The Biology, Pathology and Therapeutic Use of Prostaglandins in the Eye

Carol B Toris; Vikas Gulati


Clin Lipidology. 2011;6(5):577-591. 

In This Article

Biosynthesis of PGs

Prostaglandins, thromboxanes and prostacyclins form the prostanoid class of fatty acid derivatives, a subclass of eicosanoids. PGs are extremely potent, biologically active lipid mediators that are synthesized throughout the body, including the eye. The key precursor fatty acid is arachidonic acid, which is an essential fatty acid as it cannot be synthesized de novo in animals. The primary precursor is obtained from the diet in the form of linoleic acid.

Biosynthesis of PGs (Figure 1) involves the action of multiple enzymes, some of which are rate limiting. The first step involves the production of free arachidonic acid from membrane phospholipids upon stimulation of the enzyme phospholipase A2. The next step is accomplished by catalytic activity possessed by two distinct cyclooxygenase (COX-1 and COX-2) isozymes encoded by separate genes. The COX pathway produces PGs PGG2 and PGH2, which then are converted into PGI2 by prostacyclin synthase, TXA2 by thromboxane synthase, and PGE2, PGD2 and PGF by their respective synthase enzymes. It is the analogs of PGF that are currently approved to treat elevated IOP and glaucoma.

Figure 1.

Biosynthesis of prostaglandins. Arachidonic acid, an essential fatty acid obtained from the diet in the form of linoleic acid, is metabolized by the cyclooxygenases, COX-1 and COX-2, to PGH2 via the intermediate PGG2. PGH2 is converted into PGI2 by prostacyclin synthase, TXA2 by thromboxane synthase, PGE2, PGD2 and PGF by their respective synthase enzymes. Arachidonic acid is also metabolized by lipoxygenases to HETEs and HpETEs, which are not covered in this article.
HETE: Hydroxyeicosatetraenoic acid; HpETE: Hydroperoxyeicosatetraenoic acid; LT: Leukotriene; PG: Prostaglandin; TX: Thromboxane.

The two COX enzymes have different functional roles. COX-1 is a constitutive enzyme that is present in tissues and controls the basal levels of PGs. It serves a homeostatic purpose, responding rapidly to circulating hormones, which require constant monitoring and regulation. With the aid of COX-1, PGs are produced in the endoplasmic reticulum, exit the cell and signal through G protein-linked receptors at the cell surface. COX-1 may function only when relatively high concentrations of arachidonic acid exist, such as in platelet aggregation, cell injury or acute inflammation. Unlike COX-1, COX-2 is an inducible enzyme that is not normally present in the eye. COX-2 produces prostanoids that function primarily during defined stages of cellular development or pathological conditions. COX-2 is induced by specific physiological stimuli and is expressed under the control of the proinflammatory transcription factor NF-κB in response to intracellular and extracellular stimuli, such as cytokines, growth factors and tumor promoters. COX-2 can function with low concentrations of arachidonic acid. It is believed that COX-2 initiates the synthesis of PGs that are involved in severe inflammation. With limiting concentrations of hydrogen peroxide, COX-2 may be fully active while COX-1 may not. This is thought possible because COX-2 is activated by hydrogen peroxide at concentrations that are approximately tenfold lower than those that activate COX-1.

Both COX iso-enzymes are inhibited by nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin (acetylsalicylic acid) and ibuprofen. This prevents synthesis of endogenous PGs. Because of differences in the structures of the binding sites, COX-1 is completely inhibited by aspirin, whereas COX-2 is only partially inhibited. Synthesis of COX-2 is inhibited by steroidal anti-inflammatory drugs at the level of transcription. In addition, as the active site of COX-2 is smaller than that of COX-1, a number of drugs have been developed that specifically inhibit the action of COX-2.


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