Experiments on the mode of action of piriprost (U-60,257), an inhibitor of leukotriene formation in cloned mouse mast cells and in rat basophil leukemia cells.

We studied the effect of piriprost, an inhibitor of sulfidopeptide leukotriene (LT) formation, on the generation of the known products of the 5-lipoxygenase pathway of arachidonate metabolism in calcium ionophore A23187-challenged rat basophil leukemia cells and cloned, growth factor-dependent, mouse mast cells. Piriprost inhibited the formation of 5-hydroxyeicosatetraenoic acid (5-HETE), and LTB4, and the sulfidopeptide leukotrienes (LTC4 in the mouse mast cells and both LTC4 and a mixture of LTD4 and LTE4 in the rat basophil leukemia cells) in parallel (IC50 values ranged between 9 and 14 microM for the mouse mast cells and between 15 and 50 microM for the basophil leukemia cells). Our previous observation that piriprost is only a very weak inhibitor of the solubilized LTC synthase of rat basophil leukemia cells was extended to similar enzyme preparations derived from the mouse mast cells (IC50 1.5 mM). The results are consistent with the conclusion that piriprost acts as an inhibitor of the 5-lipoxygenase reaction and that its activity in intact cells is not likely to involve the inhibition of the LTC synthase.