THE ACTIVE METABOLITE HYDROXYTAMOXIFEN OF THE ANTICANCER DRUG TAMOXIFEN INDUCES STRUCTURAL-CHANGES IN MEMBRANES

The effects of hydroxytamoxifen (OHTAM) on lipid organization of pure phospholipid liposomes, native sarcoplasmic reticulum (SR) membranes a nd liposomes of SR lipids were evaluated by intramolecular excimer for mation of 1,3-di(1-pyrenyl)propane (Py(3)Py) and by fluorescence polar ization of 1,6-diphenyl-1,3,5-hexatriene (DPH) and its derivative 3-[p -(6-phenyl)-1,3,5-hexatrienyl]phenylpropionic acid (DPH-PA). OHTAM pro motes alterations in the thermotropic profiles of DMPC, DPPC and DSPC. As detected by Py(3)Py and DPH-PA, OHTAM induces an ordering effect i n the fluid phase and a fluidizing effect in the temperature range of the cooperative phase transition. In the gel phase, no significant eff ects are noticed, except for DSPC bilayers, where Py(3)Py and DPH-PA d etect a disordering effect. In the hydrophobic region of the above mem brane systems probed by DPH, OHTAM induces only a slight fluidizing ef fect in the range of the phase transition and a small ordering effect in the fluid phase. As detected by all probes, the drug broadens the t ransition profile of DMPC and shifts the main transition temperature t o lower values. However, these effects, and so those observed for the fluid phase, decrease as the fatty acyl chain length increases. Moreov er, the drug removes the pre-transitions of DPPC and DSPC bilayers, as probed by Py(3)Py. In fluid SR native membranes and liposomes of SR l ipids, OHTAM induces a moderate ordering effect in the outer regions o f the lipid bilayer, as monitored by Py(3)Py and by DPH-PA, DPH failin g to detect any apparent effect, as observed for the fluid phase of pu re phospholipids. Apparently, OHTAM distributes preferentially in the outer region of the lipid bilayer, without significant effect in the b ulk lipid organization of the bilayer interior. The changes of OHTAM i n the bilayer dynamic properties and the different location across the bilayer thickness relative to its drug promoter (Custodio et al. (199 3) Biochim. Biophys. Acta 1150, 123-129) may be involved in the cytost atic activity of tamoxifen.