Prostaglandins

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Prostaglandins are chemical compounds from the group of eicosanoids . They act as tissue hormones in the human and higher animal organism and occur everywhere in the organism with different structures and functions. They are particularly rich in semen .

Structural formula of prostanoic acid

The basic chemical structure of prostaglandins (PG) is prostanoic acid. Three polyunsaturated C 20 - fatty acids are each starting material for the biosynthesis of prostaglandins.

Because of their diverse physiological and pathophysiological effects, the use of prostaglandins and their synthetic structural derivatives is of therapeutic interest.

discovery

The name prostaglandin is derived from English prostate gland ( prostate gland ). In 1935 prostaglandins were isolated and described in human sperm for the first time by the Swedish physiologist Ulf von Euler , and independently of that by M. W. Goldblatt . At that time it was believed that they were a specific part of prostate secretion , but it was later discovered that these substances are released from a wide variety of parts of the body, including the vesicle gland . Prostaglandins are also found in menstrual discharge, brain, lungs, kidneys, and pancreas.

In 1962 the Swedish scientists Sune Bergström and Bengt Ingemar Samuelsson isolated crystallizable derivatives , which are classified according to their solubility as PGE (ether-soluble) or PGF (phosphate-soluble; Swedish spelling). In 1982 the two and the Briton John Robert Vane received the Nobel Prize together "for their groundbreaking work on prostaglandins and related biologically active substances".

Outside higher organisms, the prostaglandin A 2 (PGA 2 ) was found in the Caribbean horn coral Plexaura homomalla .

biosynthesis

Two-step biosynthesis of PGH 2 from arachidonic acid
Biosynthesis of the most important series II prostaglandins and thromboxanes from PGH 2 (after)

The prostaglandin synthesis and fat metabolism are closely related. From the fat metabolism comes three polyunsaturated C 20 - fatty acids , are the starting materials for the prostaglandin:

With the participation of the cyclooxygenases ( COX-1 and COX-2 ) and prostaglandin synthases , the prostaglandins of series I, II and III are produced. The decisive factor here is the introduction of an oxygen molecule and subsequent ring formation with five carbon atoms.

If there is a biosynthetic disorder in omega-3 and omega-6 fatty acids, series I and series III prostaglandins cannot be formed. Series II prostaglandins are not affected, as the starting material arachidonic acid is found in every animal fat and the enzyme cyclooxygenase is also always present.

Terminology and classification

The prostaglandins are divided into three main groups, depending on the starting point of the biosynthesis:

  • Series I prostaglandins (from dihomogammalinolenic acid ), recognizable by the index number 1: Among other things, they have a strong anti-inflammatory effect and reduce blood clotting. Examples of PGs in this series are:
  • Series II prostaglandins (from arachidonic acid ) have the index number 2: their effect is opposite to that of the series I prostaglandins. They promote inflammation, constrict blood vessels , increase blood clotting and increase the perception of pain. They trigger the necessary measures in the body to react to wounds or other injuries.
The series II prostaglandins include:
  • Series III prostaglandins (from eicosapentaenoic acid ), index number 3: In addition to various other functions, they reduce the formation of series II prostaglandins and are therefore often described as anti-inflammatory.

The index numbers mean: 1 = Δ 13 E , 2 = Δ 5 Z , 13 E and 3 = Δ 5 Z , 13 E , 17 Z

The naturally occurring, biologically active PGs have a 15 ( S ) -hydroxy group. Depending on the number and position of the oxygen atoms and the position of the double bond in the cyclopentane ring , the PG are identified by letters.
It denotes: A = 9-Oxo-10-dehydro-, B = 9-Oxo-8 (12) -dehydro-, C = 9-Oxo-11-dehydro-, D = 9-Oxo-10-dehydro- E = 9-hydroxy-11-oxo-, F = 9,10-dihydroxy-, G and H = 9,11-peroxido-, I = 6,9-epoxy-11-hydroxy- and J = 11-oxo- 8 (9) -dehydro-

Structurally related to the PG are the thromboxanes (TX), which arise from PGH through the integration of an O atom at C-11 in the cyclopentane ring.

Mechanism of action

Prostaglandins modulate second messenger systems. Its effect is extremely diverse, as it varies between the different prostaglandins and is sometimes even mediated differently for a prostaglandin by different receptors.

Prostaglandin receptors belong to the group of G-protein-coupled membrane receptors . They are denoted by the letter “P” and the prefix “D”, “E”, “F”, “I” or “T” to indicate a preference for the prostaglandins D, E, F, I or thromboxanes. By 2004, four subtypes of the EP receptor had been identified: EP1 to EP4.

In addition, there are some prostaglandins (e.g. PGJ 2 ) that can activate nuclear receptors of the PPAR class, which inhibit IκB kinase and thereby inhibit the NF-κB pathway. Due to its amide structure , bimatoprost, which is derived from PG F2α , does not act on PG receptors, but on prostamide receptors .

The effects in detail are presented in the main articles on the individual prostaglandins.

Influence on the prostaglandin effect

The main focus in pharmaceutical research is on the prostaglandins from arachidonic acid (series II), as these are responsible for pain , blood clotting , inflammation and other physiological and pathophysiological processes. Various, especially chronic, clinical pictures such as rheumatism , asthma , painful conditions, allergies and high blood pressure arise with the involvement of the series II prostaglandins. The aim is to inhibit the effect of the series II prostaglandins. Typical drugs that work here are the non-steroidal anti-inflammatory drugs (e.g. acetylsalicylic acid ). Such drugs, however, not only inhibit series II prostaglandins, but also their natural counterparts from series I and III.

Dietary measures are also used to try to influence the expression of the prostaglandins in all three series. The following are described:

  1. direct absorption of the substrates, namely DGLA (e.g. found in evening primrose oil ), EPA (e.g. in fish oil ) or AA,
  2. The rate of synthesis of AA is influenced by linolenic acid (in linseed oil ), oleic acid (e.g. in olive oil ) or other substances that bind the AA-forming enzyme delta-5-desaturase.

Overview of medically used prostaglandins and analogues

Structural formula of PGE 1 (Alprostadil)
Structural formula of PGE 2 (dinoprostone)

Of the naturally occurring prostaglandins (PG) which is PGE 1 ( generic name : alprostadil), PGE 2 (generic name: dinoprostone), PGF (generic name: dinoprost) and PGI 2 ( prostacyclin , generic name: epoprostenol) used therapeutically. The specific effects of several synthetic descendants of prostaglandins are also used in application areas of various medical specialties.

Cardiovascular effect

The vasoactive and platelet aggregation-inhibiting activity of PG is used in angiology (vascular medicine) to improve blood flow in problematic arterial vascular occlusions or vasoconstriction; there are also areas of application in urology, cardiology and emergency medicine. The active ingredients are:

Effect on gastric acid and mucus secretion

In gastroenterology , the PGE 1 analog

  • Misoprostol used for the prevention of gastric mucosal damage during long-term use of non-steroidal anti-inflammatory drugs ( Cytotec ).

It is effective orally and can also be administered in a fixed combination with diclofenac .

Effect on the uterus and cervix

In gynecology , the following active ingredients are indicated due to their uterus-contracting and cervical-softening effects:

  • Dinoprostone ( Minoprost E2 ), used vaginally, for the medically indicated induction of labor ( inducing labor ) in pregnant women with an immature cervix or to induce cervical maturation in late pregnancy. It is used off-label to induce labor as a support for an abortion with medication .
  • Misoprostol for the oral treatment of bleeding complications , for induction of labor, to induce a restrained miscarriage and to support the medical abortion . These gynecological or obstetric applications are largely carried out off-label, as they are only approved in a few countries.
  • The PGE 2 derivative Sulproston administered intravenously ( Nalador ) to induce an abortion or childbirth in the event of intrauterine fetal death ( stillbirth ), and also to inhibit postpartum atonic bleeding.
  • Gemeprost , another PGE 2 analog, applied vaginally to soften and expand the cervix in preparation for evacuation of the uterus in non-pregnant and pregnant women.

Effect on the corpus luteum

  • PGF ( dinoprost ) and
  • its analogues cloprostenol and luprostiol have strong luteolytic properties. They are given in veterinary medicine (e.g. pigs, cattle, horses) intramuscularly to relocate the time of oestrus and ovulation as well as to terminate pregnancy and induce labor.

Effect on the eye

Synthetic PGF analogues lower the intraocular pressure (IOP) by improving the aqueous humor outflow . They are therefore used in ophthalmology to lower the increased intraocular pressure in patients with open-angle glaucoma (glaucoma) and ocular hypertension . Be used:

The substances can also be used as combination preparations with the beta blocker timolol if the individual substances are not sufficiently effective. In the USA, bimatoprost is also approved for the treatment of eyelash growth disorders ( Latisse ). Cloprostenol, which is used cosmetically ( eyelash growth serum ), is also said to have an eyelash growth-promoting effect .

literature

  • Peter Welzel: Prostaglandins . In: Chemistry in Our Time . tape 7 , no. 2 , 1973, p. 43-48 , doi : 10.1002 / ciuz.19730070203 .
  • Berg / Tymoczko / Stryer: Biochemistry. /, 5th edition, Spektrum Akademischer Verlag, Heidelberg 2003, ISBN 3827413036 .
  • Mutschler, Ernst: Mutschler drug effects. Pharmacology, clinical pharmacology, toxicology. 10th edition, Stuttgart 2013.

Individual evidence

  1. From Euler US: About the specific hypotensive substance of the human prostate and seminal vesicle secretion . In: Wien Klin Wochenschr . 14, No. 33, 1935, pp. 1182-3. doi : 10.1007 / BF01778029 .
  2. ^ Goldblatt MW: Properties of human seminal plasma . In: J Physiol . 84, No. 2, May 1935, pp. 208-18. PMID 16994667 . PMC 1394818 (free full text).
  3. ^ Bergström and Samuelsson: Isolation of prostaglandin E 1 from human seminal plasma. Prostaglandins and related factors. (PDF; 744 kB) In: J. Biol. Chem. 1962 (9); 237: 3005-6; PMID 13867832 (free full text access ).
  4. Donald J. Gerhart: Prostaglandin A 2 : an agent of chemical defense in the Caribbean gorgonian Plexaura homomalla . Mar. Ecol. Prog. Ser., Vol. 19, 1984; Pp. 181-187.
  5. ^ Simmons DL, Botting RM and Hla T: Cyclooxygenase Isoenzymes: The Biology of Prostaglandin Synthesis and Inhibition. (PDF; 2.0 MB) Pharmacological Reviews 2004; 56 (3): 387-437; PMID 15317910 .
  6. a b E. Teuscher: Biogenic medicines. 5th edition, Wissenschaftliche Verlagsgesellschaft, 1997, p. 411.
  7. Hu et al .: Types of dietary fat and risk of coronary heart disease: a critical review J Am Coll Nutr. 2001 Feb; 20 (1): 5-19. PMID 11293467
  8. Cheng Z et al. Effect of dietary polyunsaturated fatty acids on uterine prostaglandin synthesis in the cow. J endocrinol. 2001 Dec; 171 (3): 463-73, PMID 11739012 .
  9. Table of foods with AA .
  10. Rosenthal et al .: The effects of trans fatty acids on fatty acyl delta 5 desaturation by human skin fibroblasts. Lipids. 1984 Nov; 19 (11): 869-74. PMID 6521610
  11. margarine-institut.de: Metabolism of unsaturated fatty acids ( Memento from November 3, 2012 in the Internet Archive ).
  12. G. Geisslinger et al .: Mutschler drug effects: Pharmakologie - Klinische Pharmakologie - Toxikologie , 11th edition, 2019. P. 969 f.

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