Eicosanoids

EICOSANOIDS
DIPESH TAMRAKAR
MSC. CLINICAL BIOCHEMISTRY

OVERVIEW
 INTRODUCTION
 CLASSIFICATION
 SYNTHESIS
 REGULATION & INHIBITION
 FUNCTIONS
 BIOLOGICAL ACTIONS AND CLINICAL APPLICATIONS
 SUMMARY
2

EICOSANOIDS
 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
acid
 They are extremely potent compounds that elicit a wide range
of responses, both physiologic (inflammatory response) and
pathologic (hyper - sensitivity).
3

EICOSANOIDS
Though bearing action similarity with hormones, eicosanoids
differ from true hormones:
 Produced in small amounts in almost all tissues rather than in
specialized glands
 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-
coupled receptors.
4

CLASSIFICATIONS
Often the word prostaglandin is used to indicate all
prostanoids.
5

PROSTAGLANDINS
 1st discovered in human semen by Ulf Von Euler in 1930 ; were
found to stimulate uterine contraction and reduce blood
pressure
 Presumed to be synthesized by prostate gland hence the name.
 Later realized were synthesized in all tissues except
erythrocytes.
 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
6

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
distributed. 7

THROMBOXANES (TXS):
 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
ring.
 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
9

CYCLOOXYGENASE PATHWAY- CYCLIC PATHWAY
(SYNTHESIS OF PROSTAGLANDINS AND
THROMBOXANES)
 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
phospholipids
 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,
bradykinin etc.
12

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
endoperoxide, PGH2.
13

ISOZYMES OF PGH SYNTHASE:
 Cyclooxygenase (COX) :Two isozymes usually denoted as COX-1
and COX-2
14

3. CONVERSION OF PRIMARY PROSTAGLANDIN (PGH2) TO OTHER
EICOSANOIDS
 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.
15

THROMBOXANE
 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
 15-ketoprostaglandin is
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
acid group.
 The resultant compound is a
urinary product.
Fig: Catabolism of PGs
18

REGULATION OF PROSTAGLANDIN SYNTHESIS
INHIBITION:
 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
renal disturbances
 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
irreversibly inhibits
cyclooxygenase
 Other NSAIDs: act as
reversible inhibitors of
cyclooxygenase
20

 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
cyclooxygenase.
 Platelets cannot resynthesize cyclooxygenase because → they
lack nuclei and therefore cannot synthesize new mRNA.
 Thus, aspirin completely blocks TXA2, but only partially inhibits
PGI2.
 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.
21

INHIBITION CONTD..
 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.
22

REGULATION OF PROSTAGLANDIN SYNTHESIS CONTD…
Activators:
 Bradykinin , epinephrine, thrombin, angiotensin II, &
vasopressin. activates Phospholipase A2
 Catecholamines activates cyclooxygenase
23

BIOLOGICAL ACTIONS AND CLINICAL APPLICATIONS OF
PROSTAGLANDINS AND THROMBOXANE
1. Effects on CVS:
 Prostacyclin or PGI2- is synthesized by the vascular
endothelium.
 Vasodilatation
 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
→ vasoconstriction
→ and platelet aggregation.
Thus, prostacyclin and thromboxane are opposing in activity
24

Antihypertensive action:
 PGE2 and PGA2 → potent vasodilators, and thus lowers blood
pressure.
 Systemic BP generally falls in response to PGE and PGA
Fig: Physiological antagonism between prostacyclin (PG-I2) and
thromboxane (TX-A2)
25

2. EFFECTS ON SMOOTH MUSCLES
1. GI Musculature
 Response vary widely with species, type of muscles & type of
PGs.
 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.
Purgative action).
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
26

3. Uterine muscle
 PGE1, E2 and PG-F2α when administered IV shows contraction
of uterus.
 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
second trimesters
27

3. EFFECTS ON IMMUNITY AND INFLAMMATION
Hematological response
 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.
28

4. ACTION ON GI SECRETIONS
 Gastric Secretion:
 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.
 Pancreatic Secretion:
 action is opposite.
 There is increase in volume, bicarbonate and enzyme
content of pancreatic juice.
 Intestinal Secretion:
 Mucus secretion is increased. There is substantial
movement of water and electrolytes into intestinal lumen.
29

5. METABOLIC EFFECTS & ACTION ON ENDOCRINE
ORGANS
 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
cortex.
 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
insemination. 30

6. RENAL ACTION:
Intravenous infusion of PGE and A produces:
 Increase in renal plasma flow (RPF)
 Increase in GFR
 Increased urinary flow (diuresis)
Mechanism:
 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.
31

LIPOXYGENASE PATHWAY- LINEAR PATHWAY
(SYNTHESIS OF LEUKOTRIENES AND LIPOXINS)
Leukotrienes:
 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
groups.
 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
hydroperoxides (HPETE).
 Depending on the position of addition, 3 types of HPETE have
been found.
a) 5-HPETE: Most common and the major product of 5-
Lipoxygenase reaction in polymorphs, basophils, mast cells
and macrophages.
33

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
eicosatetraenoic acid)
 Only 5-HPETE is converted to a series of leukotrienes, the
nature of which varies according to the synthesizing tissue.
34

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-
HPETE).
2. 5-HPETE after dehydration by dehydrase, generates
leukotriene LTA4.
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.
36

FUNCTIONS OF LTS
 In general LTs appear to act as mediators in inflammation and
anaphylaxis.
 LT-C4, D4 or E4 causes Capillary Dilatation and Vascular
Permeability: they elicits erythema and wheal formation like
histamine
 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.
37

 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
reactions.
38

 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

LIPOXINS (LX)
 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-
oxygenase.
40

REACTIONS OF LIPOXYGENASE PATHWAY (CONTD..)
SYNTHESIS OF LIPOXINS
LTA4 under the action of 15-
lipoxygenase produces
lipoxins (LXA4).
LXA4 can also be produced by
sequential action of 15 and 5-
lipoxygenase on arachidonic
acid
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.
42

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