = twenty).
It is derived from arachidonic acid.
The term is now used to describe a family of closely related
derivatives of hypothetical C20 molecule named Prostanoic
They are extremely potent compounds that elicit a wide range
of responses, both physiologic (inflammatory response) and
pathologic (hyper - sensitivity).
Though bearing action similarity with hormones, eicosanoids
differ from true hormones:
Produced in small amounts in almost all tissues rather than in
Acts locally rather than after transport in blood to distant sites
Very short lived; Rapidly catabolized; and are not stored
Biological actions are mediated by plasma membrane G protein-
1st discovered in human semen by Ulf Von Euler in 1930 ; were
found to stimulate uterine contraction and reduce blood
Presumed to be synthesized by prostate gland hence the name.
Later realized were synthesized in all tissues except
This has a cyclopentane ring ( formed by carbon atoms 8 to 12)
and two side chains, with carboxyl group on one side.
Prostaglandins differ in their structure due to substituent group
and double bond on cyclopentane ring
PROSTAGLANDINS - NOMENCLATURE
Abbreviated as PG, with the class designated by a capital letter
A,B,D,E,F,G,H and I, followed by a number.
PGE and PGF; 1st isolated from the biological fluids
The letters refer to the different ring structure, except in PGG
and PGH: same ring structure (cyclo endohydroperoxide).
In the same series, depending upon double bonds on the side
chains designated as PGE1, PGE2, PGE3..etc
PGD2, PGE2, PGF2 and PGI2 and thromboxane A2 are widely
Named so because they are identified first in thrombocytes.
Structure is similar to PGs, but have an oxygen atom in the
cyclic ring and contains a six numbered heterocyclic oxane
The most common thromboxane, TXA2, contains an
additional oxygen atom attached both to carbon 9 and carbon
11 of the ring
TXA2- Vasoconstriction and platelet aggregation thus helping
clot formation. Inhibited by aspirin.
TXB2- a stable degradation product of TxA2, plays a role in
acute hepatoxicity induced by acetaminophen
CYCLOOXYGENASE PATHWAY- CYCLIC PATHWAY
(SYNTHESIS OF PROSTAGLANDINS AND
1st described by Scene Bergstrom and Bengt Samuelsson (1960)
Occurs in endoplasmic reticulum
In humans, the most important precursor for prostaglandins is
→ arachidonic acid, a polyunsaturated fatty acid with four
double bonds (eicosatetraenoic acid).
It is stored in cell membranes as the C2 ester of
phosphatidylinositol and other phospholipids
The dietary precursor of the prostaglandins is the essential fatty
acid, linoleic acid
Site: In all types of mammalian cells except RBCs
(no cyclooxygenase activity has been found in human RBCs) 11
1. RELEASE OF ARACHIDONIC ACID:
Arachidonic acid is incorporated into membrane-bound
Initially, Arachidonic acid is released from these
phospholipids by phospholipase A2 in response to a variety
of signals .It is activated by hormones like epinephrin,
2. SYNTHESIS OF PGH2:
1st step in prostgladin synthesis is
oxidative cyclization of free arachidonic
adid to yield PGH2 by prostagladin
endoperoxide synthase (PGH Synthase)
PGH synthase exhibits 2 catalytic activities
: Cyclooxygenase (COX) and Peroxidase
Initial step: Catalyzed by a cyclooxygenase
and forms the five- membered ring with
the addition of 4- atoms of oxygen. 2
between C- 9 and 11, and 2 at C-15 to
form an unstable endoperoxide,PGG2.
The hydroperoxy group at carbon 15 of
PGG2 is quickly reduced to a hydroxyl
group by a peroxidase to form another
ISOZYMES OF PGH SYNTHASE:
Cyclooxygenase (COX) :Two isozymes usually denoted as COX-1
3. CONVERSION OF PRIMARY PROSTAGLANDIN (PGH2) TO OTHER
Enzymes → cell specific, like : PGE synthase and PGD
synthase and so on.
Thus, vascular endothelium produces PGE and PGI, and
platelets produce thromboxanes (TXs).
In kidney and spleen,
isomerase catalyses production of PGE2 and
reductase catalyses production of PGF2.
Thromboxanes are highly active metabolites of the PGG2
and PGG2 type prostaglandin endoperoxides that have the
cyclopentane ring replaced by a six membered oxygen
containing (oxane) ring.
The term thromboxane is derived from the fact that these
compounds have a thrombus forming potential.
Thromboxane A synthase, present in the endoplasmic
reticulum, is abundant in lung and platelets and catalyzes
conversion of endoperoxide PGH2 to TXA2.
The half life of TXA2 is very short in water (t1/2 ~ 1 min) as
the compound is transformed rapidly into inactive
thromboxane B2 (TXB2) 16
CATABOLISM OF PGS
metabolized to the 13,14-
dihydro metabolite via reduction
of the double bond at position
13 by 13,14-PG reductase
followed by oxidation of both α
and ω side chains, and a 4-
carbon fragment is lost.
The terminal carbon of the ω
chain is oxidized to a carboxylic
The resultant compound is a
Fig: Catabolism of PGs
REGULATION OF PROSTAGLANDIN SYNTHESIS
Cortisol- inhibits Phospholipase A2 activity
NSAIDs like Aspirin, Indomethacin, Ibuprofen, phenylbutazone
inhibit both COX-1 and COX-2 and, thus, prevent the synthesis
of the parent prostaglandin, PGH2.
These NSAIDS have side effects like gastrointestinal ulcers and
NSAID like Celecoxib is selective COX-2 inhibitors, and thus are
free from those side effects. 19
Aspirin acetylates serine
at the active site and
Other NSAIDs: act as
reversible inhibitors of
In platelets: TXA2 is not formed in aspirin medication. so, there
is decreased platelet aggregation.
Therefore, aspirin is useful in preventing heart attacks (MI).
In endothelial cells: Aspirin also reduces PGI2 synthesis; but
after few hours the endothelial cells resynthesize
Platelets cannot resynthesize cyclooxygenase because → they
lack nuclei and therefore cannot synthesize new mRNA.
Thus, aspirin completely blocks TXA2, but only partially inhibits
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.
Cyclooxygenase is a “suicide” enzyme.
Self catalysed destruction rapidly inactivates the
enzyme, thus preventing excessive production of PGs.
PGs have very short half life of about 30 secs.
They are inactivated by 15-hydroxyl-prostaglandin-
dehydrogenase ( 15-OH-PGDH) which converts 15-OH
group to keto group.
BIOLOGICAL ACTIONS AND CLINICAL APPLICATIONS OF
PROSTAGLANDINS AND THROMBOXANE
1. Effects on CVS:
Prostacyclin or PGI2- is synthesized by the vascular
inhibits platelet aggregation and has a protective effect on
vessel wall against deposition of platelets.
Platelets attempting to stick to blood vessel wall release
endoperoxidase which enhance production of prostacyclin by
vascular endothelial cells
But any injury to the vessel wall inhibits PGI2 synthesis and
promotes TXA2 synthesis which causes
→ and platelet aggregation.
Thus, prostacyclin and thromboxane are opposing in activity
PGE2 and PGA2 → potent vasodilators, and thus lowers blood
Systemic BP generally falls in response to PGE and PGA
Fig: Physiological antagonism between prostacyclin (PG-I2) and
2. EFFECTS ON SMOOTH MUSCLES
1. GI Musculature
Response vary widely with species, type of muscles & type of
PG-E and F → produces contraction of longitudinal muscle from
stomach to colon. Thus, diarrhea, cramps and reflux of bile have
been noted in human volunteers given PG-E orally (i.e.
2. Bronchial muscle (Effect on respiratory tract)
PGF is a constrictor of bronchial smooth muscle
PGE is a potent bronchodilator. PGE series are used in aerosols
for relieving bronchospasm
3. Uterine muscle
PGE1, E2 and PG-F2α when administered IV shows contraction
Thus PGE2 (0.5 μg/ml) → used for induction of labour at term.
Same PG in higher doses of 5 μg/ml has been reported to be
effective in therapeutic termination of pregnancy in first and
3. EFFECTS ON IMMUNITY AND INFLAMMATION
PGs-E1, E2,D2 F1α and F2α →produce inflammation by
increasing capillary permeability.
Thus, intradermal injection of PGs in man causes wheal and
flare similar to histamine at the site of injury.
PG-E1 → potent platelet aggregation inhibitor.
So, it is useful for storage of blood platelets for transfusion
Moreover, PGEs secreted by macrophages → may decrease
B and T lymphocyte functions.
4. ACTION ON GI SECRETIONS
PGs E1, E2 and A1 (Not F2α) inhibit gastric secretion.
There is decrease in volume, acid and pepsin content.
So they can be used for preventing gastric ulcers.
action is opposite.
There is increase in volume, bicarbonate and enzyme
content of pancreatic juice.
Mucus secretion is increased. There is substantial
movement of water and electrolytes into intestinal lumen.
5. METABOLIC EFFECTS & ACTION ON ENDOCRINE
PG-Es inhibits lipolysis by inhibiting adenyl cyclase and
lowering cyclic AMP level.
PGEs has Insulin like effects on carbohydrate metabolism.
PTH-like (Parathormone) effects on bone, resulting to
mobilisation of calcium from bone producing hypercalcaemia.
Steroidogenesis: Stimulates steroid production by adrenal
Thyrotropin like effects on thyroid gland.
Luteolysis: PGs are involved in LH induced ovulation.
In cattle, if PGF2α is given, luteolysis takes place and animal
goes to oestrus.
So, better fertilization rate is achieved with timely artificial
6. RENAL ACTION:
Intravenous infusion of PGE and A produces:
Increase in renal plasma flow (RPF)
Increase in GFR
Increased urinary flow (diuresis)
PGE2 decreases cyclic AMP level in renal tubule cells and
opposes the cyclic AMP mediated action of Vasopressin on
water reabsorption in tubules.
Thus PG-E2 reduces the resorption of water in distal tubules
and collecting ducts and produce increased urinary flow (dilute
and hypotonic urine)
Output of Na+ and K+ is increased (natriuresis and kaliuresis)
PGEs stimulate renin secretion from JG cells.
Inhibitors of PGE synthesis may be used in treating diabetes
insipidus resulting from vasopressin (ADH) insufficiency.
LIPOXYGENASE PATHWAY- LINEAR PATHWAY
(SYNTHESIS OF LEUKOTRIENES AND LIPOXINS)
are the newly discovered family of conjugated trienes formed
from arachidonic acid in leucocytes, mast cells, and
macrophages by the lipoxygenase pathway, in response to
both immunologic and non-inflammatory stimuli.
LTs possess no ring in its structure but have three characteristic
conjugated double bonds.
Synthesis: from arachidonate by addition of hydroperoxy
Catabolism: Biological activity of leukotrienes is terminated by
ω-oxidation carried out by a specific cytochrome P450 enzyme
followed by β-oxidation from the ω-carboxyl position. 32
SYNTHESIS OF LEUKOTRIENES:
Arachidonic acid is converted to a variety of linear hydroperoxy
acids by a pathway involving a family of lipoxygenases (LOXs).
3 different lipoxygenases (dioxygenases) insert oxygen into the
5, 12, and 15 positions of arachidonic acid, giving rise to
Depending on the position of addition, 3 types of HPETE have
a) 5-HPETE: Most common and the major product of 5-
Lipoxygenase reaction in polymorphs, basophils, mast cells
b) 12-HPETE: 12-lipooxygenase in platelets, pancreatic
endocrine islet cells and glomerular cells of kidney produces
12-HETE (12-hydroxy eicosa tetra-enoic acid)
c) 15-HPETE: 15-lipo-oxygenase in reticulocytes, eosinophils
and T-cells produce 15-HETE (15- hydroxy-6,8,11,14
Only 5-HPETE is converted to a series of leukotrienes, the
nature of which varies according to the synthesizing tissue.
REACTIONS OF LIPOXYGENASE PATHWAY
1. 5-lipoxygenase adds O2 to C-5 of arachidonic acid resulting in
formation of 5-hydro peroxy eicosa tetraenoic acid (5-
2. 5-HPETE after dehydration by dehydrase, generates
3. LTA4 is highly unstable with a half-life of only ten seconds at
pH 7.4 and it serves as precursor for formation of LTB4, LTC4,
LTD4 and LTE4.
FUNCTIONS OF LTS
In general LTs appear to act as mediators in inflammation and
LT-C4, D4 or E4 causes Capillary Dilatation and Vascular
Permeability: they elicits erythema and wheal formation like
Action on Bronchial Muscles: Inhalation of LTs (C4, D4 or E4)
causes bronchospasm. These LTs are responsible for
constriction of bronchial muscles and vasodilation seen in
hypersensitivity reaction such as asthma.
Mucus Secretion: LTs-C4 and D4 are potent stimulators of
mucus secretion from the respiratory tract.
Chemotaxis and Chemokinetic Action:
LTs-B4 stimulates chemotaxis and chemokinesis of
neutrophils and eosinophils, which are found in large
numbers at the site of inflammation.
SRS-A (slow-reacting substance of anaphylaxis):
SRSA is produced by mast cells during anaphylactic reaction
and it is a mixture of LTs like LT-C4, D4 and E4.
These leukotrienes are responsible for intense
vasoconstriction of bronchial muscles, vasodilatation and
increased vascular permeability seen in anaphylactic/allergic
Unlike, cyclooxygenase, lipoxygenase is not inhibited by
aspirin and other anti-inflammatory drugs
So prolonged use of aspirin depresses cyclooxygenase system
and PG synthesis but enhances lipoxygenase system and
overproduction of leukotrienes with NSAID use may produce
bronchospasm and produce aspirin-induced bronchial asthma.
Inhibitors of 5-lipoxygenase and leukotriene receptor
antagonists (like Montelukast, Zafirlukast) are used in the
treatment of asthma.
NSAIDs, however, also favor synthesis of lipoxins (LXs), lipid
mediators with anti-inflammatory effects. 39
They are a group of compounds produced by leukocytes.
LXA4 is the most common variety
They are conjugated tetraenes.
They have structural similarities to the LTs.
Synthesis: By insertion of molecular oxygen at two sites in
arachidonic acid by sequential action of 5 and 15-lipo-
REACTIONS OF LIPOXYGENASE PATHWAY (CONTD..)
SYNTHESIS OF LIPOXINS
LTA4 under the action of 15-
LXA4 can also be produced by
sequential action of 15 and 5-
lipoxygenase on arachidonic
LXA4 to LXE4 are formed in a
manner similar to formation
of leukotrienes. 41
FUNCTION OF LIPOXIN:
It is anti-inflammatory and decreases immune response i.e
involved in the resolution phase of inflammation.
Thus have some complementary biological activities to LTs
and inhibit bronchial spasms.
First carried into cell side chains are oxidized and double bonds are reduced to yield inactive metabolite excreted in urine.
Prostaglandins were first isolated by Ulf von Euler in 1935 (Nobel prize in 1970). In 1982 Nobel prizes were awarded to Bengt Samuelsson (biosynthesis of PGs) and Sir John Vane (effect of aspirin on PGs).
PGE souluble in ether and PGF in phosphate buffer (fosfat in Swedish)
Prostaglandins with substituent groups and structures. Prostanoic acid is the parent nucleus for all the PGs. R1;C1 to C7 and R2; C13 – C20
PG A & PG B have same keto group at C9 .
A series having double bond between C10 and C11.
B series have a double bond between C8 and C12
PG E has a keto bond at C9 and OH group atC11
PG F series has OH group at C9 and C11
PG G & PG H have (identical ring structure) two oxygen atoms interconnected to each other and bonded at C9 and C11
PG G has hydro peroxide group at C15 and PG H has hydroxyl group at C15.
PG I series- has double ring formation,
C9 of the cyclopentane ring is linked to C-6 of the side chain by an oxygen molecule to form a second five sided ring., hence name prostacycline
2pathways: cyclooxygenase and lipooxygenase pathway
Enzyme required → microsomal prostaglandin synthase complex, (cyclooxygenase + peroxide) This enzyme is an endoplasmic reticulum membrane-bound protein that has two catalytic activities: fatty acid cyclooxygenase (COX), which requires two molecules of O2, and peroxidase, which is dependent on reduced glutathione
The overall reaction consumes →2 moles of oxygen, and → 2 moles of reduced glutathione.
COX-1: made constitutively in most tissues, and is required for maintenance of healthy gastric tissue, renal homeostasis, and platelet aggregation.
COX-2: is inducible in a limited number of tissues in response to products of activated immune and inflammatory cells.
The increase in prostaglandin synthesis subsequent to the induction of COX-2 mediates the pain, heat, redness, and swelling of inflammation, and the fever of infection.
nonsteroidal anti-inflammatory drugs [NSAIDS)
celecoxib reduce pathologic inflammatory processes while maintaining the physiologic functions of COX-1; however, their use has been associated with increased risk of heart attacks
Aspirin irreversibly acetylates and inhibits cyclo-oxygenase. Platelets cannot regenerate cyclo-oxygenase and so thromboxane A2 is not formed in platelets. Hence, there is decreased platelet aggregation. Therefore, aspirin is useful in prevention of heart attacks. By inhibiting cyclo-oxygenase, aspirin also reduces PGI2; but endothelial cells after a few hours will resynthesize cyclooxygenase. So aspirin completely blocks TXA2, but only partially inhibits PGI2. Other anti-nflammatory drugs (indomethacin and ibuprofen) also cause irreversible inhibition of enzyme. Paracetamol is a reversible inhibitor.
inhibition persists for the lifespan of the platelet (7–10 days).
The inhibition of COX-1 cannot be overcome in platelets, which lack nuclei. However, the inhibition of COX-2 can be overcome in endothelial cells, because they have a nucleus and, therefore, can generate more of the enzyme. 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
cortisol (a steroidal anti-inflammatory agent)
The opposing effects of TXA2 and PGI2 limit thrombi formation to sites of vascular injury
PGE2 is a sleep promoting substance.
PG-E1 given orally in human volunteers produces watery diarrhoea.
metabolic effects of insulin are: Stimulation of glycogen synthesis in skeletal muscle, liver and adipose tissue.
Glucangon –act by amp mechm-
slow reacting substance of anaphylaxis (SRS-A) contains LTC4, LTD4 and LTE4
Montelukast and Zafirlukast are LT receptor antagonist used in Asthma ,Seasonal allergies, Psoriasis,Rheumatoid arthritis
Synthesis of the lipoxins from arachidonic acid via transcellular interactions. Three pathways exist for the synthesis of the lipoxins. The "classic" pathway involves 5-LOX activity in leukocytes followed by 12-LOX action in platelets. The action of 15-LOX in epithelial cell (such as in the airway) followed by 5-LOX action in leukocytes is the second major lipoxin synthesis pathway. The action of aspirin on COX-2 (see the Lipid-Derived Inflammatory Modulators page for more details) in epithelial, or endothelial cells as wells as in monocytes results in the eventual production of the 15 epi-lipoxins (also referred to as aspirin triggered lipoxins, ATLs).
Evidences support a role of lipoxins in vasoactive and immunoregulatory function, e.g. as counter-regulatory compounds (chalones) of the immune response.
Chalone, a group of tissue-specific water-soluble substances produced within a tissue and that inhibit mitosis of cells of that tissue and whose action is reversible
chalones POLYPEPTIDEs or glycoproteins, released by activelydividing cells that inhibits chromosomalreproduction (MITOSIS) in cells of the tissue in which they are formed, thus controlling a tendency to HYPERPLaSIA
Biochemical basis of platelet functioning and the role of prostaglandins: Schematic representation of agonist-induced platelet activation pathways and the proposed effect of Que leading to inhibition of platelet function. Que has been demonstrated to inhibit platelet function via multiple pathways, including, inhibition of multiple signalling proteins, granule exocytosis and fibrinogen binding. Effect of Que is denoted by