prostaglandins

プロスタグランジン

WordNet

1. a potent substance that acts like a hormone and is found in many bodily tissues (and especially in semen); produced in response to trauma and may affect blood pressure and metabolism and smooth muscle activity

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2014/08/18 08:49:32」(JST)

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E₁ - Alprostadil

I₂ - Prostacyclin

The prostaglandins are a group of hormone-like 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, such as regulating the contraction and relaxation of smooth muscle tissue. Prostaglandins are not endocrine hormones, but autocrine or paracrine, which are locally acting messenger molecules. They differ from hormones in that they are not produced at a specific site but in many places throughout the human body. Also, their target cells are present in the immediate vicinity of the site of their secretion (of which there are many).

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

The abbreviation for "prostaglandin" is PG; specific prostaglandins are named with a letter (which indicates the type of ring structure) followed by a number (which indicates the number of double bonds in the hydrocarbon structure). For example, prostaglandin E1 is abbreviated PGE1 or PGE₁, and prostaglandin I2 is abbreviated PGI2 or PGI₂. The number is traditionally subscripted when the context allows, but as with many similar subscript-containing nomenclatures, the subscript is simply forgone in many database fields that can store only plain text (such as PubMed bibliographic fields), and readers are used to seeing and writing it without subscript.

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 fact, prostaglandins are produced by the seminal vesicles). It was later shown that many other tissues secrete prostaglandins for various functions. The first total syntheses of prostaglandin F_2α and prostaglandin E₂ were reported by E. J. Corey in 1969, 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.

Biochemistry

Biosynthesis

Biosynthesis 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 essential fatty acids (EFAs).

An intermediate arachidonic acid is created from diacylglycerol via phospholipase-A₂, then brought to either the cyclooxygenase pathway or the lipoxygenase pathway to form either prostaglandin and thromboxane or leukotriene respectively. 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.

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 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.

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 and growth.

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 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 and bimatoprost (a synthetic analogue of PGF_2α).

Function

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:

• cause constriction or dilation in vascular smooth muscle cells
• cause aggregation or disaggregation of platelets
• sensitize spinal neurons to pain
• induce labor
• decrease intraocular pressure
• regulate inflammation
• regulate calcium movement
• regulate hormones
• control cell growth
• acts on thermoregulatory center of hypothalamus to produce fever
• acts on mesangial cells in the glomerulus of the kidney to increase glomerular filtration rate
• acts on parietal cells in the stomach wall to inhibit acid secretion
• brain masculinization (in rats) (ref : http://www.jneurosci.org/content/33/7/2761.full.pdf+html)

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

Types

The following is a comparison of different types of prostaglandin, prostacyclin I₂ (PGI₂), prostaglandin E₂ (PGE₂), and prostaglandin F_2α (PGF_2α).

Type	Receptor	Receptor type	Function
PGI2	IP	Gs	vasodilation inhibit platelet aggregation bronchodilation
PGE2	EP1	Gq	bronchoconstriction GI tract smooth muscle contraction
	EP2	Gs	bronchodilation GI tract smooth muscle relaxation vasodilation
	EP3	Gi	↓ gastric acid secretion ↑ gastric mucus secretion uterus contraction (when pregnant) GI tract smooth muscle contraction lipolysis inhibition ↑ autonomic neurotransmitters ↑ platelet response to their agonists [1] and ↑ atherothrombosis in vivo [2]
	Unspecified		hyperalgesia pyrogenic
PGF2α	FP	Gq	uterus contraction bronchoconstriction

Role in pharmacology

Inhibition

See also: Prostaglandin antagonist and Mechanism of action of aspirin

Examples of prostaglandin antagonists are:

• NSAIDs (inhibit cyclooxygenase)
• Corticosteroids (inhibit phospholipase A2 production)
• COX-2 selective inhibitors or coxibs
• Cyclopentenone prostaglandins may play a role in inhibiting inflammation

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
• As an ingredient in eyelash and eyebrow growth beauty products due to side effects associated with increased hair growth

References

External links

• Prostaglandins at the US National Library of Medicine Medical Subject Headings (MeSH)

UpToDate Contents

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English Journal

• Intravenous epoprostenol for treatment-refractory reversible cerebral vasoconstriction syndrome (RCVS).

• Thydén AL1, Muhamad AA2, Jacobsen A3, Kondziella D4.
• Journal of the neurological sciences.J Neurol Sci.2016 May 15;364:56-8. doi: 10.1016/j.jns.2016.03.009. Epub 2016 Mar 4.
• PMID 27084217

• Inflammatory transcription factors as activation markers and functional readouts in immune-to-brain communication.

• Rummel C1.
• Brain, behavior, and immunity.Brain Behav Immun.2016 May;54:1-14. doi: 10.1016/j.bbi.2015.09.003. Epub 2015 Sep 5.
• Immune-to-brain communication pathways involve humoral mediators, including cytokines, central modulation by neuronal afferents and immune cell trafficking to the brain. During systemic inflammation these pathways contribute to mediating brain-controlled sickness symptoms including fever. Experiment
• PMID 26348582

• Lecithin-gold hybrid nanocarriers as efficient and pH selective vehicles for oral delivery of diacerein-In-vitro and in-vivo study.

• Javed I1, Hussain SZ2, Shahzad A3, Khan JM2, Ur-Rehman H2, Rehman M4, Usman F5, Razi MT3, Shah MR6, Hussain I7.
• Colloids and surfaces. B, Biointerfaces.Colloids Surf B Biointerfaces.2016 May 1;141:1-9. doi: 10.1016/j.colsurfb.2016.01.022. Epub 2016 Jan 15.
• We report the synthesis and evaluation of lecithin-gold hybrid nanocarriers for the oral delivery of drugs with improved pharmacokinetics, Au-drug interactive bioactivity and controlled drug releasing behavior at physiological pH inside human body. For this purpose, diacerein, a hydrophobic anti-art
• PMID 26816348

Japanese Journal

• プロスタグランジンによる皮膚マスト細胞の成熟と活性化

• 杉本 幸彦
• 臨床免疫・アレルギー科 63(1), 62-67, 2015-01
• NAID 40020330437

• An in vivo mouse model of primary dysmenorrhea

• , , ,
• Experimental Animals advpub(0), 2015
• … In addition, enzyme-linked immunosorbent assay kit was used to measure the levels of prostaglandins F2α/prostaglandins E2 (PGF2α/PGE2) and TXB2 (a metabolite of TXA2)/6-keto-PGF1α (a metabolite of PGI2) in the uterine tissue homogenates and plasma, respectively. …
• NAID 130005066236

• プロスタグランジンを標的とした治療 (特集 去勢抵抗性前立腺癌 : 基礎と臨床の最新研究動向) -- (臨床応用への基礎研究)

• 寺田 直樹,井上 貴博,神波 大己 [他]
• 日本臨床 72(12), 2141-2146, 2014-12
• NAID 40020270882

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