The effects of peroxisome proliferators, the ligands of a nuclear receptor peroxisome proliferator-activated receptor (PPAR) alpha, on cysteinyl leukotriene production were investigated in rodent mast cells. Peroxisome proliferators Wy-14,643 (30 microM) and fenofibrate (100 microM) significantly inhibited the cysteinyl leukotriene production that was induced by antigen (Ag) treatment after overnight sensitization to Ag specific immunoglobulin E (IgE) in a rat basophilic leukemia (RBL)-2H3 mast cell line. Similar inhibition by these drugs was observed in IgE and Ag-treated mouse bone marrow-derived mast cells, A23187-treated RBL-2H3 and A23187-treated mouse peritoneal macrophages. Wy-14,643 (30 microM) and fenofibrate (100 microM) did not affect the release of radioactivity from RBL-2H3 pre-incubated with [(3)H]-arachidonic acid, which is considered an index of phospholipase A(2) activity. Wy-14,643 (30 microM) and fenofibrate (100 microM) did not directly inhibit 5-lipoxygenase activity. Troglitazone was found to directly inhibit the activity of 5-lipoxygenase. The PPARalpha mRNA level was at less than the limit of detection for the realtime polymerase chain reaction both in RBL-2H3 and bone marrow-derived mast cells. Wy-14,643 (30 microM) and fenofibrate (100 microM) did not induce acyl-CoA oxidase mRNA in RBL-2H3, which was reported to be induced by peroxisome proliferators via PPARalpha in hepatocytes. Wy-14,643 (30 microM) and fenofibrate (100 microM) inhibited the cysteinyl leukotriene production in bone marrow-derived mast cells from PPARalpha-null mice. It was concluded that the inhibitory effects of these peroxisome proliferators on cysteinyl leukotriene production are independent of PPARalpha in mast cells.