INTERACTION OF TACROLIMUS (FK506) AND ITS METABOLITES WITH FKBP AND CALCINEURIN

Tacrolimus(FK506) is a strong immuno-suppressant and shows its activit y through inhibiting IL-2 mRNA transcription by forming pentameric com plex with intracellular receptor(FK506 binding protein 12 KDa or FKBP1 2), Ca2+, calmodulin, and calcineurin. Here, we report the binding act ivity to FKBP12, the pentameric complex formation and Con-A response i nhibiting activities of 7 metabolites. C15-demethylated metabolite(M-3 ) needed higher quantity to compete in Con-A assay and in pentamer for mation assay, although it binds more strongly to FKBP12. The result su ggests that the ability to form a pentameric complex is not a two step reaction with the first binding to FKBP12, but a single step reaction by components for the pentamer formation. (C) 1994 Academic Press, In c.