In this article we will discuss about Prostaglandins:- 1. Meaning of Prostaglandins 2. Chemistry of Prostaglandins 3. Functions 4. Clinical Importance 5. Side-effects 6. Metabolism 7. Inhibitors.
Contents:
- Meaning of Prostaglandins
- Chemistry of Prostaglandins
- Functions of Prostaglandins
- Clinical Importance of Prostaglandins
- Side-effects of Prostaglandins
- Metabolism of Prostaglandins
- Inhibitors of Prostaglandins
1. Meaning of Prostaglandins:
Prostaglandins are a group of naturally occurring substances synthesized primarily in the prostrate. They had been first isolated from extracts of human seminal fluid and of the vesicular gland of sheep. They are widely distributed in mammalian tissues, e.g., lung, kidney, thyroid, spleen, brain, iris, endometrium, gastrointestinal mucosa, amniotic fluid and menstrual fluids.
The stimulation of adrenal glands and of nerves causes the liberation of prostaglandins in the circulation. Arachidonic acid and some related C20 fatty acids with methylene-interrupted bonds synthesize a group of pharmacologically active compounds known as prostaglandins.
2. Chemistry of Prostaglandins:
a. Prostaglandins have a common structure based on prostanoic acid which contains 20 carbon atoms.
b. They are separated into four groups A, B, E and F depending on the variations in the double bonds and in the hydroxyl and ketone groups.
c. The carbon chains are bonded at the middle of the chain by a 5-membered ring.
d. A, B and E have an oxo-grouping at position 9, whereas F has a hydroxyl group in this position.
e. A has a double bond between positions 10 and 11, whereas B has a double bond between positions 8 and 12. E and F do not have a double bond in the ring but possess a hydroxyl group at position 11.
f. All active prostaglandins have at least one double bond between positions 13 and 14. Some have two double bonds, the second being between positions 5 and 6 and some prostaglandins have three double bonds, the additional bond being between positions 17 and 18.
g. The common single double bond has the trans-configuration, whereas the other double bonds have the cis-configuration.
h. All prostaglandins have a hydroxyl group at position 15 and some have another hydroxyl group at position 19.
i. When the 5-carbon ring has two hydroxyl groups, their positions give rise to the possibility of a or b isomers.
j. The six primary prostaglandins, which occur in most cells, can be converted to the 8 secondary prostaglandins that have been identified in natural materials.
k. The synthesis of prostaglandins requires the consumption of 2 molecules of O2 and 2 molecules of reduced glutathione. The synthesis is catalyzed by the prostaglandin synthetase complex. Aspirin inhibits its synthesis.
l. Fourteen prostaglandins have been isolated from male reproductive tract. These are PGA1, PGA2, PGB1, PGB2, PGE1, PGE2, PGE3 PGF1α, PGF2α, PGF3α, 19-OH PGA1, 19-OH PGA2, 19-OH PGB1, 19-OH PGB2.
[The number in subscript indicates the number of double bonds and the Greek letter the isomeric form.]
3. Functions of Prostaglandins:
a. Prostaglandins exhibit hormone-like activity. They are the most potent biologically active substance. As little as 1 ng/ml causes contraction of smooth muscle in animal.
b. They increase cAMP in platelets, thyroid, corpus luteum, fetal bone, adenohypophysis and lung; but lower cAMP in adipose tissue.
c. Although they are synthesized from the “essential fatty acids” they do not relieve symptoms of essential fatty acid deficiency, because they are too rapidly metabolized.
d. They promote the secretion of epinephrine and cause significant increase in the activity of phsophophosphorylase in liver. They produce a direct inhibitory effect on glycogen synthetase in liver.
e. They inhibit the formation of cAMP which is necessary for the activation of hormone- sensitive lipase and thus decrease lipolysis in adipose tissue. Free fatty acids stimulate more prostaglandin secretion which ultimately inhibits lypolysis.
f. They cause vasodilatation, decreased peripheral resistance, decreased blood pressure, enhanced capillary permeability.
g. They inhibit gastric secretion, increase intestinal motility and cause loose motion.
h. They are involved in spermatogenesis, sperm maturation and transport.
i. They are involved in the regulation of hypothalamic releasing factor release.
j. Infusion of PGE2 into the renal artery of dogs causes an increase in urinary volume and excretion of Na+, K+, CI−.
4. Clinical Importance of Prostaglandins:
a. Prostaglandins exert stimulatory effect on contractions of the human uterus. PGE1, PGE2, PGE2α are given intravenously to induce labor. PGE2 and PGF2α are also effective orally to induce labor.
b. They are also used as contraceptives to prevent conception.
c. PGA1 infused intravenously acts as a vasodilator and lowers the blood pressure.
d. PGE1 by inhalation produces improvement in asthmatic patients and becomes an inhibitor of gastric acidity when administered intravenously.
e. PGA1, PGE1, PGE2 and PGE1α act as vasoconstrictor on the blood vessels of the nasal mucosa and PGE1 is an effective nasal decongestant.
f. Amniotic fluid during labor contains high concentration of PGF2α which causes myometrial contractions. PGF2α is present in maternal venous blood immediately before uterine contractions in normal spontaneous labor. The placenta is the major source of prostaglandins found in the amniotic fluid and maternal circulations.
g. They are used to control inflammation.
5. Side-effects of Prostaglandins:
a. PGE2 causes uterine smooth muscle to contract when induction of labor is desired and also causes gastrointestinal smooth muscle to contract which leads to cramping and diarrhoea.
b. PGE2 irritates the muscosa lining of the throat causing pain and coughing.
6. Metabolism of Prostaglandins:
Prostaglandins are quickly metabolized by the enzyme 15-hydroxyprostaglandin dehydrogenase which is present in most mammalian tissues. This enzyme is blocked by the introduction of a methyl group at the C15 position. Then only the half-life of a prostaglandin is prolonged.
7. Inhibitors of Prostaglandins:
Aspirin, indomethacin, phenanzine, tranylcypromine.
Accumulation of Triacylglycerol in Liver:
The factors that take part in role for the accumulation of triacylglycerol are:
a. The raised level of plasma-free fatty acids formed from the mobilization of fat from adipose tissue or hydrolysis of lipoprotein by lipoprotein lipase in extra-hepatic tissue occurs.
b. Ira starvation and by feeding of high fat diets, the triacylglycerol present in liver is increased.
c. In uncontrolled diabetes mellitus fatty appearance and enlargement of liver occurs.
d. Due to metabolic Mock in else production of plasma lipoprotein triacylglycerol accumulates.
e. Alcoholism leads to triacylglycerol in liver causing cirrhosis. When ethanol is oxidized to acetaldehyde by alcohol dehydrogenase there is production of NADH. NADH competes with reducing equivalents from the other substrate for the respiratory chain inhibiting their oxidation.
The increased [NADH]/[NAD+] ratio causes a shift to the left in the equilibrium, malate ⇋ oxaloacetate which reduce the citric acid cycle. The net effect of inhibiting fatty acid oxidation is to cause increased accumulation of triacylglycerol.
f. The antibiotic puromycin inhibits protein synthesis and causes fatty liver, other substances such as chloroform, carbon tetrachloride, lead also take part for the accumulation of triacylglycerol in liver.
