Prostaglandin

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Chemical structure of prostaglandin E₁ (PGE₁).

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 form the prostanoid class of fatty acid derivatives; the prostanoid class is a subclass of eicosanoids.

1 History and name
2 Biochemistry
3 Role in pharmacology
- 3.1 Inhibition
- 3.2 Clinical uses
4 References

[edit] 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,^[1] and independently by M.W. Goldblatt,^[2] 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 researches on prostaglandins.

[edit] Biochemistry

[edit] 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^[3] (EFAs).

Gamma-linolenic acid (GLA, an ω-6 EFA, via DGLA) - yielding the series-1 prostaglandins
Arachidonic acid (AA, ω-6) - yielding series-2
Eicosapentaenoic acid (EPA, ω-3) - yielding series-3

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.

[edit] Release of prostaglandins from the cell

Prostaglandins are 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 can not 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.

[edit] 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 that COX-1 is responsible for the baseline levels of prostaglandins, whereas 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.

[edit] 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.

[edit] 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^[4] and bimatoprost^[5] (a synthetic analogue of PGF_2α).

[edit] Function

There are currently nine known receptors of prostaglandins 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). Prostaglandins thus act on a variety of cells such as vascular smooth muscle cells causing constriction or dilation, on platelets causing aggregation or disaggregation and on spinal neurons causing pain. Prostaglandins have a wide variety of actions, including, but not limited to muscular constriction and mediate inflammation. Other effects include calcium movement, hormone regulation and cell growth control. Thromboxane is created in platelets and causes vascular constriction and platelet aggregation. Prostacyclin comes from cells in the blood vessel walls and is antagonistic to thromboxane.

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.

[edit] Role in pharmacology

[edit] Inhibition

NSAIDs inhibit cyclooxygenase and reduce prostaglandin synthesis. Corticosteroids inhibit phospholipase A₂ production by boosting production of lipocortin, an inhibitor protein. Relatively new drugs, known as COX-2 selective inhibitors or coxibs, are used as specific inhibitors of COX-2. The development of these drugs allowed the circumvention of the negative gastrointestinal effects while effectively reducing inflammation. However, it was subsequently shown that both NSAIDs and Coxibs can raise the risk of myocardial infarction, when taken on a chronic basis for at least 18 months. One emerging hypothesis that may explain the cardiovascular effects is that coxibs create an imbalance in circulating TxA2 (thromboxane) and PGI2 (prostacyclin) levels. An increased in the ratio of TxA2/PGI2 could lead to increased platelet aggregation and dysregulation of platelet homeostatis.^{[citation needed]}

[edit] 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 ductus arteriosus in newborns with particular cyanotic heart defects
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).^[6]

[edit] References

^ Von Euler US. Über die spezifische blutdrucksenkende Substanz des menschlichen Prostata- und Samenblasensekrets. Klin Wochenschr 1935;14:1182–1183.
^ Goldblatt MW. Properties of human seminal plasma. J Physiol 1935;84:208-18. PMID 16994667.
^ Dorlands Medical Dictionary [1] URL reference on 10/23/05.
^ DOI:10.1021/bi036046x
^ DOI:10.1021/bi051861t
^ Medscape Early Penile Rehabilitation Helps Reduce Later Intractable ED [2] URL reference on 10/23/05.