prostaglandin

prostaglandin, any of a group of about a dozen compounds synthesized from fatty acids in mammals as well as in lower animals. Prostaglandins are highly potent substances that are not stored but are produced as needed by cell membranes in virtually every body tissue. Different prostaglandins have been found to raise or lower blood pressure and regulate smooth muscle activity and glandular secretion. One such substance, which stimulates contraction of the uterus, is used clinically to induce labor; another has been in experimental use as a birth control agent. Prostaglandins also control the substances involved in the transmission of nerve impulses, participate in the body's defenses against infection, and regulate the rate of metabolism in various tissues. Several prostaglandins have been shown to induce fever, possibly by participating in the temperature-regulating mechanisms in the hypothalamus; they also play a part in causing inflammation. The fact that aspirin and other nonsteroidal anti-inflammatory drugs have been shown to inhibit prostaglandin synthesis may account for their usefulness in reducing fever and inflammation. Many naturally occurring prostaglandins as well as many artificial forms have been synthesized in the laboratory.

Any of a class of organic compounds that occur in many animal tissues and have diverse hormonelike effects in animals (see hormone). Their common chemical structure is derived from a fatty acid with 20 carbon atoms. They have important effects on blood pressure, blood clotting, pain sensation, and reproduction mechanisms, but one prostaglandin may have different and even opposite effects in different tissues. They hold promise for treating heart disease and viral diseases and may be useful in contraception. Some substances that inhibit prostaglandin synthesis (see aspirin) are useful in controlling pain, asthma attacks, or anaphylactic shock or as anticoagulants.

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A prostaglandin is any member of a group of lipid compounds that are derived enzymatically from fatty acids and have important functions in the animal body. Every prostaglandin contains 20 carbon atoms, including a 5-carbon ring. They are mediators and have a variety of strong physiological effects; although they are technically hormones, they are rarely classified as such.

The prostaglandins together with the thromboxanes and prostacyclins form the prostanoid class of fatty acid derivatives; the prostanoid class is a subclass of eicosanoids.

History and name

The name prostaglandin derives from the prostate gland. When prostaglandin was first isolated from seminal fluid in 1935 by the Swedish physiologist Ulf von Euler, and independently by M.W. Goldblatt, it was believed to be part of the prostatic secretions (in actuality prostaglandins are produced by the seminal vesicles); it was later shown that many other tissues secrete prostaglandins for various functions.

In 1971, it was determined that aspirin-like drugs could inhibit the synthesis of prostaglandins. The biochemists Sune K. Bergström, Bengt I. Samuelsson and John R. Vane jointly received the 1982 Nobel Prize in Physiology or Medicine for their research on prostaglandins.

Biochemistry

Biosynthesis

Prostaglandins are found in virtually all tissues and organs. These are autocrine and paracrine lipid mediators that act upon platelet, endothelium, uterine and mast cells, among others. They are synthesized in the cell from the essential fatty acids (EFAs).

An intermediate is created by phospholipase-A₂, then passed into one of either the cyclooxygenase pathway or the lipoxygenase pathway to form either prostaglandin and thromboxane or leukotriene. The cyclooxygenase pathway produces thromboxane, prostacyclin and prostaglandin D, E and F. The lipoxygenase pathway is active in leukocytes and in macrophages and synthesizes leukotrienes.

Name	EFA Type	Series
Gamma-linolenic acid (GLA) via DGLA	ω-6	series-1
Arachidonic acid (AA)	ω-6	series-2
Eicosapentaenoic acid (EPA)	ω-3	series-3

Release of prostaglandins from the cell

Prostaglandins were originally believed to leave the cells via passive diffusion because of their high lipophilicity. The discovery of the prostaglandin transporter (PGT, SLCO2A1), which mediates the cellular uptake of prostaglandin, demonstrated that diffusion cannot explain the penetration of prostaglandin through the cellular membrane. The release of prostaglandin has now also been shown to be mediated by a specific transporter, namely the multidrug resistance protein 4 (MRP4, ABCC4), a member of the ATP-binding cassette transporter superfamily. Whether MRP4 is the only transporter releasing prostaglandins from the cells is still unclear.

Cyclooxygenases

Prostaglandins are produced following the sequential oxidation of AA, DGLA or EPA by cyclooxygenases (COX-1 and COX-2) and terminal prostaglandin synthases. The classic dogma is as follows:

• COX-1 is responsible for the baseline levels of prostaglandins.
• COX-2 produces prostaglandins through stimulation.

However, while COX-1 and COX-2 are both located in the blood vessels, stomach and the kidneys, prostaglandin levels are increased by COX-2 in scenarios of inflammation. A third form of COX, termed COX-3, has been identified, but its exact function is still being determined.

Prostaglandin E synthase

Prostaglandin E₂ (PGE₂) is generated from the action of prostaglandin E synthases on prostaglandin H₂ (PGH₂). Several prostaglandin E synthases have been identified. To date, microsomal prostaglandin E synthase-1 emerges as a key enzyme in the formation of PGE₂.

Other terminal prostaglandin synthases

Terminal prostaglandin synthases have been identified that are responsible for the formation of other prostaglandins. For example, hematopoietic and lipocalin prostaglandin D synthases (hPGDS and lPGDS) are responsible for the formation of PGD₂ from PGH₂. Similarly, prostacyclin (PGI₂) synthase (PGIS) converts PGH₂ into PGI₂. A thromboxane synthase (TxAS) has also been idenfitied. Prostaglandin F synthase (PGFS) catalyzes the formation of 9α,11β-PGF_2α,β from PGD₂ and PGF_2α from PGH₂ in the presence of NADPH. This enzyme has recently been crystallyzed in complex with PGD₂ and bimatoprost (a synthetic analogue of PGF_2α).

Function

There are currently nine known prostaglandin receptors on various cell types. Prostaglandins ligate a subfamily of cell surface seven-transmembrane receptors, G-protein-coupled receptors. These receptors are termed DP1-2, EP1-4, FP, IP, and TP, corresponding to the receptor that ligates the corresponding prostaglandin (e.g., DP1-2 receptors bind to PGD2).

These varied receptors mean that Prostaglandins thus act on a variety of cells, and have a wide variety of actions:

• cause constriction or dilation in vascular smooth muscle cells
• cause aggregation or disaggregation of platelets
• sensitize spinal neurons to pain
• decrease intraocular pressure
• regulate inflammatory mediation
• regulate calcium movement
• control hormone regulation
• control cell growth

Prostaglandins are potent but have a short half-life before being inactivated and excreted. Therefore, they exert only a paracrine (locally active) or autocrine (acting on the same cell from which it is synthesized) function.

Types

Following is a comparison of the prostaglandin types Prostaglandin I₂ (PGI₂), Prostaglandin E₂ (PGE₂) and Prostaglandin F_2α (PGF_2α).

Type	Receptor	Function
PGI2	IP	vasodilatation inhibit platelet aggregation bronchodilatation
PGE2	EP1	bronchoconstriction GI tract smooth muscle contraction
	EP2	bronchodilatation GI tract smooth muscle relaxation vasodilatation
	EP3	↓ gastric acid secretion ↑ gastric mucus secretion uterus contraction (when pregnant) GI tract smooth muscle contraction lipolysis inhibition ↑ autonomic neurotransmitters
	Unspecified	hyperalgesia pyrogenic
PGF2α	FP	uterus contraction bronchoconstriction

Role in pharmacology

Inhibition

Examples of prostaglandin antagonists are:

• NSAIDs (inhibit cyclooxygenase)
• Corticosteroids (inhibit phospholipase A2 production)
• COX-2 selective inhibitors or coxibs

However, both NSAIDs and Coxibs can raise the risk of myocardial infarction.

Clinical uses

Synthetic prostaglandins are used:

• To induce childbirth (parturition) or abortion (PGE₂ or PGF₂, with or without mifepristone, a progesterone antagonist);
• To prevent closure of patent ductus arteriosus in newborns with particular cyanotic heart defects (PGE₁)
• To prevent and treat peptic ulcers (PGE)
• As a vasodilator in severe Raynaud's phenomenon or ischemia of a limb
• In pulmonary hypertension
• In treatment of glaucoma (as in bimatoprost ophthalmic solution, a synthetic prostamide analog with ocular hypotensive activity)
• To treat erectile dysfunction or in penile rehabilitation following surgery (PGE1 as alprostadil).
• To treat egg binding in small birds

References

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