Prostaglandin

Systematic studies of prostaglandins began in 1930, when Kurzrock and Lieb found that human seminal fluid caused either stimulation or relaxation of strips of isolated human uterus. They noted that uteri from patients who had gone through successful pregnancies responded to the fluid with relaxation, while uteri from sterile women responded with contraction.{{cite journal |last1=Kurzrock |first1=Raphael |last2=Lieb |first2=Charles C. |title=Biochemical Studies of Human Semen. II. The Action of Semen on the Human Uterus |journal=Proceedings of the Society for Experimental Biology and Medicine |date=1930 |volume=28 |issue=3 |page=268 |doi=10.3181/00379727-28-5265 |s2cid=85374636 }} The name prostaglandin derives from the prostate gland, chosen when prostaglandin was first isolated from seminal fluid in 1935 by the Swedish physiologist Ulf von Euler,{{cite journal | vauthors = Von Euler US |title=Über die spezifische blutdrucksenkende Substanz des menschlichen Prostata- und Samenblasensekrets |trans-title=On the specific blood-pressure-reducing substance of human prostate and seminal vesicle secretions |journal=Wiener Klinische Wochenschrift |volume=14 |issue=33 |pages=1182–1183 |year=1935 |doi=10.1007/BF01778029|s2cid=38622866 }} and independently by the Irish-English physiologist Maurice Walter Goldblatt (1895–1967).{{cite journal | vauthors = Goldblatt MW | title = Properties of human seminal plasma | journal = The Journal of Physiology | volume = 84 | issue = 2 | pages = 208–18 | date = May 1935 | pmid = 16994667 | pmc = 1394818 | doi = 10.1113/jphysiol.1935.sp003269| url = http://www.jphysiol.org/cgi/pmidlookup?view=long&pmid=16994667 }}{{cite book |editor1-last=Rubinstein |editor1-first=William D. |editor2-last=Jolles |editor2-first=Michael A. |editor3-last=Rubinstein |editor3-first=Hillary L. |title=The Palgrave Dictionary of Anglo-Jewish History |date=2011 |publisher=Palgrave Macmillan |location=Basingstoke, England |page=333 |chapter-url=https://books.google.com/books?id=_T_HCg17ufIC&pg=PA333 |chapter=Goldblatt, Maurice Walter|isbn=978-0-230-30466-6 }}{{cite journal |last1=R.S.F.S. |title=Obituary Notices: M. W. Goldblatt |journal=British Medical Journal |date=3 June 1967 |volume=2 |issue=5552 |page=644 |doi=10.1136/bmj.2.5552.644 |s2cid=220151673 |url=https://www.bmj.com/content/2/5552/644|url-access=subscription }} Prostaglandins were believed to be part of the prostatic secretions, and eventually were discovered to be produced by the seminal vesicles. Later, it was shown that many other tissues secrete prostaglandins and that they perform a variety of functions. The first total syntheses of prostaglandin F_2α and prostaglandin E₂ were reported by Elias James Corey in 1969,{{cite book |title= Classics in Total Synthesis|url= https://archive.org/details/classicstotalmet00kcni|url-access= limited| vauthors = Nicolaou KC, Sorensen EJ |author-link=K. C. Nicolaou |year= 1996|publisher= VCH|location= Weinheim, Germany|isbn= 3-527-29284-5|page= [https://archive.org/details/classicstotalmet00kcni/page/n90 65] }} an achievement for which he was awarded the Japan Prize in 1989.

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.{{citation needed|date=January 2024}}

File:Eicosanoid synthesis.svg of eicosanoids]]

Prostaglandins are found in most tissues and organs. They are produced by almost all nucleated cells. They are autocrine and paracrine lipid mediators that act upon platelets, endothelium, uterine and mast cells. They are synthesized in the cell from the fatty acid arachidonic acid.

Arachidonic acid is created from diacylglycerol via phospholipase-A₂, then brought to either the cyclooxygenase pathway or the lipoxygenase pathway. The cyclooxygenase pathway produces thromboxane, prostacyclin and prostaglandin D, E and F. Alternatively, the lipoxygenase enzyme pathway is active in leukocytes and in macrophages and synthesizes leukotrienes.{{citation needed|date=January 2024}}

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 alone 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.{{citation needed|date=January 2024}}

Prostaglandins are produced following the sequential oxygenation of arachidonic acid, DGLA or EPA by cyclooxygenases (COX-1 and COX-2) and terminal prostaglandin syntheses. 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 and growth.

Prostaglandin E₂ (PGE₂) — the most abundant prostaglandin{{cite journal | vauthors = Ke J, Yang Y, Che Q, Jiang F, Wang H, Chen Z, Zhu M, Tong H, Zhang H, Yan X, Wang X, Wang F, Liu Y, Dai C, Wan X | title = Prostaglandin E2 (PGE2) promotes proliferation and invasion by enhancing SUMO-1 activity via EP4 receptor in endometrial cancer | journal = Tumour Biology | volume = 37 | issue = 9 | pages = 12203–12211 | date = September 2016 | pmid = 27230680 | pmc = 5080328 | doi = 10.1007/s13277-016-5087-x | quote = Prostaglandin E2 (PGE2) is the most abundant prostanoid in the human body }} — is generated from the action of prostaglandin E synthases on prostaglandin H₂ (prostaglandin H2, PGH₂). Several prostaglandin E syntheses have been identified. To date, microsomal (named as misoprostol) prostaglandin E synthase-1 emerges as a key enzyme in the formation of PGE₂.{{citation needed|date=January 2024}}

Terminal prostaglandin syntheses 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 identified.

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 crystallized in complex with PGD₂{{cite journal | vauthors = 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 | date = March 2004 | pmid = 14979715 | doi = 10.1021/bi036046x }} and bimatoprost{{cite journal | vauthors = Komoto J, Yamada T, Watanabe K, Woodward DF, 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 | date = February 2006 | pmid = 16475787 | doi = 10.1021/bi051861t }} (a synthetic analogue of PGF_2α).

There are currently ten known prostaglandin receptors on various cell types. Prostaglandins ligate a sub-family of cell surface seven-transmembrane receptors, G-protein-coupled receptors. These receptors are termed DP1-2, EP1-4, FP, IP1-2, and TP, corresponding to the receptor that ligates the corresponding prostaglandin (e.g., DP1-2 receptors bind to PGD2).

The diversity of receptors means that prostaglandins act on an array of cells and have a wide variety of effects such as:

• create eicosanoids hormones
• act on thermoregulatory center of hypothalamus to produce fever
• increase mating behaviors in goldfish{{Cite web|url=https://www.researchgate.net/publication/226044617|title=Hormonal and pheromonal control of spawning in goldfish (PDF Download Available)|website=ResearchGate|language=en|access-date=2017-02-04}}
• cause the uterus to contract{{efn|Prostaglandins are released during menstruation, due to the destruction of the endometrial cells, and the resultant release of their contents.{{cite journal | vauthors = Lethaby A, Duckitt K, Farquhar C | title = Non-steroidal anti-inflammatory drugs for heavy menstrual bleeding | journal = The Cochrane Database of Systematic Reviews | issue = 1 | pages = CD000400 | date = January 2013 | pmid = 23440779 | doi = 10.1002/14651858.CD000400.pub3 }}{{Update inline|reason=Updated version https://www.ncbi.nlm.nih.gov/pubmed/31535715|date = November 2019}} Release of prostaglandins and other inflammatory mediators in the uterus cause the uterus to contract. These substances are thought to be a major factor in primary dysmenorrhea.Wright, Jason and Solange Wyatt. The Washington Manual Obstetrics and Gynecology Survival Guide. Lippincott Williams & Wilkins, 2003. {{ISBN|0-7817-4363-X}}{{page needed|date=January 2013}}{{cite journal | vauthors = Harel Z | title = Dysmenorrhea in adolescents and young adults: etiology and management | journal = Journal of Pediatric and Adolescent Gynecology | volume = 19 | issue = 6 | pages = 363–71 | date = December 2006 | pmid = 17174824 | doi = 10.1016/j.jpag.2006.09.001 }}{{cite journal |last1=Bofill Rodriguez |first1=M |last2=Lethaby |first2=A |last3=Farquhar |first3=C |title=Non-steroidal anti-inflammatory drugs for heavy menstrual bleeding. |journal=The Cochrane Database of Systematic Reviews |date=19 September 2019 |volume=2019 |issue=9 |pages=CD000400 |doi=10.1002/14651858.CD000400.pub4 |pmid=31535715|pmc=6751587 }}}}
• prevent gastrointestinal tract from self-digesting, contributing to its mucosal defence in multifactorial way.{{Cite journal |last=Wallace |first=John L. |date=October 2008 |title=Prostaglandins, NSAIDs, and Gastric Mucosal Protection: Why Doesn't the Stomach Digest Itself? |url=https://www.physiology.org/doi/10.1152/physrev.00004.2008 |journal=Physiological Reviews |language=en |volume=88 |issue=4 |pages=1547–1565 |doi=10.1152/physrev.00004.2008 |issn=0031-9333|url-access=subscription }}

==Types==

The following is a comparison of different types of prostaglandin, including prostaglandin I₂ (prostacyclin; PGI₂), prostaglandin D₂ (PGD₂), prostaglandin E₂ (PGE₂), and prostaglandin F_2α (PGF_2α).{{cite journal | vauthors = Moreno JJ | title = Eicosanoid receptors: Targets for the treatment of disrupted intestinal epithelial homeostasis | journal = European Journal of Pharmacology | volume = 796 | pages = 7–19 | date = February 2017 | pmid = 27940058 | doi = 10.1016/j.ejphar.2016.12.004 | s2cid = 1513449 }}

{{see also|Prostaglandin antagonist|Mechanism of action of aspirin}}

Examples of prostaglandin antagonists are:

• NSAIDs (inhibit cyclooxygenase) and COX-2 selective inhibitors or coxibs
• Corticosteroids (inhibit phospholipase A₂ production)
• Cyclopentenone prostaglandins may play a role in inhibiting inflammation
• Vitamin D₃ and vitamin K₂.{{cite journal| author=Kieronska-Rudek A, Kij A, Kaczara P, Tworzydlo A, Napiorkowski M, Sidoryk K | display-authors=etal| title=Exogenous Vitamins K Exert Anti-Inflammatory Effects Dissociated from Their Role as Substrates for Synthesis of Endogenous MK-4 in Murine Macrophages Cell Line. | journal=Cells | year= 2021 | volume= 10 | issue= 7 | page=1571| pmid=34206530 | doi=10.3390/cells10071571 | pmc=8303864 | doi-access=free}}{{cite journal| author=Koshihara Y, Hoshi K, Shiraki M| title=Vitamin K2 (menatetrenone) inhibits prostaglandin synthesis in cultured human osteoblast-like periosteal cells by inhibiting prostaglandin H synthase activity. | journal=Biochem Pharmacol | year= 1993 | volume= 46 | issue= 8 | pages= 1355–62 | pmid=8240383 | doi=10.1016/0006-2952(93)90099-i }}{{cite journal| author=Krishnan AV, Srinivas S, Feldman D| title=Inhibition of prostaglandin synthesis and actions contributes to the beneficial effects of calcitriol in prostate cancer. | journal=Dermatoendocrinol | year= 2009 | volume= 1 | issue= 1 | pages= 7–11 | pmid=20046582 | doi=10.4161/derm.1.1.7106 | pmc=2715203 }}

Synthetic prostaglandins are used:

• To induce childbirth (parturition) or abortion (PGE₂ or PGF_{2(misoprostol)}, with or without mifepristone, a progesterone antagonist)
• Induction of labour{{cite web | title=WHO Recommendations for Induction of Labour | website=NCBI Bookshelf | url=https://www.ncbi.nlm.nih.gov/books/NBK131965/ | access-date=2020-07-15 | quote= Induction of labour is defined as the process of artificially stimulating the uterus to start labour (1). It is usually performed by administering oxytocin or prostaglandins to the pregnant woman or by manually rupturing the amniotic membranes.}}
• To prevent closure of ductus arteriosus in newborns with particular cyanotic heart defects (PGE₁)
• As a vasodilator in severe Raynaud syndrome 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) (PGF_2α)
• To treat erectile dysfunction or in penile rehabilitation following surgery (PGE1 as alprostadil).Medscape [http://www.medscape.com/viewarticle/515218 Early Penile Rehabilitation Helps Reduce Later Intractable ED]
• To measure erect penis size in a clinical environment{{cite journal |doi=10.1111/bju.13010 |doi-access=free |pmid=25487360 |title=Am I normal? A systematic review and construction of nomograms for flaccid and erect penis length and circumference in up to 15 521 men |journal=BJU International |volume=115 |issue=6 |pages=978–986 |year=2015 |last1=Veale |first1=David |last2=Miles |first2=Sarah |last3=Bramley |first3=Sally |last4=Muir |first4=Gordon |last5=Hodsoll |first5=John}}
• 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 |access-date=2008-01-26 |last=LaBonde, MS, DVM |first=Jerry| publisher=Michigan Veterinary Medical Association |archive-url = https://web.archive.org/web/20080227041626/http://www.michvma.org/documents/MVC%20Proceedings/Labonde2.pdf |archive-date = 2008-02-27}}

The original synthesis of prostaglandins F2α and E2 is shown below. It involves a Diels–Alder reaction which establishes the relative stereochemistry of three contiguous stereocenters on the prostaglandin cyclopentane core.{{cite journal |last1=Corey |first1=E. J. |last2=Weinshenker |first2=N. M. |last3=Schaaf |first3=T. K. |last4=Huber |first4=W. |year=1969 |title=Stereo-controlled synthesis of prostaglandins F-2a and E-2 (dl)|journal=Journal of the American Chemical Society |volume=91 |issue=20 |pages=5675–7 |doi=10.1021/ja01048a062 |pmid=5808505}}

File:Prostaglandin Diels-Alder Corey.png

Cold exposure and IUDs may increase prostaglandin production.{{cite book |author=Mary Anne Koda-Kimble |title=Handbook of Applied Therapeutics | edition=8th |language=en |publisher=Lippincott Williams & Wilkins |year=2007 |page=1104 |isbn=978-0-7817-9026-0 }}

• Oxaprostaglandin, a type of prostaglandin
• Prostamides, a chemically related class of physiologically active substances

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• {{MeshName|Prostaglandins}}

{{Hormones}}

{{Eicosanoids}}

{{Oxytocics}}

{{Drugs for peptic ulcer and GORD}}

{{Antiglaucoma preparations and miotics}}

{{Urologicals}}

{{Prostanoidergics}}

{{Authority control}}