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 and liposomes of SR lipids were evaluated by intramolecular excimer formation of 1,3-di(1-pyrenyl)propane (Py(3)Py) and by fluorescence polarization 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 promotes alterations in the thermotropic profiles of DMPC, DPPC and DSPC. As detected by Py(3)Py and DPH-PA, OHTAM induces an ordering effect in the fluid phase and a fluidizing effect in the temperature range of the cooperative phase transition. In the gel phase, no significant effects are noticed, except for DSPC bilayers, where Py(3)Py and DPH-PA detect a disordering effect. In the hydrophobic region of the above membrane systems probed by DPH, OHTAM induces only a slight fluidizing effect 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 transition profile of DMPC and shifts the main transition temperature to lower values. However, these effects, and so those observed for the fluid phase, decrease as the fatty acyl chain length increases. Moreover, 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 lipids, OHTAM induces a moderate ordering effect in the outer regions of the lipid bilayer, as monitored by Py(3)Py and by DPH-PA, DPH failing to detect any apparent effect, as observed for the fluid phase of pure phospholipids. Apparently, OHTAM distributes preferentially in the outer region of the lipid bilayer, without significant effect in the bulk lipid organization of the bilayer interior. The changes of OHTAM in the bilayer dynamic properties and the different location across the bilayer thickness relative to its drug promoter (Custódio et al. (1993) Biochim. Biophys. Acta 1150, 123-129) may be involved in the cytostatic activity of tamoxifen.