Custódio J B, Almeida L M, Madeira V M
Laboratório de Bioquímica, Faculdade de Farmácia, Universidade de Coimbra, Portugal.
Biochim Biophys Acta. 1993 Dec 12;1153(2):308-14. doi: 10.1016/0005-2736(93)90420-5.
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.
通过1,3 - 二（1 - 芘基）丙烷（Py(3)Py）的分子内激基缔合物形成以及1,6 - 二苯基 - 1,3,5 - 己三烯（DPH）及其衍生物3 - [对 - （6 - 苯基）- 1,3,5 - 己三烯基]苯丙酸（DPH - PA）的荧光偏振，评估了羟基他莫昔芬（OHTAM）对纯磷脂脂质体、天然肌质网（SR）膜以及SR脂质脂质体的脂质组织的影响。OHTAM促进了二肉豆蔻酰磷脂酰胆碱（DMPC）、二棕榈酰磷脂酰胆碱（DPPC）和二硬脂酰磷脂酰胆碱（DSPC）热致相变曲线的改变。如通过Py(3)Py和DPH - PA所检测到的，OHTAM在流体相中诱导有序化效应，在协同相变温度范围内诱导流化效应。在凝胶相中，除了DSPC双层膜外未观察到显著影响，在DSPC双层膜中Py(3)Py和DPH - PA检测到无序化效应。在由DPH探测的上述膜系统的疏水区域中，OHTAM在相变范围内仅诱导轻微的流化效应，在流体相中诱导较小的有序化效应。如所有探针所检测到的，该药物拓宽了DMPC的相变曲线并将主要转变温度移至较低值。然而，随着脂肪酰链长度增加，这些效应以及在流体相中观察到的效应会减弱。此外，如通过Py(3)Py所探测的，该药物消除了DPPC和DSPC双层膜的预转变。在流体态的SR天然膜和SR脂质脂质体中，如通过Py(3)Py以及DPH - PA所监测的，OHTAM在脂质双层的外部区域诱导适度的有序化效应，而DPH未能检测到任何明显效应，这与纯磷脂的流体相情况相同。显然，OHTAM优先分布在脂质双层的外部区域，对双层内部的整体脂质组织没有显著影响。OHTAM在双层动态性质方面的变化以及相对于其药物促进剂在双层厚度上的不同定位（Custódio等人（1993年）《生物化学与生物物理学报》1150, 123 - 129）可能与他莫昔芬的细胞生长抑制活性有关。
