THE ANTICANCER DRUG TAMOXIFEN INDUCES CHANGES IN THE PHYSICAL-PROPERTIES OF MODEL AND NATIVE MEMBRANES

The interactions of tamoxifen with lipid bilayers of model and native membranes were investigated by fluorescence polarization of 1,6-diphen yl-1,3,5-hexatriene (DPH) and by intramolecular excimer formation of 1 ,3-di(1-pyrenyl)propane (Py(3)Py). The effects of TAM on liposomes of DMPC, DPPC and DSPC are temperature dependent. In the fluid phase, TAM reduces dynamics of the upper bilayer region as observed by Py(3)Py a nd has no effect on the hydrophobic region as detected by DPH. In the gel phase, the effects of TAM evaluated by Py(3)Py are not discernible for DMPC and DPPC bilayers, whereas DSPC bilayers become more fluid. However, DPH detects a strong fluidizing effect of TAM in the hydropho bic region of the above membrane systems, where DPH distributes, as co mpared with the small effects detected by Py(3)Py. TAM decreases the m ain phase transition temperature but does not extensively broaden the transition thermotropic profile of pure lipids, except for bilayers of DMPC where TAM induces a significant broadening detected with the two probes. In fluid liposomes of sarcoplasmic reticulum lipids and nativ e membranes, TAM induces an ordering effect, as evidenced by Py(3)Py, failing DPH to detect any apparent effect as observed for the fluid ph ase of liposomes of pure lipid bilayers. These findings confirm the hy drophobic nature of tamoxifen and suggest that the localization and ef fects of TAM are modulated by the order and fluidity of the bilayer. T hese changes in the dynamic properties of lipids and the non-specific interactions with membrane lipids, depending on the order or fluidity of the biomembrane, may be important for the multiple cellular effects and action mechanisms of tamoxifen.