Prostaglandins and Related Compounds 1Dr. Nikhat Siddiqi.

Dr. Nikhat Siddiqi 1

Prostaglandins and Related Compounds


• Prostaglandins, and the related compounds thromboxanes and leukotrienes, are collectively known as eicosanoids to reflect their origin from polyunsaturated fatty acids with 20 carbons.

• They are extremely potent compounds that elicit a wide range of responses, both physiologic and pathologic.

• Although they have been compared to hormones in terms of their actions, eicosanoids differ from the true hormones in that they are produced in very small amounts in almost all tissues rather than in specialized glands.

• Their biologic actions are mediated by plasma membrane G protein–coupled receptors, which are different in different organ systems.


Examples of prostaglandin structures

• Prostaglandins are named as follows: PG plus a third letter (for example, A, D, E, F), which designates the type and arrangement of functional groups in the molecule.

• PGI2 is known as prostacyclin.• The subscript number

indicates the number of double bonds in the molecule.

• Thromboxanes are designated by TX and leukotrienes by LT.


Synthesis of prostaglandins and thromboxanes

• The dietary precursor of the prostaglandins is the essential fatty acid, linoleic acid.

• It is elongated and desaturated to arachidonic acid, the immediate precursor of the predominant class of prostaglandins (those with two double bonds) in humans.


Synthesis of PGH2

• The first step in the synthesis of prostaglandins is the oxidative cyclization of free arachidonic acid to yield PGH2 by prostaglandin endoperoxide synthase (PGH synthase).

• 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 .


• PGH2 is converted to a variety of prostaglandins and thromboxanes, as shown in, by cell-specific synthases.


Isozymes of PGH synthase• Two isozymes, usually denoted

as COX-1 and COX-2, of the synthase are known.

• COX-1 is 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.


Inhibition of prostaglandin synthesis

• The synthesis of prostaglandins can be inhibited by a number of unrelated compounds.

• For example, cortisol (a steroidal anti-inflammatory agent) inhibits phospholipase A2 activity and, therefore, the precursor of the prostaglandins, arachidonic acid, is not available.


• Aspirin, indomethacin, and phenylbutazone (all nonsteroidal anti-inflammatory agents [NSAIDS]) inhibit both COX-1 and COX-2 and, therefore, prevent the synthesis of the parent prostaglandin, PGH2.


Synthesis of leukotrienes• Arachidonic acid is converted to a

variety of linear hydroperoxy acids by a separate pathway involving a family of lipoxygenases.

• For example, neutrophils contain 5-lipoxygenase, which converts arachidonic acid to 5-hydroxy-6,8,11,14 eicosatetraenoic acid (5-HPETE).

• 5-HPETE is converted to a series of leukotrienes, the nature of the final products varying according to the tissue.

• Leukotrienes are mediators of allergic response and inflammation.


Role of prostaglandins in platelet homeostasis

• In addition to their roles in mediating inflammation, fever, and allergic response, and ensuring gastric integrity and renal function, eicosanoids are involved in a diverse group of physiologic functions, including ovarian and uterine function, bone metabolism, nerve and brain function, smooth muscle regulation, and platelet homeostasis.

• Thromboxane A2 (TXA2) is produced by activated platelets. It promotes adherence and aggregation of circulating platelets, and contraction of vascular smooth muscle, thus promoting formation of blood clots (thrombi).

• Prostacyclin (PGI2), produced by vascular endothelial cells, inhibits platelet aggregation and stimulates vasodilation, and so impedes thrombogenesis.

• The opposing effects of TXA2 and PGI2 limit thrombi formation to sites of vascular injury.

• Aspirin has an antithrombogenic effect. It inhibits TX A2 synthesis from arachidonic acid in platelets by irreversible acetylation and inhibition of COX-1.

Prostaglandins and Related Compounds 1Dr. Nikhat Siddiqi.

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