Eicosanoid mechanisms of action

A variety of biochemical and molecular mechanisms have been described to explain how PUFAs can modulate immune cell fate and function. The primary mechanism of action of dietary n-3 PUFAs involves the replacement of AA in the lipid membrane of the cells with either EPA or DHA. This, in effect, competitively inhibits the oxygenation of AA by the COX enzymes. For example, the EPA-induced suppression in the production of AA-derived eicosanoids is followed by a subsequent increase in the production of those from EPA. Generally, the EPA-derived eicosanoids are considered to be much less potent than those from AA, thus explaining, at least partially, the anti-inflammatory effects of PUFAs. A similar mechanism of action can be demonstrated for DHA, either directly or by retroconversion to EPA. 

Smith WL. The eicosanoids and their biochemical mechanisms of action. Biochem J 1989 259 315-324. Sweetman S, editor. Martindale the complete drug reference. 35th ed. London Pharmacentical Press 2007. Tripathi KD. Essentials of medical pharmacology. 5th ed. 

Weissmann, G., Aspirin. Sci. Am. 264 84-90, 1991. An interesting article that discusses the mechanism of action of aspirin in connection with eicosanoid metabolism. 

WL Smith. Eicosanoid biosynthesis and mechanism of action. Am J Physiol 263 F181-F191, 1992. 

Smith WL. 1989. The eicosanoids and their biochemical mechanism of action Biochem. J. 259 315-24... 

MECHANISM OF ACTION OF EICOSANOIDS Many of the responses just described can be understood in light of the distribution of eicosanoid receptors and their coupling to second-... 

C. Mechanism of Action Most eicosanoid effects appear to be brought about by activation of cell surface receptors that are coupled by G proteins to adenylyl cyclase (producing cAMP) or the phosphatidylinositol cascade (producing IP3 and DAG second messengers). 

Fig. 5.1. (Opposite page) Possible mechanisms of actions of the eicosanoids in cell signaling. The eicosanoids are synthesized within cells, where they can exert their effects by modulating the activity of ion channels, protein kinases and other target proteins. They can also be extruded into the extracellular medium by selective membrane transporters. Once outside, they can bind to and activate C protein-linked membrane receptors on neighboring cells.

Fitzgerald GA, Murray R, Moran N, Funk C, Charman W, Clarke R, Furci L, Fitzgerald DJ. Mechanisms of eicosanoid action. Adv Prostaglandin Thromboxane LeukotRes 1991 21B 577-81. 

PGE and PGF derivatives lower intraocular pressure. The mechanism of this action is unclear but probably involves increased outflow of aqueous humor from the anterior chamber via the uveoscleral pathway (see Clinical Pharmacology of Eicosanoids). 

Eicosanoid receptors are G protein-coupled receptors known effector mechanisms include activation or inhibition of adenylate cyclase and activation of phospholipase C. Duration of action is usually short inactivation occurs by oxidative metabolism either locally or in the lung, which is strategically placed for complete clearance of the circulating blood volume. 

Figure 12.2. Alternate pathways of arachidonic acid release (a), and cellular locations of enzymes involved in eicosanoid formation (b). a Arachidonic acid may be directly released by phospholipase (PLA2), or alternatively by the successive action of phospholipase C (PLC) and diacylglycerol (DAG) lipase, b The major mechanism of release involves a cytosohc phospholipase A2 (CPLA2). An increase of Ca in response to an extrinsic signal causes binding of cPL A2 to the nuclear membrane. Cyclooxygenase (COX) and Lipoxygenase (LOX) form their respective intermediates, which are further processed by cytosolic enzymes to prostaglandins (PG), thromboxanes (TG), and leukotrienes (LT), respectively.

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