Transcellular Biosynthesis of Leukotrienes: Is Leukotriene A₄ a Mediator?

Abstract

The enzymatic steps involved in the synthesis of prostaglandins, thromboxanes, and leukotrienes have been elucidated in substantial detail in numerous biochemical studies (1,2). In most cases, these studies involved the addition of radiolabeled arachidonic acid to homogenous cell suspensions with characterization of the resultant radiolabeled metabolites. Thus, most of the studies during the 1960s and 1970s were designed to establish those oxidative pathways of arachidonic acid within a single cell type. As a result, the metabolic patterns of eicosanoids generated by a given cell type has been fairly well established, for example, those cells which are found in the blood have been studied in great detail and their primary cyclooxygenase and lipoxygenase metabolites are known (Table 1). While most cells in the blood do metabolize arachidonic acid by one or more cascades, there are some cells which do not participate in the oxidative conversion of arachidonic acid into reactive intermediates. Table 1 indicates that the red blood cell and the lymphocyte (3) cannot metabolize arachidonic acid by either the cyclooxygenase or lipoxygenase pathways. Normally, one considers most cells in the blood to have a

Table 1 Arachidonic Acid Metabolites Generated by Stimulation of Isolated Blood Cells

substantial capacity for the production of active eicosanoids. For example, platelets are known to produce thromboxane A₂, a pro-aggregatory substance in response to stimulation and that this eicosanoid plays an important role in thrombus formation (4). The neutrophil on the other hand appears only to have a 5-lipoxygenase pathway for metabolism of arachidonic acid and stimulation of this cell leads to the formation of LTB₄, a chemotactic factor (5). The eosinophil and basophil also metabolize arachidonate by the 5-lipoxygenase pathway and convert the reactive LTA₄ into the sulfidopeptide leukotriene LTC₄, the potent smooth muscle contracting agent and substance which enhances capillary permeability (6). The studies in this manner have greatly expanded our understanding of the complexity of arachidonic acid metabolism and the role which the eicosanoid metabolites may play in health and disease. However, it appears that the synthesis of eicosanoids may be more complex than only occurring within one cell and may involve cell-cell interactions.