Medical brain Notes 3

  Pharmacology of Eicosanoids Eicosanoid mediators are derived from arachidonic acid (eicosatetraenoic) and related poly-unsaturated fatty acids, such as acid eicosapentanoic acid. These fatty acids are mainly found as constituents of phospholipids in cellular membranes (Figure 12.1a), and it is from there that they are mobilized for eicosanoid mediator synthesis. The major classes of eicosanoids are prostaglandins, thromboxanes, and leukotrienes. Eicosanoids are very widespread in the mammalian organism – most cells synthesize them. Figure 12.1.  Overview of eicosanoid metabolism. a: Structures   of eicosanoid precursor fatty acids, and their occurrence in mem-brane phospholipids (PC is shown as an example). Arachidonic acid is the `prototypic' precursor; eicosatrienoic and eicosapen-tanoic acid differ from it by the a lackingor an additional double bond, respectively. b: Conversion of precursor fatty acids occurs by various enzymes, notably cyclooxygenases and lipoxygen...

  Biosynthesis of eicosanoids The first step in the formation of eicosanoid mediators consists in the release of the precursor fatty acids from the membrane phospholipids. This release may happen along several possible metabolic routes (Figure 12.2a). The ma-jor physiological mechanism of release consists in the acti-vation of a cytosolic phospholipase A 2  (cPLA 2 ) by Ca ++  in response to an extracellular signal. cPLA 2  then attaches to the nuclear (and probably ER) membranes, which appear to be the major reservoir of arachidonic acid and its analogs. Figure 12.2.  Alternate pathways of arachidonic acid release (a),   and cellular locations of enzymes involved in eicosanoid forma-tion (b). a: Arachidonic acid may be directly released by phos-pholipase A 2  (PLA 2 ), or alternatively by the successive action of phospholipase C (PLC) and diacylglycerol (DAG) lipase. b: The major mechanism of release involves a cytosolic phospholipase A 2  (cPLA ...

  Cyclooxygenase inhibitors   Cyclooxygenase occurs in three isoforms in the mammalian organism:   •       Cox-1 is constitutively expressed and responsible for most of the `housekeeping' functions of eicosanoids, including processes such as calcium metabolism in the bone, and stomach mucous membrane maintenance. It is also responsible for synthesis of thromboxanes in thrombocytes and of prostacyclin (PGI) in endothelial cells, which have antagonistic function in thrombocyte aggregation and activation (see later).   •       Cox-2 is inducible and mostly expressed in inflammato-ry cells; it is considered the main culprit in the release of prostaglandins at sites of inflammation. Since anti-in-flammatory therapy is the main therapeutic application of Cox inhibitors, there is considerable interest in the development of drugs selectively acting on this form.   •       Cox-3 is a splice varian...

Lipoxygenases and related drugs The other major group of enzymes that are involved in the synthesis of eicosanoid mediators are the lipoxygenases. There are three different such enzyme specificities – 5-, 12-, and 15-lipoxygenase, which introduce a hydroperoxy group at the respective carbons of arachidonic acid. Reduc-tion of these hydroperoxides (HPETEs) leads to hydrox-yl derivatives (HETEs). These apparently are mediators in their own rights, but they can also be further converted to lipoxins by the successive action of different lipoxygenas-es, as illustrated in Figure 12.12b for 15- and 5-lipoxyge-nase. Lipoxins seem to have anti-inflammatory activity. While the reactive groups in the active sites of cyclooxyge-nases and lipoxygenase are quite different, their catalyticmechanisms are actually similar in that both start out with the abstraction of a hydrogen from the fatty acid and the subsequent combination with an oxygen radical (cf. Fig-ures 12.6 and 12.12). Interestingly, while...