A mechanism of benefit of soy genistein in asthma: Inhibition of eosinophil p38-dependent leukotriene synthesis

Background: Dietary intake of the soy isoflavone genistein is associated with reduced severity of asthma, but the mechanisms responsible for this effect are unknown. Objective: To determine whether genistein blocks eosinophil leukotriene C₄ (LTC₄) synthesis and to evaluate the mechanism of this effect, and to assess the impact of a 4-week period of soy isoflavone dietary supplementation on indices of eosinophilic inflammation in asthma patients. Methods: Human peripheral blood eosinophils were stimulated in the absence and presence of genistein, and LTC₄ synthesis was measured. 5-lipoxygenase (5-LO) nuclear membrane translocation was assessed by confocal immunofluorescence microscopy. Mitogen-activated protein (MAP) kinase activation was determined by immunoblot. Human subjects with mild-to-moderate persistent asthma and minimal or no soy intake were given a soy isoflavone supplement (100 mg/day) for 4 weeks. The fraction of exhaled nitric oxide (FE_NO) and ex vivo eosinophil LTC₄ production were assessed before and after the soy isoflavone treatment period. Results: Genistein inhibited eosinophil LTC₄ synthesis (IC₅₀ 80 nm), blocked phosphorylation of p38 MAP kinase and its downstream target MAPKAP-2, and reduced translocation of 5-LO to the nuclear membrane. In patients with asthma, following 4 weeks of dietary soy isoflavone supplementation, ex vivo eosinophil LTC₄ synthesis decreased by 33% (N=11, P=0.02) and FE_NO decreased by 18% (N=13, P=0.03). Conclusion: At physiologically relevant concentrations, genistein inhibits eosinophil LTC₄ synthesis in vitro, probably by blocking p38- and MAPKAP-2-dependent activation of 5-LO. In asthma patients, dietary soy isoflavone supplementation reduces eosinophil LTC₄ synthesis and eosinophilic airway inflammation. These results support a potential role for soy isoflavones in the treatment of asthma.