Prostaglandin

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [3]

Overview

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,[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.

Biochemistry

Biosynthesis

Biosynthesis of eicosanoids. (series-2)
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).


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

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.

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 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.

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.

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 PGF 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).

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:

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

Inhibition

See Prostaglandin antagonist

Clinical uses

Synthetic prostaglandins are used:

References

  1. Von Euler US. Über die spezifische blutdrucksenkende Substanz des menschlichen Prostata- und Samenblasensekrets. Klin Wochenschr 1935;14:1182–1183.
  2. Goldblatt MW. Properties of human seminal plasma. J Physiol 1935;84:208-18. PMID 16994667.
  3. Dorlands Medical Dictionary [1] URL reference on 10/23/05.
  4. Komoto J, Yamada T, Watanabe K, Takusagawa F (2004). "Crystal structure of human prostaglandin F synthase (AKR1C3)". Biochemistry. 43 (8): 2188–98. PMID 14979715. 
  5. Komoto J, Yamada T, Watanabe K, Woodward D, Takusagawa F (2006). "Prostaglandin F2alpha formation from prostaglandin H2 by prostaglandin F synthase (PGFS): crystal structure of PGFS containing bimatoprost". Biochemistry. 45 (7): 1987–96. PMID 16475787. 
  6. Medscape Early Penile Rehabilitation Helps Reduce Later Intractable ED [2] URL reference on 10/23/05.


Cost Effectiveness of Prostaglandin

| group5 = Clinical Trials Involving Prostaglandin | list5 = Ongoing Trials on Prostaglandin at Clinical Trials.govTrial results on ProstaglandinClinical Trials on Prostaglandin at Google


| group6 = Guidelines / Policies / Government Resources (FDA/CDC) Regarding Prostaglandin | list6 = US National Guidelines Clearinghouse on ProstaglandinNICE Guidance on ProstaglandinNHS PRODIGY GuidanceFDA on ProstaglandinCDC on Prostaglandin


| group7 = Textbook Information on Prostaglandin | list7 = Books and Textbook Information on Prostaglandin


| group8 = Pharmacology Resources on Prostaglandin | list8 = AND (Dose)}} Dosing of ProstaglandinAND (drug interactions)}} Drug interactions with ProstaglandinAND (side effects)}} Side effects of ProstaglandinAND (Allergy)}} Allergic reactions to ProstaglandinAND (overdose)}} Overdose information on ProstaglandinAND (carcinogenicity)}} Carcinogenicity information on ProstaglandinAND (pregnancy)}} Prostaglandin in pregnancyAND (pharmacokinetics)}} Pharmacokinetics of Prostaglandin


| group9 = Genetics, Pharmacogenomics, and Proteinomics of Prostaglandin | list9 = AND (pharmacogenomics)}} Genetics of ProstaglandinAND (pharmacogenomics)}} Pharmacogenomics of ProstaglandinAND (proteomics)}} Proteomics of Prostaglandin


| group10 = Newstories on Prostaglandin | list10 = Prostaglandin in the newsBe alerted to news on ProstaglandinNews trends on Prostaglandin</small>


| group11 = Commentary on Prostaglandin | list11 = Blogs on Prostaglandin

| group12 = Patient Resources on Prostaglandin | list12 = Patient resources on ProstaglandinDiscussion groups on ProstaglandinPatient Handouts on ProstaglandinDirections to Hospitals Treating ProstaglandinRisk calculators and risk factors for Prostaglandin


| group13 = Healthcare Provider Resources on Prostaglandin | list13 = Symptoms of ProstaglandinCauses & Risk Factors for ProstaglandinDiagnostic studies for ProstaglandinTreatment of Prostaglandin

| group14 = Continuing Medical Education (CME) Programs on Prostaglandin | list14 = CME Programs on Prostaglandin

| group15 = International Resources on Prostaglandin | list15 = Prostaglandin en EspanolProstaglandin en Francais

| group16 = Business Resources on Prostaglandin | list16 = Prostaglandin in the MarketplacePatents on Prostaglandin

| group17 = Informatics Resources on Prostaglandin | list17 = List of terms related to Prostaglandin


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