EICOSONOIDS

Family of compounds originated from 20c(eicosa) polysaturated fatty acids. Four families; Prostaglandins(PG), Thromboxanes(TX), Prostacyclins(PGI) AND

Leukotrines (LT)& lipoxines(LX)

SYNTHESIS of prostaglandins, thromboxanes and prostacyclines(prostenoids):o Dietary precursor- lenoleic acid elongated and desaturated arachidonic acid

(released by membrane bound PLs and released by phospholipade A2)

o Arachidonic acid(immediate precursor) oxidative cyclization(prostaglandin endoperoxide synthase-PGH synthase) PGH2 converted to a variety of prostenoids

o PGH synthase- two catalytic activities: COX-cycloxygenase-dependant on 2 mols of O2 Peroxidase- dependant on reduced glutathione(GSH)

o Isozymes of prostaglandin endoperoxide synthase(2): COX 1- constitutely made in most tissues- healthy gastric tissue, renal

homeostasis & platelet aggregation COX2-made only when needed(non-constitutive expression). Mediates

pain, head, redness, and swelling of inflammation and fever of infection

o Inhibitors of prostaglandin synthesis- (details in figure) ASPRIN- inhibits both COX1 and COX2- reason for its toxicity systemic

inhibition of cox1, resulting in kidney and stomach dmage associated with impaired bld clotting.

CELECOXIB and also NSAIDs can increase risks of heart attacks

Synthesis of leukotrienes : o Arachidonic acid (5- lipoxygenase) 5- hydroperoxyeicosatetraenoic

acid series of leukotrienes(LTA4, LTC4,LTB4)

o These mediate allergic responses and inflammation

o Inhibitors of 5-lipoxygenase(Zileuton) and antagonists of its receptors-G-protein coupled receptors-leukotrienes act on these(Montelukast, Zafirlukast) are used in treating asthma.

Role of prostaglandins in platelet homeostasis: o Thromboxane A2(produced by platelets) and prostacyclin(by endothelial

cells) have opposing effects-vasoconstriction vs vasodilation; pro-platelet aggregator vs anti-aggregator etc.

o BASIS OF LOW-DOSE ASPRIN THERAPY- it inhibits TXA2 synthesis from arachidonic acid by irreversible acetylation and inhibition of COX-1; anucleate platelets cant overcome this, but endothelial cells can overcome low dose by producing new enzymes coz they are nucleate. SO VASODILATION AND PLATELET AGGREGATION INHIBITION PERSISTS while THROBOXANE activity is inhibited.