prostaglandin

E₁ - Alprostadil

I₂ - Prostacyclin

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 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 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.^[3]

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. (series-2)

Prostaglandins are found in most tissues and organs. They are produced by all nucleated cells except lymphocytes. 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^[4] (EFAs).

An intermediate is created from phospholipase-A₂, then brought out of 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 enzyme pathway is inactive 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 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. A third form of COX, termed COX-3 is thought to exist in the brain and may be associated with relief of Headaches when on NSAID therapy.

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 crystallyzed in complex with PGD₂^[5] and bimatoprost^[6] (a synthetic analogue of PGF_2α).

Function

There are currently nine 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, Ip, 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:

• cause constriction or dilation in vascular smooth muscle cells
• cause aggregation or disaggregation of platelets
• sensitize spinal neurons to pain
• decrease intraocular pressure
• regulate inflammatory mediation
• regulate calcium movement
• control hormone regulation
• control cell growth

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, prostaglandin I₂ (PGI₂), prostaglandin E₂ (PGE₂), and prostaglandin F_2α (PGF_2α).

Role in pharmacology

Inhibition

Examples of prostaglandin antagonists are:

• NSAIDs (inhibit cyclooxygenase)
• Corticosteroids (inhibit phospholipase A2 production)
• COX-2 selective inhibitors or coxibs

However, both NSAIDs and Coxibs can raise the risk of myocardial infarction.

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).^[10]
• To treat egg binding in small birds^[11]
• As an ingredient in eyelash and eyebrow growth beauty products due to side effects associated with increased hair growth

References

External links

• MeSH Prostaglandins