Pharmacologic Modulation of Leukotriene Biosynthesis by Incorporation of Alternative Unsaturated Fatty Acids (20:5 and 22:6)

Abstract

The 5-lipoxygenase pathway for oxidative metabolism of unsaturated fatty acids was first recognized less than 10 years ago with the definition of 5S-hydroxy-eicosatetraenoic acid (5-HETE) as a product, l and its potential biological relevance to inflammation was defined solely by the modest chemotactic activity of 5-HETE.2 However, major interest in this pathway did not occur until 5 years ago when leukotriene B4 (LTB4), 5S,12R-dihydroxy-6,14-cis-8,10-trans-eicosatetraenoic acid was first described3 and the elusive “slow reacting substance of anaphylaxis (SRS-A),” was chemically defined as three additional leukotriene products of this pathway: LTC4, 5S-hydroxy-6R-S-glutathionyl-7,9-trans-11,14-cis-eicosatetraenoic acido; LTD4, 5S-hydroxy-6R-S-cysteinylglycyl-7,9-trans-11,14-cis-eicosatetraenoic acid5-7; and LTE4, 5S-hydroxy-6R-S-cysteinyl-7,9-trans-11,14-cis-eicosatetraenoic acid.8 That efforts to decrease the generation of the leukotriene compounds could have a significant effect in down-regulating a variety of inflammatory events has been strongly suggested by several types of data developed over the past 5 years, with regard to the breadth of proinflammatory effects manifested by these compounds, indications that a variety are mediated via specific receptors that do not recognize other naturally-occurring compounds, an expanding knowledge of the inflammatory cell types which serve as sources for the leukotrienes, and the demonstration that leukotrienes are recoverable from complex biological fluids in both in vivo models of inflammation and human disease. Although there is potential for antagonizing the biological effects of each leukotriene at the end-organ receptor level, the present discussion will focus mainly on regulation of leukotriene biosynthesis as an anti-inflammatory therapeutic approach. Furthermore, the potential of dietary alteration as an adjunct to developing pharmacotherapeutic inhibitors of the 5-lipoxygenase pathway will be specifically considered.