Mechanism of aminobisphosphonate action: Characterization of alendronate inhibition of the isoprenoid pathway

Alendronate (ALN), an aminobisphosphonate compound used for the treatment o f osteoporosis and other disorders of bone resorption, has been suggested t o 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-dep endent inhibition of [H-3]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 s ynthase). The inhibition is competitive with respect to allylic pyrophospha te substrates, but not IPP, suggesting that ALN acts as an allylic pyrophos phate analog and binds to the free enzyme. The K-i is in the 0.5 mu M range . (C) 1999 Academic Press.