Mechanism of Aminobisphosphonate Action: Characterization of Alendronate Inhibition of the Isoprenoid Pathway

Abstract Alendronate (ALN), an aminobisphosphonate compound used for the treatment of osteoporosis and other disorders of bone resorption, has been suggested to act by inhibition of the formation of GGPP. In the present study we used an S 10 homogenate fraction of rat liver to show that ALN causes a dose-dependent inhibition of [ 3 H]MVA incorporation into sterols and a concomitant increase in incorporation of radiolabel into IPP and DMAPP. We further show that ALN is a potent inhibitor of cytosolic trans -prenyltransferase (FPP synthase). The inhibition is competitive with respect to allylic pyrophosphate substrates, but not IPP, suggesting that ALN acts as an allylic pyrophosphate analog and binds to the free enzyme. The K i is in the 0.5 μM range.