Effects of L-leucine methyl ester (Leu-OMe) on mouse peritoneal mast cells: characterization of histamine release versus cytotoxicity.

L-Leucine methyl ester (Leu-OMe), a lysosomotropic compound, has been found to eliminate several lysosome-rich cellular subtypes and all natural killer cell function from peripheral blood mononuclear cells. In this report, the effect of Leu-OMe on mouse peritoneal mast cells is described. The L-Leu-OMe induced the release of histamine from mouse peritoneal mast cells in a dose-dependent manner (0.25 to 3 mM), while its D-stereoisomer had no effect. L-Leu-OMe displayed also a potent histamine release effect on purified mast cells, indicating a direct effect on mast cells. The monitoring of radioactive chromium release versus histamine release showed that both processes may be unrelated for Leu-OMe concentrations inferior to 1.5 mM. At higher doses, L-Leu-OMe, but not its D-stereoisomer, exerted a potent cytotoxic effect on mast cells. The secretory effect of Leu-OMe was temperature- and energy-dependent. Experiments performed in the absence of extracellular calcium and magnesium demonstrated that these divalent cations were not necessary for the Leu-OMe-induced histamine release, and their deprivation even involved a higher histamine release. The secretory characteristics of the Leu-OMe-induced histamine release appeared to be different from those of the IgE-induced ones. These results support the conclusion that exposure of mouse peritoneal mast cells to high doses of L-Leu-OMe results in killing of these cells, that are new targets of this lysosomotropic agent.