Prostaglandins and leukotrienes

The metabolites of arachidonic acid (eicosanoids) are an important group of compounds playing a major role in the modulation of intracellular reactions & in intercellular communication. In response to cell stimulation, calcium flows activate phospholipases which release arachidonic acid. The latter is then metabolised by various oxygenases.

Thus a cyclooxygenase (prostaglandin G2/H2 synthetase) produces the endoperoxides PGG2 and PGH2, themselves converted by specific enzymes into biologically active compounds (see diagram). Thromboxane A2 (TXA2), the main metabolite of the platelets and the renal mesangial cells, is a powerful inducer of platelet aggregation agent and a vasoconstrictor. Prostacyclin (PGI2) produced by the vascular cells (endothelial or smooth muscle cells), is a powerful anti-aggregation agent and a vasodilator. According to their differentiation, the monocytes/macrophages are capable of producing one or other of these compounds. Finally, the majority of the body cells produce prostaglandins, which may be bronchoconstrictive or vasoconstrictive (PGD2, PGF2a), vasodilators (PGE2) or anti-aggregation agents (PGD2).

Moreover, the lipoxygenases all lead to monohydroxylated derivatives of arachidonic acid the role of which is still not fully understood. On the other hand, 5-lipoxygenase produces leukotrienes (LT) B4, C4, D4, E4 (see diagram). The neutrophils mainly synthetize LTB4 endowed with very powerful chemotactic properties for the polynuclears. The LTC4 produced by eosinophils or the mastocytes is a bronchoconstrictor which differs from histamine by its slow, prolonged action. It has properties of vasopermeation and vasoconstriction of both large and small blood vessels. The monocytes / macrophages also synthetize leukotrienes. Cells with-out 5-lipoxygenase can metabolise LTA4 originating from neutrophils into LTB4 (this is the case with the red blood corpuscles which possess a hydrolase) or into LTC4 (in the case of the platelets or vascular cells which possess an LTC4 synthetase). This mechanism is called transcellular metabolism. The ubiquity of the eicosanoids explains the proliferation of studies devoted to the subject in many fields of research. These compounds in fact constitute specific markers of cellular activation "in vitro". Moreover, measurement of certain of the urinary metabolites of TXs, of PGs or LTs constitutes a non-invasive method for the assessment of the activity of certain cells "in vivo".

The pharmacological action of these compounds largely reproduces the effects found in pathological reactions such as inflammation, asthma and the cardiovascular illnesses, etc.... Many drugs which may oppose their synthetis or their effects have been developed, the best-known of which is aspirin. This molecule inhibits cyclooxygenase by linking at the active site of the enzyme and irreversible acetylation of a serine residue. New specific synthesis inhibitors or antagonists are now being studied, and clinical tests will make it possible to assess their therapeutic benefits.

For further information & references please call Dr. Xavier MORGE

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