Anticancer drugs tamoxifen and 4hydroxytamoxifen as effectors of phosphatidylethanolamine lipid polymorphism

The interaction of tamoxifen (TMX) and its metabolite 4-hydroxytamoxifen (HTMX) with a biomimetic membrane model system composed of 1,2-dielaidoylphosphatidylethanolamine (DEPE) has been studied using a biophysical approach. Incorporation of TMX into DEPE bilayers gives rise to a progressive broadening of the L_β/L_α phase transition and a downward temperature shift. The L_β/L_α phase transition presents multiple endotherms, indicating a lateral segregation of TMX/DEPE domains within the plane of the bilayer. TMX and HTMX also widen and shift the L_α to hexagonal-H_II transition toward lower values, the phase diagrams showing that both compounds facilitate formation of the H_II phase. TMX increases motional disorder of DEPE acyl chains in the L_β, L_α and H_II phases, whereas the effect of HTMX is clearly different. In addition, neither TMX nor HTMX significantly perturb the hydration state of the polar headgroup region of DEPE. Molecular dynamics (MD) simulations indicate that these drugs do not affect membrane thickness, area per lipid, or the conformation of DEPE molecules. As a general rule, the interaction of HTMX with DEPE is qualitatively similar to TMX but less intense. However, a significant difference shown by MD is that HTMX is mainly placed around the center of each monolayer while TMX is located mainly at the center of the membrane, also having a greater tendency to cluster formation. These results are discussed to understand the modulation of phosphatidylethanolamine lipid polymorphism carried out by these drugs, which could be of relevance to explain their effects on enzyme activity or membrane permeabilization.