Pharmacological modulation of leukotriene and platelet activating factor biosynthesis and activities by alternative...

The 5-lipoxygenase pathway for the oxidative metabolism of unsaturated fatty acids was first recognized less than 10 years ago with the definition of 5-S hydroxy eicosatetraenoic acid (5-HETE) as a product, and its potential biological relevance to inflammation was suggested solely by the modest chemotactic activity of this compound. Major interest in this pathway did not occur until 5 years later when leukotriene B4 (LTB4) was first described, and the slow-reacting substance of anaphylaxis (SRS-A) was chemically defined as three additional leukotriene products of tis pathway: leukotriene C4 (LTC4), leukotriene D4 (LTD4) and leukotriene E4 (LTE4). The possibility that the inhibition of the generation of leukotriene compounds might have a significant effect in limiting a variety of inflammatory disorders was suggested by the extensive pro-inflammatory effects demonstrated by these substances, the demonstration that many inflammatory cells generate leukotrienes, and the finding that the leukotrienes can be detected in complex biological fluids in vivo. Although there is a potential for inhibiting the biological activities of each leukotriene at the receptor level, the present paper will focus completely on the approach of limiting leukotriene synthesis and biological activities through the provision of alternative substrate fatty acids.