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Eicosanoids, metabolism

Biosynthesis of eicosanoids involves two steps: arachidonic acid release and its transformation into active products.

Arachidonic acid release

In the body, fatty acids, including arachidonic acid, are mainly incorporated in membrane phospholipids: phosphatidylcholine, phosphatidyl-ethanol-amine, phosphatidylinositol. Arachidonic acid is released from phospholipids. One of the enzymes responsible of this release is phospholipase A2 whose activity is inhibited by lipocortin, annexin released under the influence of the glucocorticoids. Drugs with lipocortinomimetic activity are under development.

There are several phospholipases with different points of action on phospholipids.

Arachidonic acid metabolism: cyclooxygenase pathway

Arachidonic acid can be oxidized either by cyclo-oxygenases, or by lipoxygenases which are iron metallo-enzymes, at the origin of the formation of anandamide.

Cyclo-oxygenases, COX, are called thus because they lead to the formation of a cyclopentanic cycle or PGH synthases because they lead to formation of prostaglandin H.

The oxidation of arachidonic acid by cyclo-oxygenases gives the endoperoxydes PGH2 and PGB2 which are precursors of the prostaglandins PGE2, PGF2, PGI2 (called prostacyclin and now epoprostenol) and of thromboxanes (TX).

One distinguishes 3 types of cyclo-oxygenase isoenzymes, COX,

  • type I, or COX-1, constitutive, present in stomach, kidney, thrombocytes,
  • type II, or COX-2, inducible, present after induction in fibroblasts, macrophages, chondrocytes and uterus. These last are induced by cytokines like the mitogenic IL-1 and TNFa and compounds. Their expression is inhibited by glucocorticoids. There are also constitutive COX-2 particularly in brain, kidneys, stomach.
  • type III, or COX-3, constitutive, primarily present in brain.

As shown below, cyclooxygenase action is the step necessary to the formation of prostaglandins H2 which are the substrates at the origin of the formation of thromboxanes and prostaglandins. Cyclooxygenase inhibition thus results in a decrease of prostaglandin and thromboxane formation and, consequently, of their effects.

Biosynthesis of prostaglandins and thromboxanes from the PGH2 is not similar in all tissues. Thus, thromboxane biosynthesis by thromboxane synthase prevails in the blood platelets, whereas prostaglandin and prostacyclin biosynthesis prevails in the vascular endothelium.

Cyclo-oxygenases are inhibited by nonsteroidal antiinflammatory drugs, NSAID.

Chemical structures of PGE2, TXB2 and LTB4

Arachidonic acid metabolism: lipoxygenase pathway

Arachidonic acid oxidation by lipoxygenases which are nonheminic dioxygenases, leads to hydroperoxyacides (HPETE or hydroxyperoxyeicosatetraenoïc) and leukotrienes LTB4, cystéinyl-leukotrienes LTC4, LTD4 and LTE4, lipoxins and hepoxylins whose chemical structure and properties resemble those of leukotrienes.

According to the carbon atom on which oxygen (peroxide) is fixed, one distinguishes in particular a 5-lipooxygenase and a 12-lipoxygenase:

  • 5-lipoxygenase is present in various cells, neutrophils, eosinophils, monocytes, macrophages, mast cells, keratinocytes. Its full activity requires the presence of a membrane protein called FLAP (Five-lipoxygenase-activating protein) which binds arachidonic acid and placing it in contact of the enzyme. The 5-lipooxygenase leads to the formation of leukotrienes LTA4, LTB4 which, by addition of a molecule of glutathione, is transformed into LTC4. The LTC4, by loss of a glutamic acid under the influence of G-glutamyl-transferase, gives LTD4 which itself is transformed into LTE4 under the influence of a dipeptidase by loss of glycine.
  • 12-lipoxygenase is present in thrombocytes and skin and also in certain tumoral cells. It could play a part in the development of psoriasis.

Lipoxygenases are also involved in the metabolism of miscelleaneous xenobiotics such as styrene, benzopyrenes, parathion. Possible inhibition by drugs could modify the metabolism of these poisons.

Anandamide pathway

The biosynthesis of anandamide is carried out from arachidonic acid and phosphatidylethanolamine. The enzymes responsible for this biosynthesis are not well known. Anandamide is inactivated by anandamidase which causes its hydrolysis into arachidonic acid and ethanolamine.

Catabolism (inactivation) of eicosanoids

All arachidonic acid derivatives are quickly, in less than a few minutes, inactivated in the body by several complex reactions which we will not point out here.

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Quizz : Q 101
The precursor of prostaglandins and leukotrienes is:
glutamic acid
citric acid
pyruvic acid
arachidonic acid
mevalonic acid

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