Professional Documents
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UNSATURATED
FATTY ACIDS
and
EICOSANOIDS
Marion G. Rivera, M.D.
OBJECTIVES
Enumerate some
important
polyunsaturated fatty
acids and their
physiological roles
Trace the cyclooxygenase
and lipooxygenase
pathways responsible for
the formation of the
various classes of
eicosanoids
Describe the homeostatic
functions and the role in
pain control and
inflammation of
eicosanoids
IMPORTANCE
OF
UNSATURATED
FATTY ACIDS
UNSATURATED
FATTY ACIDS
GEOMETRIC
ISOMERISM OF C18
MONOUNSATURATED
FATTY ACIDS
TRANSUNSATURATED
FATTY ACIDS
TRANSUNSATURATED
FATTY ACIDS
ESSENTIAL
FATTY ACIDS
Linoleic acid
Linolenic acid
Arachidonic acids
Are polyunsaturated
fatty acids
DEFICIENCY OF
ESSENTIAL
FATTY ACIDS
In animals
In humans
Skin symptoms,
impairment in lipid
transport
Reported in infants
receiving formula low in
fats and in adults on
parenteral feeding without
fats
Prevented by an essential
fatty acid intake of 1-2% of
the total caloric
requirement
UNSATURATED
FATTY ACIDS
MONOUNSATURA
TED FATTY ACIDS
POLYUNSATURAT
ED FATTY ACIDS
family
Synthesized with 9
desaturase enzyme
system in combination
with chain elongation
and desaturation
6 and 3 families
Desaturation and
chain elongation
system is greatly
diminished:
DOCOSAHEXAEN
OIC ACID (DHA)
EICOSANO
IDS
EICOSANOIDS
Prostaglandins (PG)
Tromboxanes (TX)
Leukotrienes (LT)
Lipoxins (LX)
EICOSANOIDS
EICOSANOIDS
Membrane Phospholipids
Arachidonate
Leukotrienes
Prostaglandins
and Lipoxins
and Tromboxanes
ARACHIDONA
TE
CYCLOOXYGE
NASE
PATHWAY
Catalyzed by
Prostaglandin H
Synthase which
possess 2 separate
enzyme activities: (1)
Cyclooxygenase and
(2) Peroxidase
Products:
Prostaglandins,
Prostacyclins and
Tromboxanes
CYCLOOXYGENAS
E PATHWAY
CYCLOOXYG
ENASE
Present as two
isoenzymes
Is a suicide enzyme
capable of selfcatalyzed destruction
PROSTAGLAN
DINS
BIOLOGIC
ACTIONS OF
PROSTAGLANDIN
S
Cardiovascular
Renal
BIOLOGIC
ACTIONS OF
PROSTAGLANDIN
S
Gastrointestinal
Increases peristaltic
action in intestine;
regulates secretion of
mucin; inhibits gastric
acid secretion
Reproductive
Stimulates uterine
activity leading to
expulsion of fetus and
placenta
BIOLOGIC
ACTIONS OF
PROSTAGLANDIN
S
Nervous system
Metabolic
Increases formation of
cAMP in platelets,
thyroid, corpus luteum,
fetal bone,
adenohypophysis and
lungs but reduces cAMP
in renal tubule cells and
adipose tissue
BIOLOGIC
ACTIONS OF
PROSTAGLANDIN
S
Evokes chemokinesis of T
cells
When generated by
immune cells
(macrophages, mast cells,
B cells)
BIOLOGIC
ACTIONS OF
PROSTAGLANDIN
S
Tromboxane (TXA2)
Synthesized in platelets
Causes vasoconstriction
and platelet
aggregation
Prostacyclin (PGI2)
Produced by endothelial
cells in blood vessel
walls
Inhibits platelet
aggregation
REGULATION OF
PROSTAGLANDIN
METABOLISM
Control of biosynthesis
is poorly understood
Prostaglandins are
rapidly inactivated by
15hydroxyprostaglandin
dehydrogenase
ASPIRIN
Irreversibly inactivates
cyclooxygenase activity
by acetylating a Ser
residue and blocking the
enzymes active site
At low doses, reduces the
probability of heart
attacks and stroke by
inhibiting the synthesis of
tromboxane
MECHANISM OF
ACTION OF
ASPIRIN
NON-STEROIDAL
ANTIINFLAMMATORY
AGENTS (NSAIDS)
Inhibition of COX-2 is
responsible for the antiinflammatory effects of
these drugs
Inhibition of COX-1 is
responsible for the
recognized toxicities of
NSAIDs
Renal insufficiency
COX-2 SPECIFIC
INHIBITORS
COX-2 SPECIFIC
INHIBITORS
LIPOXYGENASE
PATHWAY
Insert oxygen at 5, 12
and 15 position of
arachidonic acid giving
rise to hydroperoxides
5-lipoxygenase forms
leukotrienes
Combined action of 15lipoxygenase and
5lipoxygenase forms
lipoxins
LIPOOXYGENAS
E PATHWAY
Mixture of leukotrienes
C4, D4, E4
100-1000x more potent
than histamine or
prostaglandin as
constrictor of bronchial
musculature; among
the principal mediators
of asthma
Antagonists to
leukotriene receptors
has been used as
treatment for
bronchial asthma
(e.g. Montelukast)
LIPOOXYGENAS
E PATHWAY
Lipoxins
Has anti-inflammatory
role
Inhibits the chemotactic
responses and
degranulation induce by
leukotrienes
Inhibits neutrophil and
eosinophil migration
and adhesion
OMEGA-3 FATTY
ACIDS
EICOSAPENTAE
NOIC ACID
KEY POINTS
Biosynthesis of
unsaturated fatty acids is
catalyzed by desaturase
and elongase enzymes
Animals have 4, 5, 6
and 9 desaturases but
cannot insert double
bonds beyond 9 thus
the essential fatty acids
linoleic, linolenic and
arachidonic must be
obtained from the diet
KEY POINTS
The cyclooxygenase
pathway produces
prostaglandins,
thromboxane and
prostacyclin
The lipoxygenase
pathway produces
leukotrienes and lipoxins
Non-steroidal antiinflammatory agents
(NSAIDs) inhibit
cyclooxygenase
Aspirin irreversibly
inhibits cyclooxygenase
by acetylating a serine
residue in the active site
KEY POINTS