A prostaglandin is any member of a group of
lipidcompounds that are derived enzymatically from fatty acids and have important functions in the animalbody. Every prostaglandin contains 20 carbonatoms, 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 prostanoidclass 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 fluidin 1935by the Swedish physiologist Ulf von Euler, [cite journal |author=Von Euler US |title=Über die spezifische blutdrucksenkende Substanz des menschlichen Prostata- und Samenblasensekrets |journal=Wien Klin Wochenschr |volume=14 |issue=33 |pages=1182–3 |year=1935 |url=http://www.springerlink.com/content/g602m231xpw85226/fulltext.pdf] and independently by M.W. Goldblatt, [cite journal |author=Goldblatt MW |title=Properties of human seminal plasma |journal=J Physiol |volume=84 |issue=2 |pages=208–18 |year=1935 |month=May |pmid=16994667 |pmc=1394818 |doi= |url=http://www.jphysiol.org/cgi/pmidlookup?view=long&pmid=16994667] 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.
1971, it was determined that aspirin-like drugs could inhibit the synthesis of prostaglandins. The biochemists Sune K. Bergström, Bengt I. Samuelssonand John R. Vanejointly received the 1982 Nobel Prize in Physiology or Medicinefor their research on prostaglandins.
sDorlandsDict|three/000039082|essential fatty acid (EFA)] (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, prostacyclinand prostaglandin D, E and F. The lipoxygenase pathway is active in leukocytes and in macrophages and synthesizes leukotrienes.
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 transportersuperfamily. Whether MRP4 is the only transporter releasing prostaglandins from the cells is still unclear.
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, stomachand 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-PGF2α,β from PGD2 and PGF2α from PGH2 in the presence of NADPH. This enzyme has recently been crystallyzed in complex with PGD2 [cite journal |author=Komoto J, Yamada T, Watanabe K, Takusagawa F |title=Crystal structure of human prostaglandin F synthase (AKR1C3) |journal=Biochemistry |volume=43 |issue=8 |pages=2188–98 |year=2004 |pmid=14979715 |doi=10.1021/bi036046x] and bimatoprost [cite journal |author=Komoto J, Yamada T, Watanabe K, Woodward D, Takusagawa F |title=Prostaglandin F2alpha formation from prostaglandin H2 by prostaglandin F synthase (PGFS): crystal structure of PGFS containing bimatoprost |journal=Biochemistry |volume=45 |issue=7 |pages=1987–96 |year=2006 |pmid=16475787 |doi=10.1021/bi051861t] (a synthetic analogue of PGF2α).
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
* sensitize spinal
neurons to pain
* decrease intraocular pressure
* regulate inflammatory mediation
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.
Role in pharmacology
Examples of prostaglandin antagonists are:
NSAIDs (inhibit cyclooxygenase)
Corticosteroids(inhibit phospholipase A2 production)
COX-2 selective inhibitorsor coxibs
However, both NSAIDs and Coxibs can raise the risk of
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 arteriosusin newborns with particular cyanotic heart defects (PGE1)
* To prevent and treat
peptic ulcers (PGE)
* As a vasodilator in severe
Raynaud's phenomenonor ischemiaof a limb
* In treatment of
glaucoma(as in bimatoprostophthalmic solution, a synthetic prostamide analog with ocular hypotensive activity)
* To treat
erectile dysfunctionor in penile rehabilitation following surgery (PGE1 as alprostadil).Medscape " [http://www.medscape.com/viewarticle/515218 Early Penile Rehabilitation Helps Reduce Later Intractable ED] "]
* To treat egg binding in small
birds[cite web |url=http://www.michvma.org/documents/MVC%20Proceedings/Labonde2.pdf |title=Avian Reproductive and Pediatric Disorders |accessdate=2008-01-26 |last=LaBonde, MS, DVM |first=Jerry| publisher=Michigan Veterinary Medical Association]
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