MODE OF ACTION OF THE LEUKOTRIENE SYNTHESIS (FLAP) INHIBITOR BAY-X-1005 - IMPLICATIONS FOR BIOLOGICAL REGULATION OF 5-LIPOXYGENASE

Five-lipoxygenase (5-LOX) inhibition is gaining increasing importance as a novel approach to therapy of allergic asthma and other inflammato ry diseases. Presently, two types of inhibitors are known, direct 5-LO X inhibitors (LOI) and the FLAP (five lipoxygenase activating protein) binding leukotriene synthesis inhibitors (LSI). The 5-LOX selective a nd orally active quinoline LSI, BAY X 1005, shares many mechanistic fe atures with the indole LSI, MK-886. The binding of BAY X 1005 to FLAP correlates with LTB(4) synthesis inhibition. BAY X 1005 has been shown to bind to the 18 kD protein FLAP. BAY X 1005 inhibits 5-LOX transloc ation from the cytosol to membranes and reverses 5-LOX translocation. The use of BAY X 1005 has helped to elucidate part of the complex FLAP /5-LOX interaction by showing that FLAP appears to represent a 5-LOX s ubstrate transfer protein channelling endogenous and exogenous arachid onic acid to the leukotriene synthetizing 5-LOX. This notion presented by our group in 1992 has stimulated further mechanistic studies. Thes e findings have additionally led to the hypothesis that substrate comp etition is not confined to the LSI/FLAP interaction but may also be tr ue for the LOI/5-LOX interaction and that even mixed LSI/LOI 5-LOX inh ibitors are feasible, yet have not been described. Further mechanistic work on LSI will be orientated not only to further elucidate the comp lex FLAP/5-LOX interaction, but also to identify FLAP-related eicosano id binding proteins.