Prostaglandins

Prostaglandins, PG, are almost ubiquitously present in the organism and are characterized by a broad pharmacological spectrum of activity. Prostaglandins belong to the eicosanoids and act like "tissue hormones". Substrates of the biosynthesis of prostaglandins are polyunsaturated C20 fatty acids such as arachidonic acid. The C20 fatty acids and their derivatives are also called eicosanoids (Greek "eicosi" = 20 ). The inhibition of the prostaglandin biosynthesis and that of the thromboxanes is today regarded as the essential biochemical effect of the widely used non-steroidal anti-inflammatory drugs.

Prostaglandins are normally not stored in the various organs and cells, but are re-synthesized and released in response to various stimuli.

The different subforms are distinguished according to structure, formation, occurrence, effect and regulation:

• Prostaglandin D2 (PGD2)
• Prostaglandin E2 (PGE2)
• Prostaglandin I2 (PGI2) = Prostacyclin
• Prostaglandin F2alpha (PGF2alpha)
• 6-keto-prostaglandin F1alpha (metabolite of PGI2)
• Prostaglandin G2 (PGG2) (endoperoxide)
• Prostaglandin H2 (PGH2) (endoperoxide)
• Thromboxane A2 (TXA2)
• Thromboxane B2 (TXB2) (inactive metabolite of TXA2)

The C20 fatty acid metabolism and the biosynthesis of PG are closely related. The activity of the enzyme fatty acid cyclooxygenase produces prostaglandins (PG) and thromboxanes (TX) from the C20 fatty acids.

The activity of lipoxygenases produces hydroperoxide derivatives and hydroxide derivatives. The 5-lipoxygenase is responsible for the formation of leukotrienes (LT).

Via the fat metabolism, a total of 10 unsaturated C20 fatty acids are formed by dehydration and chain extension. These differ mainly in the degree of oxidation of the C-atoms 9 and 11. 3 of 10 C20 fatty acids (series 1 - series 3) are formed by the specific cyclooxygenases (COX-1 and COX-2) and by the subsequent action of different prostaglandin synthases to form 3 biologically differently effective series with the starting derivatives:

Dihomogammalinolenic acid = 8,11,14-eicosatrienoic acid (series 1)

Arachidonic acid (series 2- this includes PGE2, PGE2alpha, thromboxanes A2 and B2)

Eicosapentaenoic acid (series 3 - this includes PGE3, PGE3alpha).

The prostaglandins are divided into different series by letters: A,B,C,D,E,F,G,H,X,I (e.g. prostaglandin A, prostaglandin B, etc.) There are also subgroups defined by the number of double bonds. The number of double bonds is indicated by an index on the name (e.g. prostaglandin E2 - 2 double bonds, PGE3 - 3 double bonds). The letter designations characterize the substitutions on the ring structure of the PG molecule.

Cyclic prostaglandins are called prostacyclins and are identified by the letter X (PGX).

Prostaglandin derivatives are used as external agents in glaucoma therapy. For about 2 decades they have been used increasingly in cosmetics as "eyelash serums" to lengthen the eyelashes (see also eyelash lengthening with prostaglandin analogues).

Leukotrienes: The leukotrienes (LT), which are produced by the specific lipoxygenases (5-lipoxygenase), are classified with letters analogous to the prostaglandins (leukotrien A - D). In the nomenclature of leukotrienes, suffixes (e.g. leukotrien D4) indicate the number of double bonds in the molecule, in leukotrien D4 4 double bonds.

Thromboxanes: In various cells and organelles (e.g. thrombocytes), the PG endoperoxides PGG2 and PGH2 are metabolized by the enzyme TX synthase to form thrombboxane A2 (has a vasoconstrictive effect and promotes platelet aggregation). Other products of this enzymatic function is HHT (L-hydroxy-5,8,10-heptadecatrienoic acid), whose biological function is not assured. The chemically unstable compounds TXA2 and PGI2 are very quickly hydrolyzed to the stable but biologically inactive products TXB2 and 6-keto-PGF1alpha.

Inactivation of cyclooxygenase-dependent arachidonic acid metabolites

Circulating PG of the E and F series are inactivated mainly in the lungs. In a single lung passage, up to 95% of an injected dose is metabolized. In addition to the lung, inactivation also occurs in the kidney, spleen, gastrointestinal tract and placenta. The thromboxane TXA2 hydrolyses non-enzymatically with a half-life of about 30 seconds to the biologically inactive TXB2.

The substrates of the eicosanoid biosynthesis, such as arachidonic acid, are mostly present in the cells in esterified form in the membrane phospholipids. The concentrations of free arachidonic acid, however, are very low. Only free arachidonic acid can serve as a substrate for cyclooxygenase or lipoxygenases. Thus, the eicosanoid biosynthesis primarily depends on the release of the C20 fatty acids from the membrane phospholipids. This is done, for example, by the activity of the membrane-bound phosopholipase A2 or phosopholipase C. The activation of the eicosanoid biosynthesis takes place by chemical, physiological, pathophysiological and pharmacological stimuli. Many of these stimuli increase the intracellular calcium concentration and thereby enhance phospholipase activity.

Prostaglandins have a broad physiological and pathophysiological spectrum of activity. They unfold their effectiveness via prostaglandin receptors. Prostaglandin receptors belong to the group of G-protein coupled membrane receptors. They are designated 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. So far, 4 subtypes of the EP receptor have been identified:

1. Hu et al (2001) Types of dietary fat and risk of coronary heart disease: a critical review J Am Coll Nutr 20:5-19.
2. Rosenthal et al (1984) The effects of trans fatty acids on fatty acyl delta 5 desaturation by human skin fibroblasts. Lipids 19: 869-874.
3. By Euler US (1935) On the specific antihypertensive substance of human prostate and seminal vesicle secretions. Wien Klin Weekly Report 33: 1182-1183.