Pathways for the synthesis of eicosanoids. Phospholipase A2 is the one enzyme common to the formation of all the eicosanoids; it is the site at which stimuli act. Anti-inflammatory steroids inhibit phospholipase A2. The step mediated by cyclooxygenase is inhibited by aspirin and other nonsteroidal anti-inflammatory drugs (termed NSAIDs).

PART TWO Biological Control Systems

Vander et al.: Human Physiology: The Mechanism of Body Function, Eighth Edition

PART TWO Biological Control Systems

The synthesis of eicosanoids begins when an appropriate stimulus—hormone, neurotransmitter, paracrine agent, drug, or toxic agent—activates an enzyme, phospholipase A2, in the plasma membrane of the stimulated cell. As shown in Figure 7-6, this enzyme splits off arachidonic acid from the membrane phospholipids, and the arachidonic acid can then be metabolized by two pathways. One pathway is initiated by an enzyme called cyclooxygenase (COX) and leads ultimately to formation of the cyclic endoperoxides, prostaglandins, and thromboxanes. The other pathway is initiated by the enzyme lipoxygenase and leads to formation of the leukotrienes. Within both of these pathways, synthesis of the various specific eicosanoids is enzyme-mediated. Accordingly, beyond phospholipase A2, the eicosanoid-pathway enzymes found in a particular cell determine which eicosanoids the cell synthesizes in response to a stimulus.

Each of the major eicosanoid subdivisions contains more than one member, as indicated by the use of the plural in referring to them (prostaglandins, for example). On the basis of structural differences, the different molecules within each subdivision are designated by a letter—for example, PGA and PGE for prostaglandins of the A and E types—which then may be further subdivided—for example, PGE2.

Once synthesized in response to a stimulus, the eicosanoids are not stored to any extent but are released immediately and act locally; accordingly, the eicosanoids are categorized as paracrine and autocrine agents. After they act, they are quickly metabolized by local enzymes to inactive forms. The eicosanoids exert a bewildering array of effects, many of which we will describe in future chapters.

Finally, a word about drugs that influence the eicosanoid pathway since these are perhaps the most commonly used drugs in the world today. At the top of the list must come aspirin, which inhibits cy-clooxygenase and, therefore, blocks the synthesis of the endoperoxides, prostaglandins, and thromboxanes. It and the new drugs that also block cyclooxygenase are collectively termed nonsteroidal anti-inflammatory drugs (NSAIDs). Their major uses are to reduce pain, fever, and inflammation. The term "nonsteroidal" distinguishes them from the adrenal steroids (Chapters 10 and 20) that are used in large doses as anti-inflammatory drugs; these steroids inhibit phospholi-pase A2 and thus block the production of all eicosanoids.

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Essentials of Human Physiology

Essentials of Human Physiology

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